A hollow multi-shell structure oral drug carrier with controllable internal microenvironment and its preparation method and application

Abstract

The present invention specifically relates to an oral drug carrier with a hollow multi-shell structure and a preparation method and application with a controllable internal microenvironment, which belongs to the field of biomaterial technology. The oral drug carrier is a hollow multi-shell structure with a nanoscale, and has an adjustable acidic microenvironment inside, which can adjust the uniform distribution or gradient distribution of acid and drugs as needed; a controllable acidic microenvironment is constructed in the hollow multi-shell material at a micro-nano scale, which improves the transmission efficiency of drug molecules and acid molecules; the nano-confined pores reduce the crystallinity of the drug, and the rough surface gives it a long retention characteristic in the intestine. The oral drug delivery system can effectively improve the dissolution and release of the drug, and significantly improve the oral bioavailability of the drug.

Description

Technical Field

[0001] The invention belongs to the technical field of biomaterials, and relates to a hollow multi-shell structure oral drug carrier with controllable internal microenvironment, a preparation method and an application thereof. Background Art

[0002] Oral administration refers to the introduction of drugs into the human body through the oral route, which are then absorbed through the digestive system. Compared with injection administration, oral administration has the advantages of easy acceptance by patients and autonomous administration. However, there are the following problems with the oral administration system of pH-dependent drugs: ① Such drugs have the characteristics of low solubility and high permeability at neutral pH, which limits absorption in the intestine; ② Oral delivery is difficult to overcome the adverse effects of gastric acid and digestive enzymes, affecting the stability of the drug; ③ Insufficient intestinal residence time leads to the inability of the drug to be fully absorbed, thereby affecting bioavailability. Therefore, in order to improve the oral availability of pH-dependent drugs, the common strategy is to construct drug carriers, improve the solubility of drugs, and prolong the retention time of drugs in the intestine.

[0003] CN109700777A discloses a pH-dependent drug hydrophobic skeleton sustained-release tablet and a preparation method thereof. By adding a pH regulator such as dihydrated calcium hydrogen phosphate, disodium hydrogen phosphate or calcium silicate to the sustained-release tablet, the pH value of the microenvironment can be maintained to promote drug dissolution, thereby improving the in vitro release of the pH-dependent drug. However, the system can only construct a uniformly mixed pH environment at the macroscopic tablet scale, and cannot adjust the pH of the local microenvironment at the micro-nano scale. In addition, due to the limitations of the preparation technology, the pH gradient in the preparation cannot be adjusted as needed, and thus an excellent effect is not achieved in the gastrointestinal environment after actual oral administration.

[0004] CN101632668A discloses a kind of oral pharmaceutical preparation of dabigatran etcxilate, by enclosing a barrier layer and a drug layer on the surface of an organic acid pill core, physical separation of organic acid and active drug is realized. The process coats an active drug suspension on the organic acid pill core, and when dissolving, the organic acid pill core provides an acidic microenvironment for the medicine. However, the method requires multilayer coating, and the preparation method is complicated, and there will be uneven drug layer in the drug application process simultaneously, and the bulk drug loss is large, and the problems such as the finished product yield is low, and the drug micropill prepared is a large particle with a large particle size, which is easily removed by the body when actually oral administration, and is difficult to control the acidic microenvironment when the drug is dissolved.

[0005] In summary, a controllable oral carrier with an internal microenvironment of nanomaterials is provided, which provides a pH microenvironment that is conducive to drug dissolution during drug dissolution, and can regulate the spatial distribution of the acidic microenvironment as needed to improve the solubility of pH-dependent drugs in the intestine and prolong the retention time of the carrier in the intestine, which is of great significance for improving the oral bioavailability of pH-dependent drugs. Summary of the invention

[0006] In order to improve the bioavailability of BSCII drugs, it is necessary to construct an oral capsule with a controllable internal microenvironment at the micro-nano scale to improve the efficiency of material transfer; at the same time, the confinement effect of micro-nano pores is used to improve the crystallinity of the drug, and the gastrointestinal retention time is prolonged by regulating the morphology of the material, thereby improving the dissolution and absorption of the drug.

[0007] In view of the defects and shortcomings of existing oral drug capsules, the purpose of the present invention is to provide an oral carrier with controllable internal pH microenvironment and its preparation method and application. The oral drug carrier is a nano-sized hollow multi-shell structure (HoMS), and the hollow multi-shell structure is loaded with pH regulators and drugs; the distribution of the pH regulators and drugs in the hollow multi-shell structure is controllable. As a drug carrier, the microspheres can enhance adhesion to the villi of the small intestine and prolong the retention time in the intestine by using their rough surface; reduce the crystallinity of the drug by using its nano-confined pores; and regulate the internal acidic microenvironment by using the controllable distribution of the pH regulator in the micro-nano space, thereby enhancing the dissolution of the drug near the epithelial tissue of the small intestine and significantly improving the oral bioavailability of the drug.

[0008] The present invention is achieved through the following technical solutions:

[0009] In a first aspect, the present invention provides an oral drug carrier with a hollow multi-shell structure and a controllable internal microenvironment. The oral drug carrier is a hollow multi-shell structure, and the hollow multi-shell structure is loaded with a pH regulator and a drug, and has a nanoscale size; the distribution of the pH regulator and the drug in the hollow multi-shell structure is controllable.

[0010] Based on the above hollow multi-shell structure oral drug carrier with controllable internal microenvironment, the preparation method thereof includes:

[0011] (1) Preparation of hollow multi-shell metal oxide microspheres;

[0012] (2) mixing a pH adjuster, a drug, and a solvent to obtain a mixed solution having a molar concentration ratio of the pH adjuster to the drug of 1:5 to 5:1;

[0013] (3) placing the metal oxide microspheres with a hollow multi-shell structure in a vacuum environment, slowly dropping the mixed solution obtained in step (2) with the same molar concentration ratio thereinto, performing vacuum loading, and constructing hollow multi-shell structured drug-loaded microspheres with an internal acid-drug mixture;

[0014] or,

[0015] The mixed solution with different molar concentration ratios was added dropwise three times, and then the acid and drug molecules remaining on the surface were washed, and the acid gradient inside the hollow multi-shell drug-loaded microspheres was regulated by controlling the vacuum degree and the standing time, so as to construct the hollow multi-shell drug-loaded microspheres with internal acid gradient;

[0016] (4) centrifuging and vacuum drying the mixture to obtain drug-loaded microspheres with controllable internal microenvironment; (5) mixing the drug-loaded microspheres with a disintegrant and encapsulating them in commercially available enteric-coated gelatin capsules to obtain oral capsules.

[0017] In the above steps:

[0018] In step (1), the preparation method of the hollow multi-shell structured metal oxide microspheres is not particularly limited. There are many methods in the prior art for synthesizing the hollow multi-shell structured metal oxide microspheres.

[0019] In step (1), the hollow multi-shell structure metal oxide material is a mixture of one or more of TiO2, ZnO, and Fe3O4.

[0020] In step (2), the drug is one of pH-dependent BCS Class II poorly soluble drugs such as carvedilol, dabigatran etexilate mesylate, verapamil, dipyridamole, vinpocetine, etc., preferably dabigatran etexilate mesylate.

[0021] In step (2), the solvent is one or two of deionized water, dichloromethane, methanol, ethanol, and acetone, and methanol is more preferably used.

[0022] In step (2), the pH adjuster is one or a combination of two of fumaric acid, tartaric acid, maleic acid, citric acid, and L-ascorbic acid, and tartaric acid is more preferred.

[0023] In step (2), the molar ratio of the pH regulator to the drug is preferably 1:1.

[0024] In step (3), the number of vacuum loading drugs is 1-10 times.

[0025] The acid-drug ratio described in step (3) is such that when constructing acid-drug mixed hollow multi-shell drug-loaded microspheres, the molar concentration ratio of the acid to the drug inside the drug-loaded microspheres is 1:5-5:1, for example, 1:5, 1:4, 1:3, 1:2, 1:4, 2:1, 3:1, 4:1, 5:1, and more preferably 1:1.

[0026] In step (3), the mass concentration ratio of metal oxide microspheres to drugs is 1:10-1:1, which can be 1:10, 1:6, 1:5, 1:2, 1:1, and more preferably 1:5.

[0027] In step (3), a hollow multi-shell drug-loaded microsphere with an internal acid gradient is constructed, and a mixed solution with different molar concentration ratios is added dropwise three times. After each addition, the acid and drug remaining on the outside of the microsphere are washed with a solvent, and the gradient of the acid and drug is controlled by controlling the vacuum degree and the standing time;

[0028] The molar concentration ratios of the acid and the drug added three times are: 3:1, 1:1, 1:0; 3:1, 1:1, 1:3; 5:1, 1:1, 1:5; 5:1, 2:1, 1:2 or 2:1, 1:1, 1:3;

[0029] In step (3), the vacuum degree ranges from 0 to -0.1 MPa;

[0030] In step (3), the standing time is 0 to 15 minutes;

[0031] In step (3), the solvent used for cleaning is one of ethanol, methanol, deionized water and acetone solvents, preferably ethanol.

[0032] In step (4), the number of centrifugation and vacuum drying is 1-10 times, more preferably 3-8 times.

[0033] In step (4), the centrifugal speed is 12000-4500 rpm / min, more preferably 6000 rpm / min, and the centrifugal time is 5 min.

[0034] In step (4), the vacuum drying time is 6-24 hours, more preferably 12 hours, and the temperature of the vacuum drying oven is set to 60°C.

[0035] In a second aspect, the present invention provides a hollow multi-shell structure oral capsule with controllable internal microenvironment for use in dabigatran mesylate oral medication, which has excellent release effect in the intestinal environment.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] (1) The hollow multi-shell structured microspheres in the present invention achieve pH regulation of the microenvironment within the micro-nano scale, and can regulate the gradient distribution of the acidic microenvironment as needed. The nano-confined pores allow the drug to exist in an amorphous form, thereby improving the dissolution and release of pH-dependent poorly soluble drugs.

[0038] (2) The present invention utilizes hollow multi-shell structured microspheres as drug carriers, and utilizes their surface roughness to achieve adhesion to the villi of the small intestine and long-term retention in the intestine. The multi-layer structure provides a delayed release effect, so that the drug can be concentrated as close to the small intestinal epithelial mucosa as possible, and has an excellent release effect in the intestinal environment, thereby improving bioavailability.

[0039] (3) The oral capsule provided by the present invention is simple to prepare, has high biosafety, and is low in cost, and has broad development prospects in the field of oral administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is a scanning electron microscope photograph of the three-shell TiO2HoMS drug-loaded microspheres with controllable internal acid environment prepared in Example 1.

[0041] Figure 2 This is the SEM-element distribution diagram of the three-shell TiO2HoMS drug-loaded microspheres with controllable internal acid environment prepared in Example 1.

[0042] Figure 3 This is the XRD pattern of the three-shell TiO2HoMS drug-loaded microspheres with controllable internal acidic microenvironment prepared in Example 1.

[0043] Figure 4 This is a microscopic photograph of the intestinal retention of the hollow multi-shell structure oral drug delivery system.

[0044] Figure 5 This is a microscopic distribution picture of the hollow multi-shell structure oral drug delivery system in the intestine. DETAILED DESCRIPTION

[0045] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and embodiments, but is not limited thereto. Any modification or equivalent replacement of the technical solution of the present invention that does not depart from the spirit and scope of the technical solution of the present invention should be included in the protection scope of the present invention.

[0046] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is further described in detail below with reference to the accompanying drawings and embodiments. Example 1

[0047] A TiO2 HoMS drug delivery system with an internal microenvironment pH controllable at an acid-drug ratio of 1:3, comprising the following steps:

[0048] (1) Preparation of hollow multi-shell structures:

[0049] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0050] (2) Regulation of the acid-drug ratio

[0051] 47 mg of dabigatran etexilate mesylate and 3 mg of tartaric acid were dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 1:3.

[0052] (3) Preparation of drug-loaded hollow multi-shell oxide microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 1:3

[0053] 10 mg of three-shell TiO2 HoMS was placed at the bottom of a two-flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was vacuumed for 3 minutes to keep the negative pressure in the flask, and then the above mixed solution was slowly added thereto so that the mass concentration of HoMS, acid and drug was 1:5. It was then washed with ethanol, and this step was repeated 3 times. The flask was centrifuged at a speed of 6000 rpm / min and dried in a vacuum drying oven at 60°C for 12 hours to obtain drug-loaded hollow multi-shell oxide microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 1:3. Example 2

[0054] A TiO2 HoMS drug delivery system with an acid-drug ratio of 1:1 and a controllable internal microenvironment pH, comprising the following steps:

[0055] (1) Preparation of hollow multi-shell structures:

[0056] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0057] (2) Regulation of the acid-drug ratio

[0058] 40 mg of dabigatran etexilate mesylate and 10 mg of tartaric acid were dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 1:1.

[0059] (3) Preparation of drug-loaded hollow multi-shell oxide microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 1:1

[0060] 10 mg of three-shell TiO2 HoMS was placed at the bottom of a two-flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was vacuumed for 3 minutes to keep the negative pressure in the flask, and then the above mixed solution was slowly added thereto so that the mass concentration of HoMS, acid and drug was 1:5. It was then washed with ethanol, and this step was repeated 3 times. The flask was centrifuged at a speed of 6000 rpm / min and dried in a vacuum drying oven at 60°C for 12 hours to obtain drug-loaded hollow multi-shell oxide microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 1:1. Example 3

[0061] A TiO2 HoMS drug delivery system with an acid-drug ratio of 3:1 and controllable internal microenvironment pH, comprising the following steps:

[0062] (1) Preparation of hollow multi-shell structures

[0063] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0064] (2) Regulation of the acid-drug ratio

[0065] 25 mg of dabigatran etexilate mesylate and 20 mg of tartaric acid were dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 3:1.

[0066] (3) Preparation of drug-loaded hollow multi-shell oxide microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 3:1

[0067] 10 mg of three-shell TiO2 HoMS was placed at the bottom of a two-necked flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was vacuumed for 3 minutes to keep the negative pressure in the flask, and then the above mixed solution was slowly added thereto so that the mass concentration of HoMS to acid and drug was 1:5. It was then washed with ethanol, and this step was repeated 3 times. The flask was centrifuged at a speed of 6000 rpm / min and dried in a vacuum drying oven at 60°C for 12 hours to obtain drug-loaded hollow multi-shell oxide microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 3:1. Example 4

[0068] A TiO2 HoMS drug delivery system with an acid-drug ratio of 2:1 and controllable internal microenvironment pH, comprising the following steps:

[0069] (1) Preparation of hollow multi-shell structures:

[0070] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0071] (2) Regulation of the acid-drug ratio

[0072] 34 mg of dabigatran etexilate mesylate and 16 mg of tartaric acid were dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 2:1.

[0073] (3) Preparation of drug-loaded hollow multi-shell oxide microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 2:1

[0074] 25 mg of three-shell TiO2 HoMS was placed at the bottom of a two-necked flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, vacuum was applied for 3 minutes to keep the bottle in a negative pressure state, and then the above mixed solution was slowly added thereto so that the mass concentration of HoMS, acid and drug was 1:2. It was then washed with ethanol, and this step was repeated 10 times. The flask was centrifuged at a speed of 12000 rpm / min and dried in a vacuum drying oven at 60°C for 6 hours to obtain drug-loaded TiO2 HoMS with controllable internal acidic microenvironment. Example 5

[0075] A TiO2 HoMS drug delivery system with an internal microenvironment pH controllable at an acid-drug ratio of 1:2, comprising the following steps:

[0076] (1) Preparation of hollow multi-shell structures:

[0077] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0078] (2) Regulation of the acid-drug ratio

[0079] 45.5 mg of dabigatran etexilate mesylate and 4.5 mg of tartaric acid were dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 1:2.

[0080] (3) Preparation of drug-loaded TiO2 HoMS with controllable internal acidic microenvironment and high drug concentration ratio

[0081] 50 mg of three-shell TiO2 HoMS was placed at the bottom of a two-necked flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was vacuumed for 3 minutes to keep the negative pressure in the flask, and then the above mixed solution was slowly added dropwise to make the mass concentration of HoMS and the drug 1:1. It was then washed with ethanol, centrifuged at 4500 rpm / min and dried in a vacuum drying oven at 60°C for 24 hours to obtain drug-loaded TiO2 HoMS with controllable internal acidic microenvironment. Example 6

[0082] A TiO2 HoMS drug delivery system with a low drug concentration ratio and a controllable internal microenvironment pH, comprising the following steps:

[0083] (1) Preparation of hollow multi-shell structures:

[0084] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0085] (2) Regulation of the acid-drug ratio

[0086] 40 mg of dabigatran etexilate mesylate and 10 mg of tartaric acid were dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 1:1.

[0087] (3) Preparation of drug-loaded TiO2 HoMS with controllable internal acidic microenvironment at low drug concentration ratio

[0088] 25 mg of three-shell TiO2 HoMS was placed at the bottom of a two-necked flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, vacuum was applied for 3 minutes to keep the bottle in a negative pressure state, and then the above mixed solution was slowly added thereto so that the mass concentration of HoMS, acid and drug was 1:1. It was then washed with ethanol, and this step was repeated 10 times. The flask was centrifuged at a speed of 12000 rpm / min and dried in a vacuum drying oven at 60°C for 6 hours to obtain drug-loaded TiO2 HoMS with a controllable internal acidic microenvironment. Example 7

[0089] A TiO2 HoMS drug delivery system with a high drug concentration ratio and controllable internal microenvironment pH, comprising the following steps:

[0090] (1) Preparation of hollow multi-shell structures:

[0091] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0092] (2) Regulation of the acid-drug ratio

[0093] 48 mg of dabigatran etexilate mesylate and 10 mg of tartaric acid were dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 1:1.

[0094] (3) Preparation of a drug-loaded TiO2 HoMS with a controllable internal acidic microenvironment and high drug concentration ratio

[0095] 10 mg of three-shell TiO2 HoMS was placed at the bottom of a two-necked flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was vacuumed for 3 minutes to keep the negative pressure in the flask, and then the above mixed solution was slowly added thereto so that the mass concentration of HoMS to the drug was 1:10. It was then washed with ethanol, centrifuged at 4500 rpm / min and dried in a vacuum drying oven at 60°C for 24 hours to obtain drug-loaded TiO2 HoMS with a controllable internal acidic microenvironment. Example 8

[0096] This embodiment prepares a TiO2 HoMS drug-carrying system with a controllable internal microenvironment and a decreasing acid gradient from the inside to the outside. The molar concentration ratios of acid and drug during three loadings are 5:1, 1:1, and 0:1, respectively, and includes the following steps:

[0097] (1) Preparation of hollow multi-shell structures

[0098] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0099] (2) Regulation of the acid-drug ratio

[0100] 25, 40, 50 mg of dabigatran mesylate and 25, 10, 0 mg of tartaric acid were dissolved in 1 mL of methanol respectively to obtain three mixed solutions with molar concentration ratios of 5:1, 1:1, and 0:1.

[0101] (3) The three-shell TiO2 HoMS material was placed at the bottom of a two-flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was evacuated for 3 minutes to maintain a negative pressure state, and the vacuum degree in the container was controlled to be -0.1 MPa. Then, a methanol solution of tartaric acid and dabigatran etexilate mesylate with a concentration ratio of 5:1 was first added dropwise, and the mixture was allowed to stand for 15 minutes. The drug remaining on the surface was washed with ethanol. Then, the vacuum degree in the container was adjusted to -0.05 MPa, and a mixed solution with a concentration ratio of 1:1 was added dropwise, and the mixture was allowed to stand for 5 minutes and washed with ethanol. Finally, the container was adjusted to normal pressure, and a drug solution with an acid-drug concentration ratio of 0:1 was added dropwise, and the mixture was washed with ethanol. After centrifugation at 6000 rpm / min, the mixture was dried in a vacuum drying oven at 60°C for 12 hours to obtain a TiO2 HoMS drug delivery system with a decreasing acid gradient from the inside to the outside. Example 9

[0102] This embodiment prepares a TiO2 HoMS drug-carrying system with a controllable internal microenvironment and a decreasing acid gradient from the inside to the outside. The molar concentration ratios of acid and drug during three loadings are 4:1, 1:1, and 1:3, respectively. The system comprises the following steps:

[0103] (1) Preparation of hollow multi-shell structures:

[0104] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0105] (2) Regulation of the acid-drug ratio

[0106] 25, 40, 47 mg of dabigatran mesylate and 25, 10, 3 mg of tartaric acid were dissolved in 1 mL of methanol to obtain mixed solutions with molar concentration ratios of 4:1, 1:1, and 1:3, respectively.

[0107] (3) The three-shell TiO2 HoMS material was placed at the bottom of a two-necked flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was evacuated for 3 minutes to maintain a negative pressure state, and the vacuum degree in the container was controlled to be -0.1 MPa. Then, a methanol solution of tartaric acid and dabigatran etexilate mesylate with a concentration ratio of 5:1 was first added dropwise, and the mixture was allowed to stand for 15 minutes. The residual drug on the surface was washed with ethanol. Then, the vacuum degree in the container was adjusted to -0.05 MPa, and a mixed solution with a concentration ratio of 1:1 was added dropwise, and the mixture was allowed to stand for 5 minutes, and washed with ethanol. Finally, the container was adjusted to normal pressure, and a drug solution with an acid-drug concentration ratio of 1:3 was added dropwise, and the mixture was washed with ethanol. After centrifugation at 6000 rpm / min, the mixture was dried in a vacuum drying oven at 60°C for 12 hours to obtain a TiO2 HoMS drug delivery system with a decreasing acid gradient from the inside to the outside. Example 10

[0108] This embodiment prepares a TiO2 HoMS drug-carrying system with a controllable internal microenvironment and a decreasing acid gradient from the inside to the outside. The molar concentration ratios of acid and drug during three loadings are 1:0, 1:1, and 1:3, respectively. The system comprises the following steps:

[0109] (1) Preparation of hollow multi-shell structures:

[0110] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0111] (2) Regulation of the acid-drug ratio

[0112] 0, 40, 48 mg of dabigatran etexilate mesylate and 30, 10, 2 mg of tartaric acid were dissolved in 1 mL of methanol to obtain mixed solutions with molar concentration ratios of 1:0, 1:1, and 1:5, respectively.

[0113] (3) The three-shell TiO2 HoMS material was placed at the bottom of a two-flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was evacuated for 3 minutes to maintain a negative pressure state, and the vacuum degree in the container was controlled to be -0.1 MPa. Then, a methanol solution of tartaric acid and dabigatran etexilate mesylate with a concentration ratio of 1:0 was first added dropwise, and the mixture was allowed to stand for 15 minutes. The drug remaining on the surface was washed with ethanol. Then, the vacuum degree in the container was adjusted to -0.05 MPa, and a mixed solution with a concentration ratio of 1:1 was added dropwise, and the mixture was allowed to stand for 5 minutes and washed with ethanol. Finally, the container was adjusted to normal pressure, and a drug solution with an acid-drug concentration ratio of 1:5 was added dropwise, and the mixture was washed with ethanol. After centrifugation at 6000 rpm / min, the mixture was dried in a vacuum drying oven at 60°C for 12 hours to obtain a TiO2 HoMS drug delivery system with a decreasing acid gradient from the inside to the outside. Embodiment 11

[0114] This embodiment prepares a TiO2 HoMS drug-carrying system with a controllable internal microenvironment and a decreasing acid gradient from the inside to the outside. The molar concentration ratios of acid and drug during three loadings are 2:1, 1:1, and 1:3, respectively. The system comprises the following steps:

[0115] (1) Preparation of hollow multi-shell structures:

[0116] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0117] (2) Regulation of the acid-drug ratio

[0118] 34, 40, 46 mg of dabigatran mesylate and 16, 10, 4 mg of tartaric acid were dissolved in 1 mL of methanol to obtain mixed solutions with molar concentration ratios of 2:1, 1:1, and 1:3, respectively.

[0119] (3) The three-shell TiO2 HoMS material was placed at the bottom of a two-flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was evacuated for 3 minutes to maintain a negative pressure state, and the vacuum degree in the container was controlled to be -0.1 MPa. Then, a methanol solution of tartaric acid and dabigatran etexilate mesylate with a concentration ratio of 2:1 was first added dropwise, and the mixture was allowed to stand for 15 minutes. The drug remaining on the surface was washed with ethanol. Then, the vacuum degree in the container was adjusted to -0.05 MPa, and a mixed solution with a concentration ratio of 1:1 was added dropwise, and the mixture was allowed to stand for 5 minutes and washed with ethanol. Finally, the container was adjusted to normal pressure, and a drug solution with an acid-drug concentration ratio of 1:3 was added dropwise, and the mixture was washed with ethanol. After centrifugation at 6000 rpm / min, the mixture was dried in a vacuum drying oven at 60°C for 12 hours to obtain a TiO2 HoMS drug delivery system with a decreasing acid gradient from the inside to the outside. Example 12

[0120] This embodiment prepares a TiO2 HoMS drug-carrying system with a controllable internal microenvironment and a decreasing acid gradient from the inside to the outside. The molar concentration ratios of acid and drug during three loadings are 5:1, 1:1, and 1:3, respectively. The system comprises the following steps:

[0121] (1) Preparation of hollow multi-shell structures:

[0122] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm;

[0123] (2) Regulation of the acid-drug ratio

[0124] 21, 40, 47 mg of dabigatran mesylate and 30, 10, 3 mg of tartaric acid were dissolved in 1 mL of methanol to obtain mixed solutions with molar concentration ratios of 5:1, 1:1, and 1:3, respectively.

[0125] (3) The three-shell TiO2 HoMS material was placed at the bottom of a two-necked flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was evacuated for 3 minutes to maintain a negative pressure state, and the vacuum degree in the container was controlled to be -0.1 MPa. Then, a methanol solution of tartaric acid and dabigatran etexilate mesylate with a concentration ratio of 5:1 was first added dropwise, and the mixture was allowed to stand for 15 minutes. The residual drug on the surface was washed with ethanol. Then, the vacuum degree in the container was adjusted to -0.05 MPa, and a mixed solution with a concentration ratio of 1:1 was added dropwise, and the mixture was allowed to stand for 5 minutes, and washed with ethanol. Finally, the container was adjusted to normal pressure, and a drug solution with an acid-drug concentration ratio of 1:3 was added dropwise, and the mixture was washed with ethanol. After centrifugation at 6000 rpm / min, the mixture was dried in a vacuum drying oven at 60°C for 12 hours to obtain a TiO2 HoMS drug delivery system with a decreasing acid gradient from the inside to the outside. Embodiment 13

[0126] A ZnO HoMS drug delivery system with a controllable internal microenvironment and an acid-drug ratio of 1:1, comprising the following steps:

[0127] (1) Preparation of hollow multi-shell structures

[0128] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M Zn(NO3)2 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30°C water bath for heating and adsorption for 12 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60°C oven for 24 h to obtain a precursor. The precursor was then calcined in a muffle furnace, heated to 500°C at 5°C / min, and kept warm for 3 h. After natural cooling, a three-shell ZnO HoMS with a size of about 0.8 μm was obtained.

[0129] (2) Regulation of the acid-drug ratio

[0130] 35 mg of verapamil and 15 mg of citric acid were dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 1:1.

[0131] (3) 10 mg of three-shell ZnO HoMS was placed at the bottom of a two-necked flask. One flask was connected to a vacuum pump through a glass piston valve, and a syringe was inserted into the other flask. First, vacuum was drawn for 3 min to keep the flask in a negative pressure state. Then, the above mixed solution was slowly added dropwise to make the mass concentration of HoMS to acid and drug to be 1:5. Then, the flask was washed with ethanol and this step was repeated 3 times. The flask was centrifuged at 6000 rpm / min and dried in a vacuum drying oven at 60°C for 12 h to obtain drug-loaded ZnO HoMS microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 1:1. Embodiment 14

[0132] An Fe2O3 HoMS drug delivery system with a controllable internal microenvironment and an acid-drug ratio of 1:1, comprising the following steps:

[0133] (1) Preparation of hollow multi-shell structures

[0134] 0.6 g of carbon sphere template was dispersed in 30 mL of 1 M FeCl3 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 40 °C water bath for heating and adsorption for 12 h. The adsorbed mixture was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 °C oven for 24 h to obtain a precursor. The precursor was then calcined in a muffle furnace, heated to 500 °C at 2 °C / min, and kept warm for 2 h. After natural cooling, a three-shell Fe2O3 HoMS with a size of about 0.9 μm was obtained.

[0135] (2) Regulation of the acid-drug ratio

[0136] 33 mg of vinpocetine and 17 mg of fumaric acid were dissolved in 1 mL of dichloromethane to obtain a mixed solution with a molar concentration ratio of 1:1.

[0137] (3) 10 mg of three-shell Fe2O3HoMS was placed at the bottom of a two-necked flask. One flask was connected to a vacuum pump through a glass piston valve, and a syringe was inserted into the other flask. The flask was first vacuumed for 3 min to maintain a negative pressure. The mixed solution was then slowly added dropwise to make the mass concentration of HoMS to acid and drug to be 1:5. The flask was then washed with acetone and the step was repeated 3 times. The flask was centrifuged at 6000 rpm / min and dried in a vacuum drying oven at 60 °C for 12 h to obtain drug-loaded Fe2O3 HoMS microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 1:1. Embodiment 15

[0138] A method for preparing an oral capsule with a hollow multi-shell structure having a controllable internal microenvironment, comprising the following steps:

[0139] (1) Preparation of hollow multi-shell structures

[0140] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixture was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 12 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 2 h, and then naturally cooled to obtain a three-shell TiO2 HoMS with a size of about 0.6 μm;

[0141] (2) Regulation of the acid-drug ratio

[0142] 40 mg of dabigatran etexilate mesylate and 10 mg of tartaric acid were respectively dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 1:1.

[0143] (3) 10 mg of three-shell TiO2HoMS was placed at the bottom of a two-necked flask. One flask was connected to a vacuum pump through a glass piston valve, and a syringe was inserted into the other flask. First, vacuum was applied for 3 min to keep the flask under negative pressure. Then, the mixed solution was slowly added dropwise to make the mass concentration of HoMS to acid and drug to be 1:5. The flask was then washed with acetone and the step was repeated 3 times. The flask was centrifuged at 6000 rpm / min and dried in a vacuum drying oven at 60 °C for 12 h to obtain drug-loaded TiO2HoMS microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 1:1.

[0144] (4) After the above materials were vacuum dried, TiO2HoMS containing 2 mg of dabigatran mesylate was poured into commercially available enteric-coated gelatin capsules according to the prescribed amount. Example 16

[0145] An oral capsule with a hollow multi-shell structure with controllable internal microenvironment, comprising the following steps:

[0146] (1) Preparation of hollow multi-shell structures

[0147] 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixture was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 12 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 2 h, and then naturally cooled to obtain a three-shell TiO2 HoMS with a size of about 0.6 μm;

[0148] (2) Regulation of the acid-drug ratio

[0149] 21, 40, 47 mg of dabigatran mesylate and 30, 10, 3 mg of tartaric acid were dissolved in 1 mL of methanol to obtain mixed solutions with molar concentration ratios of 5:1, 1:1, and 1:3, respectively.

[0150] (3) The three-shell TiO2 HoMS material was placed at the bottom of a two-necked flask. One flask was connected to a vacuum pump through a glass piston valve, and a syringe was inserted into the other flask. First, a vacuum was drawn for 3 minutes to keep the flask in a negative pressure state. Then, a methanol solution of tartaric acid and dabigatran etexilate mesylate with a concentration ratio of 5:1 was first added dropwise, and the drug remaining on the surface was washed with ethanol; then, a mixed solution with a concentration ratio of 1:1 was added dropwise, and washed with ethanol; finally, a drug solution with an acid-drug concentration ratio of 1:3 was added dropwise, and washed with ethanol. After centrifugation at 6000 rpm / min, the solution was dried in a vacuum drying oven at 60°C for 12 hours to obtain a TiO2 HoMS drug delivery system with a decreasing acid gradient from the inside to the outside.

[0151] (4) After the above materials were vacuum dried, TiO2HoMS containing 2 mg of dabigatran mesylate was poured into commercially available gelatin capsules according to the prescribed amount. Embodiment 17

[0152] An oral capsule with a hollow multi-shell structure with controllable internal microenvironment, comprising the following steps:

[0153] (1) Preparation of hollow multi-shell structures

[0154] 0.6 g of carbon ball template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon balls were evenly dispersed by ultrasound. The mixture was placed in a 30 °C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water three times, and dried in a 60 °C oven for 12 h to obtain a precursor; it was then calcined in a muffle furnace, heated to 500 °C at 2 °C / min, and kept warm for 2 h. After natural cooling, a three-shell TiO2 HoMS with a size of about 0.6 μm was obtained.

[0155] (2) Regulation of the acid-drug ratio

[0156] 40 mg of dabigatran etexilate mesylate and 10 mg of tartaric acid were respectively dissolved in 1 mL of methanol to obtain a mixed solution with a molar concentration ratio of 1:1.

[0157] (3) 10 mg of three-shell TiO2HoMS was placed at the bottom of a two-necked flask. One flask was connected to a vacuum pump through a glass piston valve, and a syringe was inserted into the other flask. First, vacuum was applied for 3 min to keep the flask under negative pressure. Then, the mixed solution was slowly added dropwise to make the mass concentration of HoMS to acid and drug to be 1:5. The flask was then washed with acetone and the step was repeated 3 times. The flask was centrifuged at 6000 rpm / min and dried in a vacuum drying oven at 60 °C for 12 h to obtain drug-loaded TiO2HoMS microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 1:1.

[0158] (4) After the above materials were vacuum dried, TiO2HoMS containing 2 mg of dabigatran mesylate and 2 mg of effervescent disintegrant were poured into commercially available gelatin capsules according to the prescribed amount. Embodiment 18

[0159] An oral capsule with a hollow multi-shell structure with controllable internal microenvironment, comprising the following steps:

[0160] (1) 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 °C water bath for heating and adsorption for 18 h. The adsorbed mixture was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 °C oven for 12 h to obtain a precursor. The precursor was then calcined in a muffle furnace, heated to 500 °C at 2 °C / min, and kept warm for 2 h. After natural cooling, a three-shell TiO2 HoMS with a size of about 0.6 μm was obtained.

[0161] (2) 21, 40, and 47 mg of dabigatran mesylate and 30, 10, and 3 mg of tartaric acid were dissolved in 1 mL of methanol to obtain mixed solutions with molar concentration ratios of 5:1, 1:1, and 1:3, respectively.

[0162] (3) The three-shell TiO2 HoMS material was placed at the bottom of a two-necked flask. One flask was connected to a vacuum pump through a glass piston valve, and a syringe was inserted into the other flask. First, a vacuum was drawn for 3 minutes to keep the flask in a negative pressure state. Then, a methanol solution of tartaric acid and dabigatran etexilate mesylate with a concentration ratio of 5:1 was first added dropwise, and the drug remaining on the surface was washed with ethanol; then, a mixed solution with a concentration ratio of 1:1 was added dropwise, and washed with ethanol; finally, a drug solution with an acid-drug concentration ratio of 1:3 was added dropwise, and washed with ethanol. After centrifugation at 6000 rpm / min, the solution was dried in a vacuum drying oven at 60°C for 12 hours to obtain a TiO2 HoMS drug delivery system with a decreasing acid gradient from the inside to the outside.

[0163] (4) After the above materials were vacuum dried, TiO2HoMS containing 2 mg of dabigatran mesylate and 6 mg of sodium carboxymethyl starch disintegrant were poured into commercially available enteric gelatin capsules according to the prescribed amount. Embodiment 19

[0164] An oral capsule based on a hollow multi-shell structure with controllable internal microenvironment, comprising the following steps:

[0165] (1) 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 °C water bath for heating and adsorption for 18 h. The adsorbed mixture was centrifuged, and the lower layer of solid was taken out. The solid was washed three times with deionized water and dried in a 60 °C oven for 12 h to obtain a precursor. The precursor was then calcined in a muffle furnace, heated to 500 °C at a rate of 2 °C / min, and kept warm for 2 h. After natural cooling, a three-shell TiO2 HoMS with a size of about 0.6 μm was obtained.

[0166] (2) Regulation of the acid-drug ratio

[0167] 21, 40, 47 mg of dabigatran mesylate and 30, 10, 3 mg of tartaric acid were dissolved in 1 mL of methanol to obtain mixed solutions with molar concentration ratios of 5:1, 1:1, and 1:3, respectively.

[0168] (3) 10 mg of three-shell TiO2HoMS was placed at the bottom of a two-necked flask. One flask was connected to a vacuum pump through a glass piston valve, and a syringe was inserted into the other flask. First, vacuum was applied for 3 min to keep the flask under negative pressure. Then, the mixed solution was slowly added dropwise to make the mass concentration of HoMS to acid and drug to be 1:5. The flask was then washed with acetone and the step was repeated 3 times. The flask was centrifuged at 6000 rpm / min and dried in a vacuum drying oven at 60 °C for 12 h to obtain drug-loaded TiO2HoMS microspheres with a controllable internal acidic microenvironment and an acid-drug ratio of 1:1.

[0169] (4) After the above materials were vacuum dried, TiO2HoMS containing 3 mg of dabigatran mesylate and 1 mg of effervescent disintegrant were poured into commercially available enteric gelatin capsules according to the prescribed amount. Comparative Example 1

[0170] In order to verify the effect of the acidic microenvironment brought by the hollow multi-shell structure on drug release and absorption, the inventors injected an equal amount of 2 mg of dabigatran etexilate mesylate into a gelatin capsule treated with Eudragit L30D-55. The enteric coating layer of the gelatin capsule can also be triethyl citrate. Comparative Example 2

[0171] In order to verify the effect of the acidic microenvironment brought by the hollow multi-shell structure on drug release and absorption, the inventors used TiO2 HoMS loaded with an equal amount of dabigatran mesylate to prepare oral capsules. The specific steps are as follows:

[0172] (1) 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 °C water bath for heating and adsorption for 18 h. The adsorbed mixture was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 °C oven for 12 h to obtain a precursor. The precursor was then calcined in a muffle furnace, heated to 500 °C at 2 °C / min, and kept warm for 2 h. After natural cooling, a three-shell TiO2HoMS with a size of about 0.6 μm was obtained.

[0173] (2) Dissolve 50 mg of dabigatran etexilate mesylate in 1 mL of methanol to obtain a drug solution with a mass concentration of 50 mg / L.

[0174] (3) The three-shell TiO2 HoMS material was placed at the bottom of a two-necked flask. One flask was connected to a vacuum pump through a glass piston valve, and a syringe was inserted into the other flask. The flask was first vacuumed for 3 min to maintain a negative pressure. The drug solution was then added and the drug remaining on the surface was cleaned with ethanol. This was repeated three times. The flask was then centrifuged at 6000 rpm / min and dried in a vacuum drying oven at 60 °C for 12 h to obtain the TiO2 HoMS drug delivery system.

[0175] (4) After the above materials were vacuum dried, TiO2HoMS containing 2 mg of dabigatran mesylate was poured into commercially available enteric-coated gelatin capsules according to the prescribed amount.

[0176] Experimental Example 1 Characterization of the morphology and elements of the drug delivery system

[0177] Scanning electron microscopy (SEM) was used to characterize the surface morphology of the hollow multi-shell material and the structure after drug loading. The working voltage of SEM was 5-15kV, and the working voltage of TEM was 200kV.

[0178] The results are as follows Figure 1 As shown in the figure, the surface of TiO2 HoMS is relatively rough and consists of obvious grain accumulation, which helps to improve the retention in the intestine. In addition, the samples loaded with acid and drug were sliced ​​and observed using a focused ion beam (FIB). Figure 2 As shown, the successful loading of the drug inside the shell can be seen from the uniform distribution of the N element, confirming the effectiveness of the vacuum adsorption loading scheme.

[0179] Experimental Example 2 Testing the Crystallization State of Drugs in Hollow Multi-shell Structures

[0180] X-ray powder diffraction (XRD) was used to analyze the phase state and crystal structure of the sample. The working voltage was 40 kV, the working current was 30 mA, the Cu target was used, the wavelength of the Kα diffraction line was 1.5405 Å, and the data were collected at a scanning speed of 6° / min between 5°-90° 2θ angles. The results are shown in Figure 2. Figure 3 As shown in the figure, dabigatran etexilate showed obvious diffraction peaks at 2θ=11.1°, 17.7°, 18.1°, 19.9°, 22.1° and 22.9°, but after being loaded into TiO2HoMS, no corresponding crystallization peaks were observed, confirming that the nano-confined pores of TiO2 HoMS regulated the amorphous state of the drug, as shown in Figure 3 shown.

[0181] Experimental Example 3 Testing the intestinal retention of HoMS oral carrier

[0182] HoMS were labeled with fluorescent marker cy-7 and loaded into enteric-coated capsules. Rats were given the drug by gavage and euthanized at specific times. The intestines of the rats were removed and sliced ​​and then observed under a confocal microscope.

[0183] The results are as follows Figure 4 As shown in the figure, TiO2 HoMS can stay in the intestine for about 24 hours and will not enter other organs. Figure 5 ), and found that HoMS can fit close to the narrow gaps between the villi of the small intestine, indicating that the unique micro-nano size of HoMS as an oral carrier can prolong the retention time and thus improve the absorption rate of the drug.

[0184] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a hollow multi-shell structure oral drug carrier with controllable internal microenvironment, characterized in that: The following steps are involved: (1) Preparation of hollow multi-shell structures 0.6 g of carbon sphere template was dispersed in 30 mL of 3 M TiCl4 solution, and the carbon spheres were evenly dispersed by ultrasound. The mixture was placed in a 30 ° C water bath for heating and adsorption for 18 h. The adsorbed mixed solution was centrifuged, and the lower layer of solid was taken out, washed with deionized water for 3 times, and dried in a 60 ° C oven for 24 h to obtain a precursor; then it was placed in a muffle furnace for calcination, heated to 500 ° C at 2 ° C / min, and kept warm for 3 h, and then naturally cooled to obtain a three-shell TiO2HoMS with a size of about 0.6 μm; (2) Regulation of the acid-drug ratio 25, 40, 50 mg of dabigatran mesylate and 25, 10, 0 mg of tartaric acid were dissolved in 1 mL of methanol to obtain three mixed solutions with a molar concentration ratio of 5:1, 1:1, and 0:1; (3) The three-shell TiO2 HoMS material was placed at the bottom of a two-flask, one of which was connected to a vacuum pump through a glass piston valve, and the other was inserted with a syringe. First, the flask was evacuated for 3 minutes to keep the negative pressure in the flask, and the vacuum degree in the container was controlled to be -0.1 MPa. Then, a methanol solution of tartaric acid and dabigatran etexilate with a concentration ratio of 5:1 was first added dropwise, and the mixture was allowed to stand for 15 minutes. The residual drug on the surface was washed with ethanol. Then, the vacuum degree in the container was adjusted to -0.05 MPa, and a mixed solution with a concentration ratio of 1:1 was added dropwise, and the mixture was allowed to stand for 5 minutes, and washed with ethanol. Finally, the container was adjusted to normal pressure, and a drug solution with an acid-drug concentration ratio of 0:1 was added dropwise, and the mixture was washed with ethanol. After centrifugation at 6000 rpm / min, the mixture was dried in a vacuum drying oven at 60°C for 12 hours to obtain TiO2 HoMS drug-loaded microspheres with a decreasing acid gradient from the inside to the outside.

2. The preparation method according to claim 1, characterized in that: The drug-loaded microspheres are mixed with a disintegrant and encapsulated in a gelatin capsule to obtain an oral capsule.

3. Use of the drug-loaded microspheres obtained according to the preparation method of claim 1 or 2 in the preparation of dabigatran mesylate oral medicine.

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