Drug-loaded nano mesoporous magnesium oxide and preparation method thereof

Abstract

The invention relates to drug-loading nano mesoporous magnesium oxide and a preparation method thereof, the particle size range of nano mesoporous magnesium oxide particles is 50-150nm, the surfaces of the particles have rich mesoporous structures, and the pore size range is 2-20nm. The surface of the particle has positive potential in absolute ethyl alcohol, and Zeta potential is distributed within the range of 10-100 mV. The preparation method comprises the following steps: (1) preparing a magnesium oxalate precursor which is a mixture of magnesium oxalate and CTAB (cetyltrimethyl ammonium bromide), (2) preparing nano magnesium oxide particles, placing the precursor mixture in a quartz crucible, placing the quartz crucible in a muffle furnace, and calcining at 200 DEG C for 1 hour to completely decompose CTAB in the mixture to obtain pure magnesium oxalate, raising the temperature to 530 DEG C and calcining for 1-6 hours to fully decompose the magnesium oxalate to obtain the nano magnesium oxide particles. The obtained particles are beneficial to loading of anti-tumor drugs, and the dissolution rate of the particles is high in a slightly acidic environment with the pH value being 5.0.

Description

Technical Field

[0001] The invention relates to a material belonging to the biological field, and in particular to a magnesium oxide nanomaterial that can be used as a drug carrier. The material is suitable for preparing a tumor drug targeting carrier or a drug carrier for human body use for other purposes, and has an auxiliary drug efficacy function. Background Art

[0002] Nano drug carriers can deliver one or more drugs at the same time, which can not only improve the solubility and stability of drugs, but also regulate the release rate of drugs, achieve active or passive targeting of drugs to diseased tissue cells, especially tumors, improve drug utilization, and reduce the toxic side effects of drugs on normal cells or tissues.

[0003] At present, there are many types of nano drug carriers. Generally speaking, inorganic nanoparticles have more stable structures, such as traditional gold, silver, copper, iron and other nanoparticles and their oxides. However, the toxic side effects of nanocarriers composed of these elements are relatively large. Magnesium oxide is easily metabolized and has fewer toxic side effects, and has a good application prospect in the field of drug carriers in the future. However, nano magnesium oxide currently has a large particle size as a drug carrier and is uneven in size. For example, patent publication number CN108619518A provides a method for preparing micro-nano magnesium oxide drug carriers, which mixes MgCO3 with oxalic acid to obtain a hydrated magnesium oxalate intermediate product MgC2O4·nH2O; calcination obtains micro-nano structured magnesium oxide, the average size of which is 2.3μm, and only about 5% or less of the nanoscale structure. Although patent publication number CN114477246A provides a method for preparing spherical nano magnesium oxide, the prepared magnesium oxide has a particle size of about 40nm and is mainly used as a thermal conductive filler, the purpose of which is to improve the thermal conductivity of its composite material. It is to dissolve magnesium acetate tetrahydrate and CTAB in ethanol to obtain magnesium acetate ethanol solution; dissolve oxalic acid in deionized water to obtain oxalic acid solution; the two are continuously ultrasonically stirred, then centrifuged multiple times with deionized water and ethanol, and then dried at 60-90°C for 8-12h, and then calcined at 550-650°C for 2-4h. It does not consider the surface potential and surface morphology. Secondly, although patent publication number CN108996530B provides a method for preparing nano magnesium oxide, it uses magnesium nitrate and sodium carbonate as raw materials to prepare nano magnesium oxide with a particle size of 2-22nm. The prepared nano magnesium oxide is mainly used in the field of disinfection, mainly providing the degradation effect of paraoxon. The above inventions obviously do not consider the physical and chemical properties, size, geometry, surface potential and surface ligand shape of nano drug carriers, thus affecting the application effect of nano drug delivery. The purpose of the present invention is to design a nano drug carrier with specific physical and chemical properties, which can effectively improve the delivery effect of the nano drug delivery system, thereby improving the efficacy and reducing the toxic and side effects of drugs. Summary of the invention

[0004] In order to overcome the problems of unstable physical and chemical properties and excessive toxic and side effects of existing nano drug carriers, the present invention provides a nano-mesoporous magnesium oxide for drug delivery and a preparation method. The carrier of the nano-mesoporous magnesium oxide is mainly composed of magnesium oxide, has a specific size, and has a large number of micropores and mesopores on the surface, which is convenient for carrying anti-tumor drugs; and has a more sensitive response to pH value, a faster dissolution rate in the acidic environment of the tumor, and also has auxiliary effects such as anti-inflammatory and analgesic.

[0005] The technical solution adopted by the present invention to solve its technical problem is: a drug-carrying nano-mesoporous magnesium oxide, the particle size range of the drug-carrying nano-mesoporous magnesium oxide particles is 50-150nm, the surface of the drug-carrying nano-mesoporous magnesium oxide particles has a rich mesoporous structure, and the pore size range is 2-20nm.

[0006] Furthermore, the drug-carrying nano-mesoporous magnesium oxide particles have a positive potential on the surface in anhydrous ethanol, and the Zeta potential is distributed in the range of 10 to 100 mV.

[0007] A method for preparing nano-mesoporous magnesium oxide for drug loading, comprising the following steps:

[0008] (1) Preparation of magnesium oxalate precursor:

[0009] Using magnesium chloride hexahydrate as a magnesium source, oxalic acid dihydrate as a precipitant, a mixture of water and n-butanol as a solvent, CTAB as a dispersant, and acetic acid to increase the hydrogen ion concentration, a magnesium oxalate precursor is synthesized through a coprecipitation reaction, and the obtained precursor is a mixture of magnesium oxalate and CTAB;

[0010] (2) Preparation of Nano-MgO Particles

[0011] The precursor mixture is placed in a quartz crucible and calcined in a muffle furnace at 200°C for 1 hour to completely decompose the CTAB in the mixture to obtain pure magnesium oxalate. The mixture is then heated to 530°C and calcined for 1 to 6 hours to fully decompose the magnesium oxalate to obtain nano-magnesium oxide particles.

[0012] Furthermore, the mass ratio of magnesium chloride hexahydrate to oxalic acid dihydrate is in the range of 1 to 3 parts of magnesium chloride hexahydrate to 3 to 1 parts of oxalic acid dihydrate, and a mixed solvent of 1 to 3 parts of deionized water and 1 to 10 parts of n-butanol is added at a volume ratio.

[0013] Furthermore, during the coprecipitation reaction synthesis process, 0.25-1.25 wt % of CTAB and 36-50 wt % of high concentration acetic acid are added to improve the dispersibility of magnesium oxalate.

[0014] Furthermore, the specific method for preparing nano magnesium oxide particles is as follows: placing a beaker with an appropriate amount of solvent into a water bath, adding a certain amount of magnesium chloride hexahydrate and an appropriate amount of CTAB after the temperature reaches a predetermined reaction temperature, stirring evenly, adding a certain amount of oxalic acid dihydrate and acetic acid, using alcohol and deionized water as detergents, retaining the lower layer of precipitate after multiple decantations, and obtaining a magnesium oxalate precursor after drying.

[0015] Furthermore, the reaction temperature is 40-80°C, the reaction time is 20-60min, the speed of the magnetic stirrer is 100-1000r / min, the stirring is continued for 20min, and after multiple decantations, the mixture is dried at 90-100°C for 1h.

[0016] Furthermore, along with the decomposition of magnesium oxalate, a large number of mesopores and micropores appeared on the surface of the nano-magnesium oxide particles after releasing gas, with an average pore size of 14 nm and a pore size distribution range of 2 to 20 nm.

[0017] Compared with the prior art, the advantages of the present invention are:

[0018] (1) Compared with other existing drug carrier materials, magnesium oxide itself has very low toxicity to the human body. It has long been widely used as a gastric acid neutralizer in clinical practice. At the same time, some studies on the toxicity of magnesium oxide have shown that within a fairly large dosage range, magnesium oxide has a high biosafety, and nano-magnesium oxide has a higher drug permeability in the body than micro-magnesium oxide. In addition, it is metabolized faster and its metabolites are safer.

[0019] (2) Compared with the magnesium oxide currently sold on the market, the magnesium oxide synthesized by this method has a more concentrated particle size distribution, a more regular shape, and a surface densely covered with micropores and mesopores, mainly mesopores. The surface carries a positive charge in anhydrous ethanol, which is conducive to the loading of drugs and achieves efficient drug delivery.

[0020] (3) Compared with nano magnesium oxide produced by the current similar process, the present invention adjusts the experimental process parameters and optimizes the dispersion process, thereby producing magnesium oxide with a particle size (50 to 150 nm) that is more suitable as a drug carrier, and weakens the agglomeration of nano magnesium oxide particles, making the product more suitable for the delivery of anti-tumor drugs.

[0021] (4) The magnesium source used in the present invention is magnesium chloride hexahydrate, which has a large reserve in seawater and is easy to obtain. Other compounds used are also relatively common and have relatively mature production processes. At the same time, the preparation process of the present invention is simple, the production time is short, and the preparation process is easy to control, so the present invention has high production efficiency and low cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the BET adsorption curve of nano-mesoporous magnesium oxide targeted drug carrier;

[0023] Figure 2 This is the morphology of nano-mesoporous magnesium oxide under a scanning electron microscope;

[0024] Figure 3 This is the microscopic morphology of nano magnesium oxide obtained in Example 1;

[0025] Figure 4 The particle size distribution of nano magnesium oxide prepared in Example 1;

[0026] Figure 5 This is the nitrogen adsorption-desorption curve of nano magnesium oxide prepared in Example 1;

[0027] Figure 6 This is the pore size distribution diagram of nano magnesium oxide prepared in Example 1. DETAILED DESCRIPTION

[0028] The present invention is further described below in conjunction with the accompanying drawings and embodiments, but the present invention is not limited to the scope of the embodiments.

[0029] The invention discloses a drug-carrying nano-mesoporous magnesium oxide, wherein the particle size of the nano-mesoporous magnesium oxide particles ranges from 50 to 150 nm, the surface of the nano-mesoporous magnesium oxide particles has a rich mesoporous structure, and the pore size ranges from 2 to 20 nm. The surface of the nano-mesoporous magnesium oxide particles has a positive potential in anhydrous ethanol, and the Zeta potential distribution ranges from 10 to 100 mV.

[0030] The preparation method of the drug-carrying nano-mesoporous magnesium oxide:

[0031] (1) Preparation of magnesium oxalate precursor:

[0032] The precursor magnesium oxalate microparticles were synthesized by coprecipitation reaction using magnesium chloride hexahydrate as a magnesium source, oxalic acid dihydrate as a precipitant, and a mixture of water and n-butanol as a solvent. The experimental parameters were adjusted to obtain magnesium oxalate nanoparticles with a specific particle size (100-200 nm). The dispersibility of the obtained nanoparticles was improved by adding CTAB (hexadecyltrimethylammonium bromide) to form colloidal bundles, using a mixture of n-butanol and water as a solvent to reduce the dielectric constant of the solvent, and adding acetic acid to adjust the pH value to change the surface charge of the nanoparticles.

[0033] The ratio of the amount of magnesium chloride to oxalic acid is between 1 and 3:1 and 3, the reaction temperature is 40 to 80°C, the reaction time is 20 to 60 minutes, and a magnetic water bath constant temperature stirring pot is used for heating and stirring to ensure that the particle size of the obtained microparticles is uniform. The solvent is a mixed solution of deionized water and n-butanol in a volume ratio of 1 to 3:1 to 10. The specific procedure is: put a beaker with an appropriate amount of solvent into a water bath, and after the temperature reaches the predetermined reaction temperature, add a certain amount of magnesium chloride hexahydrate and an appropriate amount of CTAB, stir evenly, add a certain amount of oxalic acid dihydrate and acetic acid, keep warm and stir for 20 minutes at a speed of 100 to 1000 r / min, use alcohol and deionized water as detergents, retain the lower precipitate after multiple decantations, and dry at 90 to 100°C for 1 hour to obtain a magnesium oxalate precursor.

[0034] (2) Preparation of Nano-MgO Particles

[0035] The obtained precursor is a mixture of magnesium oxalate and CTAB. The precursor mixture is placed in a quartz crucible and calcined in a muffle furnace at 200°C for 1 hour to completely decompose the CTAB in the mixture to obtain pure magnesium oxalate. The temperature is then raised to 530°C and calcined for 1 to 6 hours to fully decompose the magnesium oxalate to obtain nano magnesium oxide. As magnesium oxalate decomposes, a large number of pores will appear on the surface of the particles due to the release of gas. Through testing, they are mainly mesopores and micropores with an average pore size of 14nm.

[0036] The obtained particles are conducive to the loading of anti-tumor drugs and have good stability in the human body environment. The particle dissolution rate is fast in a slightly acidic environment with a pH value of 5.0. The BET adsorption curve and scanning diagram of the prepared particles are shown in Figure 2. Figure 1 , Figure 2 shown.

[0037] The following examples use magnesium chloride hexahydrate with a purity of more than 99% and oxalic acid with a purity of more than 99.8% as the main raw materials, and the purity of the other auxiliary materials is also more than 99%. The microscopic morphology of the prepared magnesium oxide particles was observed by scanning electron microscopy, the particle size distribution and surface charge distribution were tested by laser particle size analyzer, and the pore size distribution and pore volume were tested by nitrogen adsorption and desorption experiments. The characterization results are shown in Figures 3 to 6 .

[0038] Example:

[0039] The steps of preparing magnesium oxalate by coprecipitation method and then calcining and decomposing the precursor magnesium oxalate to prepare nano-mesoporous magnesium oxide are as follows:

[0040] 1) A beaker containing 200 mL of deionized water and n-butanol in a volume ratio of 1:2 was placed in a constant temperature magnetic stirring pot. After the temperature reached 60°C, 20.33 g of magnesium chloride hexahydrate and 1.0 g of CTAB were added. After stirring evenly, 12.61 g of oxalic acid dihydrate and 36% acetic acid were added. The mixture was stirred at a speed of 800 r / min for 20 min. Anhydrous ethanol and deionized water were used as detergents, respectively. The lower precipitate was retained by decantation for multiple times, and the mixture was dried at 90-100°C for 1 h to obtain a magnesium oxalate precursor.

[0041] 2) The precursor mixture is placed in a quartz crucible, and calcined in a muffle furnace at 200° C. for 1 h to completely decompose the CTAB in the mixture to obtain pure magnesium oxalate, and then the temperature is raised to 530° C. and calcined for 2 h to fully decompose the magnesium oxalate to obtain nano magnesium oxide.

[0042] The obtained magnesium oxide was characterized in various ways, including determining its physical properties through SEM, DLS, BET and other means, and placing it in SBF simulated body fluids with different pH values ​​(5.0 and 7.4) to simulate its dissolution rate in tumor and normal human environments.

[0043] The results show that the particle size of the nano-mesoporous magnesium oxide prepared in this example is between 50 and 200 nm, with a large number of pores with an average diameter of 14.1 nm distributed on the surface and a total pore volume of 0.431 cm 3 / g, and its surface potential in anhydrous ethanol is 50mV, which shows good drug loading performance. At the same time, the dissolution rate experimental results show that the dissolution rate is extremely slow in the simulated body fluid of pH=7.4, and the corrosion rate is fast in the simulated body fluid of pH=5.0, indicating that the prepared carrier can quickly decompose in the slightly acidic environment simulating the surrounding of the tumor and remain stable in the slightly alkaline environment simulating the normal human body.

Claims

1. A drug-carrying nano-mesoporous magnesium oxide, characterized in that: The particle size range of the drug-carrying nano-mesoporous magnesium oxide particles is 50-150 nm. The surface of the drug-carrying nano-mesoporous magnesium oxide particles has a rich mesoporous structure, and the pore size range is 2-20 nm.

2. The drug-carrying nano-mesoporous magnesium oxide according to claim 1, characterized in that: The surface of the drug-carrying nano-mesoporous magnesium oxide particle has a positive potential in anhydrous ethanol, and the Zeta potential is distributed in the range of 10 to 100 mV.

3. A method for preparing nano-mesoporous magnesium oxide for drug loading according to claim 1 or 2, characterized in that: The steps are: (1) Preparation of magnesium oxalate precursor: Using magnesium chloride hexahydrate as a magnesium source, oxalic acid dihydrate as a precipitant, a mixture of water and n-butanol as a solvent, CTAB as a dispersant, and acetic acid to increase the hydrogen ion concentration, a magnesium oxalate precursor is synthesized through a coprecipitation reaction, and the obtained precursor is a mixture of magnesium oxalate and CTAB; (2) Preparation of Nano-MgO Particles The precursor mixture is placed in a quartz crucible and calcined in a muffle furnace at 200° C. for 1 hour to completely decompose the CTAB in the mixture to obtain pure magnesium oxalate. The mixture is then heated to 530° C. and calcined for 1 to 6 hours to fully decompose the magnesium oxalate to obtain nano-magnesium oxide particles.

4. The method for preparing drug-carrying nano-mesoporous magnesium oxide according to claim 3, characterized in that: The mass ratio of magnesium chloride hexahydrate to oxalic acid dihydrate is in the range of 1 to 3 parts of magnesium chloride hexahydrate to 3 to 1 parts of oxalic acid dihydrate, and a mixed solvent of 1 to 3 parts of deionized water and 1 to 10 parts of n-butanol is added at the same time.

5. The method for preparing drug-carrying nano-mesoporous magnesium oxide according to claim 3, characterized in that: During the coprecipitation reaction synthesis process, 0.25-1.25 wt % of CTAB and 36-50 wt % of high concentration acetic acid are added to improve the dispersibility of magnesium oxalate.

6. The method for preparing drug-carrying nano-mesoporous magnesium oxide according to claim 3, characterized in that: The specific method for preparing nano magnesium oxide particles is as follows: a beaker with an appropriate amount of solvent is placed in a water bath, and after the temperature reaches a predetermined reaction temperature, a certain amount of magnesium chloride hexahydrate and an appropriate amount of CTAB are added, and after stirring evenly, a certain amount of oxalic acid dihydrate and acetic acid are added, and alcohol and deionized water are used as detergents. After multiple decantations, the lower layer of precipitate is retained, and the magnesium oxalate precursor is obtained after drying.

7. The method for preparing drug-carrying nano-mesoporous magnesium oxide according to claim 6, characterized in that: The reaction temperature is 40-80°C, the reaction time is 20-60min, the speed of the magnetic stirrer is 100-1000r / min, the stirring is continued for 20min, and after multiple decantations, the mixture is dried at 90-100°C for 1h.

8. The method for preparing drug-carrying nano-mesoporous magnesium oxide according to claim 3, characterized in that: Along with the decomposition of magnesium oxalate, a large number of mesopores and micropores appear on the surface of nano-magnesium oxide particles after releasing gas, with an average pore size of 14nm and a pore size distribution range of 2 to 20nm.

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