A pregelatinized starch / calcium-containing mineral-berberine compound, and a preparation method and application thereof

Abstract

The application discloses a pre-gelatinized starch / calcium-containing mineral-berberine compound and a preparation method and application thereof, and comprises the following steps: mixing an organic acid salt or an inorganic acid salt, starch and water, and performing microwave treatment to obtain a starch-salt colloid solution; mixing calcium salt, berberine and ethanol to obtain an ethanol solution containing berberine and calcium salt; adding the starch-salt colloid solution into the ethanol solution containing berberine and calcium salt, stirring and reacting, performing retrogradation treatment, centrifuging to obtain a precipitate, and drying to obtain the compound. The application combines the starch "gelatinization-retrogradation" mechanism and the calcium-containing mineral biomimetic mineralization method, completes the encapsulation of berberine, and prepares the berberine compound with the pre-gelatinized starch / calcium-containing mineral as a drug delivery system, so that the berberine compound has a high drug encapsulation rate, the gastrointestinal stability of the berberine is remarkably improved, a good sustained-release effect is generated, the bioavailability of the berberine is improved, and a new way is provided for the clinical application of the berberine.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine preparation, and particularly relates to a pre-gelatinized starch / calcium-containing mineral-berberine compound and a preparation method and application thereof. BACKGROUND

[0002] Berberine is a yellow needle-like crystalline substance, odorless, extremely bitter, and is an isoquinoline alkaloid isolated from traditional Chinese medicine Huanglian, Huangbai, and Sanjizhen plants. Berberine is slightly soluble in water, easily soluble in boiling water and hot ethanol, and almost insoluble in cold ethanol, chloroform and diethyl ether. Modern pharmacological studies have shown that berberine has the effects of lowering blood sugar, lowering blood lipids, anti-oxidation, anti-inflammation, anti-tumor, and antibacterial. Berberine has a very wide antibacterial spectrum, and has a strong inhibitory effect on hemolytic streptococcus, staphylococcus aureus, helicobacter pylori, vibrio cholerae, meningococcus, shigella dysenteriae, salmonella typhi, and diphtheria bacillus in vitro.

[0003] However, although berberine has many beneficial effects, the presence of quaternary ammonium salt cation groups in the molecular structure of berberine and its self-aggregation in the stomach acid environment limit the application of berberine due to its poor water solubility and low oral bioavailability (<1%).

[0004] In the prior art, strategies for improving the bioavailability of berberine usually adopt nanometer preparations, liposomes, preparation of water-soluble prodrugs, changes in crystal form, and salts with other active ingredients of traditional Chinese medicine such as gallic acid and rhein. Although these technologies can achieve good effects, the preparation process is too complex and the cost is relatively high. In addition, changes in chemical structure may cause problems in biological safety and drug stability, which is difficult to promote.

[0005] Biomimetic mineralization is a method of introducing biological mineralization into the process of material synthesis, using organic matrix as a template to control the formation of inorganic matter, and preparing materials with unique microstructure characteristics and biological properties. Calcium carbonate and calcium oxalate are important minerals in biological mineralization products. In recent years, people have been inspired by biological mineralization, and by adding different organic matters (such as chitin, protein, polysaccharide) as mineralization templates, biomimetic mineralization of calcium-containing minerals is completed in vitro. The products of biomimetic mineralization can be wrapped on the surface of drug crystals to form a tightly structured compound to control the release of drugs.

[0006] Starch is a kind of polysaccharide with abundant reserves, good biocompatibility and biodegradability, and is often developed into a new type of material. The gelatinization-reversion stage of starch milk refers to that when starch milk is heated to a certain temperature, starch particles absorb water and swell, the hydrogen bonds in the crystalline region are broken, the crystal structure disappears, and a semi-transparent viscous liquid is formed. When placed at room temperature, the thermal motion of starch molecules weakens, and the branched starch molecules and the straight-chain starch molecules tend to arrange in parallel. Through hydrogen bonding, they approach each other and re-form mixed microcrystalline bundles. The surface of the particles forms a hard shell structure. Such surface hard shell particles can be a potential skeleton material for sustained-release preparations.

[0007] At present, biomimetic mineralization is widely used in the field of biological engineering, such as bone tissue engineering and tooth enamel repair. However, there is no literature report on the combination of biomimetic mineralization and starch gelatinization-reversion mechanism for the preparation of berberine complex by using berberine. SUMMARY

[0008] In view of the problems of the prior art, the purpose of the present application is to provide a preparation method of pre-gelatinized starch / calcium-containing mineral-berberine complex. The method is based on biomimetic mineralization and starch gelatinization-reversion mechanism to complete the encapsulation of berberine. The prepared berberine complex with pre-gelatinized starch / calcium-containing mineral as a drug delivery system can slowly release berberine in the gastrointestinal tract, and improve the bioavailability of berberine.

[0009] The present application is realized by the following technical solutions:

[0010] A preparation method of pre-gelatinized starch / calcium-containing mineral-berberine complex, comprising the following steps:

[0011] (1) mixing an organic acid salt or an inorganic acid salt, starch and water, and treating the mixture by microwave to obtain a starch-salt colloidal solution, and diluting the starch-salt colloidal solution with water;

[0012] (2) mixing a calcium salt, berberine and ethanol to obtain an ethanol solution containing berberine and calcium salt;

[0013] (3) adding the starch-salt colloidal solution prepared in step (1) into the ethanol solution containing berberine and calcium salt prepared in step (2), stirring and reacting, reversion treatment, centrifugation to obtain a precipitate, drying to obtain a pre-gelatinized starch / calcium-containing mineral-berberine complex.

[0014] In the present application, the starch-salt mixture system is first treated by microwave. The salt ions in the system can increase the dielectric loss value of the system, increase the penetration depth (Dp) value of the microwave energy, and improve the utilization rate of the microwave energy by the starch. In the starch-salt colloidal solution after microwave treatment, the crystal structure of the starch is destroyed, the hydrogen bonds are broken, and more hydroxyl groups are exposed, which can react with Ca 2+Electrostatic interactions provide more nucleation sites for calcium-containing minerals. Then, using an antisolvent method, a colloidal solution of microwave-pretreated starch-salt is dropwise added to an ethanol medium containing calcium salt berberine. The abrupt change in the solvent medium induces the formation of crystals of different shapes, sizes, and orientations, completing the encapsulation of inorganic calcium-containing minerals and berberine before starch retrogradation. Finally, utilizing the starch retrogradation mechanism, starch molecules regenerate into a hard-shell structure at a lower temperature, encapsulating the berberine coated with calcium-containing minerals, thus preparing a pregelatinized starch / calcium-containing mineral-berberine complex with slow-release function.

[0015] As a preferred technical solution of the present invention, in step (1), the organic acid salt can be at least one of oxalate, acetate or citrate, and more preferably one or more of sodium oxalate, sodium acetate or sodium citrate; the inorganic acid salt can be at least one of carbonates, and more preferably sodium carbonate or potassium carbonate.

[0016] As a preferred technical solution of the present invention, in step (1), the starch is one or more of corn starch, pea starch, tapioca starch or wheat starch.

[0017] As a preferred technical solution of the present invention, in step (1), the mass ratio of the organic acid salt or inorganic acid salt, starch and water is 0.52 to 4.24:2:30.

[0018] As a preferred embodiment of the present invention, in the microwave treatment, the time and frequency of the microwave treatment are adjusted so that the microwave energy value obtained per gram of starch is 437J to 4370J. The higher the microwave energy value, the higher the degree of starch gelatinization and the better the encapsulation rate.

[0019] As a preferred technical solution of the present invention, in step (2), the calcium salt is one or more of calcium chloride, calcium nitrate or calcium acetate.

[0020] As a preferred technical solution of the present invention, in step (2), the mass ratio of the calcium salt, berberine and ethanol is 0.43-4.44:0.25:50.

[0021] The present invention also provides a pregelatinized starch / calcium-containing mineral-berberine complex, which is prepared by the above preparation method. In the pregelatinized starch / calcium-containing mineral-berberine complex prepared by the present invention, the mass ratio of starch to calcium-containing mineral is 1:0.25-2, and the calcium-containing mineral is preferably at least one of calcium carbonate or calcium oxalate.

[0022] The present application also provides the use of the pregelatinized starch / calcium-containing mineral-berberine complex as described above in the preparation of a medicament for treating intestinal infection, conjunctivitis or suppurative otitis media. The pregelatinized starch / calcium-containing mineral-berberine complex prepared by the present application has certain resistance to gastric acid, and when entering the intestine, the starch molecules can be decomposed by amylase, resulting in the release of a large amount of berberine, which is beneficial to improve the bioavailability of berberine.

[0023] The medicament described in the present application comprises an effective amount of the pregelatinized starch / calcium-containing mineral-berberine complex and a pharmaceutically acceptable carrier.

[0024] The pharmaceutically acceptable carrier described in the present application includes but is not limited to lubricants, fillers, binders, disintegrants, pH regulators, surfactants, antioxidants, etc., and the amount used is the conventional amount in the art.

[0025] The dosage form of the medicament of the present application can be prepared according to the conventional method in the art, and the dosage form of the medicament includes but is not limited to tablets, capsules, sustained-release agents, powders, oral liquids, powders, pills or granules, etc.

[0026] Compared with the prior art, the present application has the following advantages:

[0027] The present application adopts the "gelatinization-rejuvenation" mechanism of starch and the method of combining with the biomimetic mineralization of calcium-containing minerals to complete the encapsulation of berberine, and the pregelatinized starch / calcium-containing mineral-berberine complex prepared by the present application has a high drug encapsulation rate, the gastrointestinal stability of berberine is significantly improved, and a good sustained-release effect is produced, which improves the bioavailability thereof, and provides a new way for the clinical application of berberine. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 SEM images of the pregelatinized starch / calcium carbonate-berberine complex of Comparative Example 5 (left) and Example 1 (right);

[0029] Figure 2 DSC graph of the pregelatinized starch / calcium carbonate-berberine complex of Example 1;

[0030] Figure 3 In-vitro release rate of tablets of each example and comparative example. DETAILED DESCRIPTION

[0031] The technical solutions of the present application will be described below in combination with the examples of the present application. The described examples are only a part of the examples of the present application, but not all the examples. Based on the examples in the present application, all other examples obtained by those skilled in the art without making creative efforts fall within the scope of protection of the present application.

[0032] The methods used in the embodiments of the present application are conventional methods unless otherwise specified, and the reagents used can be obtained from commercial channels.

[0033] Example 1:

[0034] A preparation method of a pregelatinized starch / calcium carbonate-berberine complex, comprising the following steps:

[0035] (1) According to the mass ratio of corn starch, sodium carbonate and ultrapure water of 2:0.53:30, mix and stir uniformly at room temperature; the prepared suspension is placed in a microwave reactor, microwave treatment is carried out according to 4370J of microwave energy per gram of starch, then ultrapure water is added for dilution, and a sodium carbonate-starch pregelatinized colloid solution is obtained;

[0036] (2) According to the mass ratio of berberine, calcium chloride and anhydrous ethanol of 0.25:0.55:50, mix and stir uniformly at room temperature until the solution color is clear and transparent, and a calcium chloride ethanol solution containing berberine is obtained;

[0037] (3) Stir the calcium chloride ethanol solution containing berberine prepared in step (2) at room temperature, then add the colloid solution prepared in step (1) to the solution prepared in step (2) at a constant speed drop by drop, precipitate for 12h, then perform regeneration treatment at low temperature of 4℃ for 12h, centrifuge at 4500rpm, take the precipitate, and wash with anhydrous ethanol and ultrapure water for 2-3 times, and finally dry the precipitate to obtain a pregelatinized starch / calcium carbonate-berberine complex.

[0038] Example 2:

[0039] A preparation method of a pregelatinized starch / calcium carbonate-berberine complex, comprising the following steps:

[0040] (1) According to the mass ratio of cassava starch, sodium carbonate and ultrapure water of 2:4.24:30, mix and stir uniformly at room temperature. The prepared suspension is placed in a microwave reactor, microwave treatment is carried out according to 4370J of microwave energy per gram of starch, then ultrapure water is added for dilution, and a colloid solution of sodium carbonate-starch pregelatinized co-treatment product is obtained;

[0041] (2) According to the mass ratio of berberine, calcium chloride and anhydrous ethanol of 0.25:4.44:50, mix and stir uniformly at room temperature until the solution color is clear and transparent, and a calcium chloride ethanol solution containing berberine is obtained;

[0042] (3) stirring the solution prepared in step (2) at room temperature, then adding the colloidal solution prepared in step (1) into the solution prepared in step (2) at a constant rate drop by drop, after 12 hours of precipitation reaction, 12 hours of back reaction treatment at low temperature of 4℃, centrifugation at 4500 rpm, taking the precipitate, and washing the precipitate with anhydrous ethanol and ultrapure water for 2-3 times, and finally drying the precipitate to obtain the pre-gelatinized starch / calcium carbonate-berberine complex.

[0043] Example 3:

[0044] A method for preparing a pre-gelatinized starch / calcium oxalate-berberine complex, comprising the following steps:

[0045] (1) mixing corn starch, sodium oxalate and ultrapure water according to the mass ratio of 2:4.18:30, and stirring uniformly at room temperature. The prepared suspension is placed in a microwave reactor, and microwave treatment is performed according to 4370J of microwave energy per gram of starch, then diluted with ultrapure water to obtain a sodium oxalate-starch pre-gelatinized colloidal solution;

[0046] (2) mixing berberine, calcium chloride and anhydrous ethanol according to the mass ratio of 0.25:3.47:50, and stirring uniformly at room temperature until the solution color is clear and transparent to obtain a calcium chloride ethanol solution containing berberine;

[0047] (3) stirring the solution prepared in step (2) at room temperature, then adding the colloidal solution prepared in step (1) into the solution prepared in step (2) at a constant rate drop by drop, after 12 hours of precipitation reaction, 12 hours of back reaction treatment at low temperature of 4℃, centrifugation at 4500 rpm, taking the precipitate, and washing the precipitate with anhydrous ethanol and ultrapure water for 2-3 times, and finally drying the precipitate to obtain the pre-gelatinized starch / calcium carbonate-berberine complex.

[0048] Example 4:

[0049] The difference between this example and example 3 is that the mass ratio of corn starch, sodium oxalate and ultrapure water is 2:0.52:30, the mass ratio of berberine, calcium chloride and anhydrous ethanol is 0.25:0.43:50, and the rest is the same as example 1.

[0050] Example 5:

[0051] The difference between this example and example 1 is that microwave treatment is performed according to 1310J of microwave energy per gram of starch, and the rest is the same as example 1.

[0052] Example 6:

[0053] Wheat starch is used instead of corn starch, and calcium acetate is used instead of calcium chloride, and the rest is the same as example 1.

[0054] Comparative Example 1

[0055] (1) The corn starch and ultrapure water were mixed in a mass ratio of 2:30, and stirred uniformly at room temperature. The prepared suspension was placed in a microwave reactor, and microwave treatment was performed at a microwave energy of 4370 J per gram of starch. After dilution with ultrapure water, a colloidal solution of pre-gelatinized starch was obtained.

[0056] (2) The berberine and anhydrous ethanol were mixed in a mass ratio of 0.25:50, and stirred uniformly at room temperature until the solution was clear and transparent in color, to obtain a berberine ethanol solution.

[0057] (3) The berberine ethanol solution prepared in step (2) was stirred at room temperature, and then the colloidal solution prepared in step (1) was added dropwise at a constant speed into the solution prepared in step (2). After precipitation reaction for 12 h, the precipitate was washed with anhydrous ethanol and ultrapure water for 2-3 times, and then dried to obtain a pre-gelatinized starch-berberine complex.

[0058] Comparative Example 2

[0059] (1) The sodium carbonate and ultrapure water were mixed in a mass ratio of 0.53:30, and stirred uniformly at room temperature. The prepared suspension was obtained as a sodium carbonate solution.

[0060] (2) The berberine, calcium chloride and anhydrous ethanol were mixed in a mass ratio of 0.25:0.55:50, and stirred uniformly at room temperature until the solution was clear and transparent in color, to obtain a berberine calcium chloride ethanol solution.

[0061] (3) The berberine calcium chloride ethanol solution prepared in step (2) was stirred at room temperature, and then the sodium carbonate solution prepared in step (1) was added dropwise at a constant speed into the solution prepared in step (2). After precipitation reaction for 12 h, the precipitate was washed with anhydrous ethanol and ultrapure water for 2-3 times, and then dried to obtain a calcium carbonate-berberine complex.

[0062] Comparative Example 3

[0063] The difference between this example and Example 1 is that the mass ratio of corn starch, sodium carbonate and ultrapure water is 2:6.36:30, and the mass ratio of berberine, calcium chloride and anhydrous ethanol is 0.25:6.66:50, and the rest is the same as Example 1.

[0064] Comparative Example 4

[0065] The embodiment is different from example 1 in that the mass ratio of corn starch, sodium carbonate and ultrapure water is 2:0.265:30, the mass ratio of berberine, calcium chloride and anhydrous ethanol is 0.25:0.275:50, and the rest is the same as example 1.

[0066] Comparative example 5:

[0067] The embodiment is different from example 1 in that the microwave treatment is carried out at a microwave energy of 437 J per gram of starch, and the rest is the same as example 1.

[0068] A suitable amount of pregelatinized starch / calcium carbonate-berberine complex prepared in example 1 and comparative example 5 is evenly sprinkled on double-sided tape, and then gold spraying treatment is carried out. After short drying, the morphology is observed by scanning electron microscopy. The SEM image is shown in Figure 1 .

[0069] In comparative example 5 (left), the surface or interior of the starch particles is covered with multiple calcium carbonate-berberine agglomerates. In example 1 (right), the spherical morphology of the starch particles has been completely lost, the particles are swollen and broken, the shape is diverse and irregular, there are a large number of pores and depressions, and the surface or interior region is inlaid with a large number of calcium carbonate-berberine agglomerates.

[0070] 5.0 mg of calcium carbonate (CC), berberine (BBR) and pregelatinized starch / calcium carbonate-berberine complex sample prepared in example 1 of pregelatinized starch (PMS10) are weighed into a crucible, sealed with a cover and placed in the sample groove of the DSC instrument. The scanning temperature range is 20-300℃, the temperature rising rate is 7 K / min, and all analyses are controlled by an empty crucible. The DSC graph is shown in Figure 2 . The broad peak of berberine at 80℃ indicates that the apparent water of berberine is removed, the broad endothermic peak in the region of 180℃-190℃ is related to the melting point of berberine, and the exothermic peak at 201℃ and the endothermic peak at 290℃ can be inferred that there is a semi-stable crystal form in the structure of berberine; the broad peak of pregelatinized starch at 90℃ is its dehydration peak, the dehydration peak of berberine in example 1 is shifted to the left and weakened, and the broad endothermic peak in the region of 180℃-190℃ and the exothermic peak at 201℃ and the endothermic peak at 290℃ are obviously weakened or disappeared, indicating that the characteristic peaks of berberine and pregelatinized starch are not simply superimposed, but crystal type changes and coating formation occur.

[0071] The examples and comparative examples prepared by the present application are subjected to the following experiments, and the test results are shown in table 1:

[0072] (1) Calculation of the encapsulation efficiency of pregelatinized starch / calcium carbonate-berberine complex

[0073] The supernatant and washing solution obtained in the above examples and comparative examples were combined and diluted to 250 ml. 5 ml of liquid was accurately pipetted and then diluted to the mark with a 10 ml volumetric flask. A certain amount of liquid was transferred to a cuvette and the absorbance of berberine was measured at 263 nm using a UV spectrophotometer. The encapsulation efficiency of berberine was calculated according to the following formula.

[0074] Drug entrapment(%)=100%*(Atotal-Asup) / Atotal

[0075] In the formula, Attotal represents the amount of berberine fed, and Asup represents the amount of berberine in the supernatant.

[0076] (2) Test of the mass ratio of starch to calcium-containing minerals in pregelatinized starch / calcium-containing mineral-berberine complex:

[0077] Ca in the sample was determined by a royal ash digestion-EDTA titration method. 2+ To determine the content, the mass ratio of starch to calcium-containing minerals is determined. Accurately weigh 100 mg of the sample into a 250 mL Erlenmeyer flask, add 6 mL of concentrated hydrochloric acid and 2 mL of concentrated nitric acid (3:1) mixed acid system, and gradually heat on an electric heating plate to digest (45℃ for 30 min, 95℃ for 30 min, 135℃ for 30 min, 200℃ for 45 min). If the digest is brownish-red, add more nitric acid to prevent sample carbonization until digestion reaches the point of white fumes, and the digest is colorless and transparent or slightly yellow. After cooling, add 100 mL of distilled water, adjust the pH of the solution to between 10 and 11 with 2.0 mol / L sodium hydroxide, add 3–5 drops of calcium reagent, and titrate with 0.01 mol / L EDTA standard solution until the solution changes from wine red to blue, which is the endpoint. The Ca2+ content in the sample can be calculated based on the volume of EDTA titrant consumed. + The mass ratio of calcium-containing minerals to starch can be calculated by determining the molar amount of calcium-containing minerals and then by considering their relative molecular weights.

[0078] (3) In vitro release behavior of pregelatinized starch / calcium-containing mineral-berberine complex tablets

[0079] Weigh an appropriate amount of the compound powder prepared in the examples and comparative examples, grind it thoroughly in a mortar, manually feed an appropriate amount of powder into the mold of a single-punch tablet press, adjust a certain pressure, and manually rotate the wheel to obtain tablets containing berberine (comparative example 2 is not tableted).

[0080] Determination according to the method for determination of dissolution and release in the 2015 edition of Chinese Pharmacopoeia (general rule 0931 third method small cup method). The berberine tablets are placed in 150 mL of pH = 1.5 non-enzyme simulated gastric acid solution (SGF) at 37°C, and the rotation speed is set to 50 rpm. At 1, 2 h, the release medium (3 mL) is removed, and the same temperature and volume of SGF is added. After the removed release medium is diluted to 10 mL with pure water, the absorbance of berberine is determined at 263 nm using a UV-visible spectrophotometer. After 2 h of release, 50 mL of 2.0 mol / L potassium dihydrogen phosphate solution is added to the above-mentioned release medium, and the pH is adjusted to 6.8 to obtain a non-enzyme simulated intestinal fluid (SIF). At 2, 4, 6, 8 h, 3 mL of the release medium is removed and the same temperature and volume of non-enzyme SIF is added. After the removed release medium is diluted to 10 mL with pure water, the absorbance of berberine is determined at 263 nm using a UV-visible spectrophotometer, and the cumulative release rate of berberine is calculated. The results are shown in Table 1 and Figure 3 .

[0081] Table 1 Test results of the tablets of the examples and the comparative examples

[0082]

[0083]

[0084] The encapsulation rate of berberine in Comparative Example 1 is 39.22%, and the cumulative release rate thereof in the simulated gastric acid solution for 2 h reaches 80.57%, which is mostly released in the gastric acid environment.

[0085] The encapsulation rate of berberine in Comparative Example 2 is only 16.54%, which is significantly lower than that of the other examples and comparative examples.

[0086] In Comparative Example 3, the mass ratio of starch to calcium carbonate is 1:3, although there is a certain sustained-release effect, the drug encapsulation rate is only 23.44%, and the drug loading amount is low.

[0087] In Comparative Example 4, the mass ratio of starch to calcium carbonate is 1:0.125, the cumulative release rate thereof in the simulated gastric acid solution for 2 h is 58.45%, but the final release rate thereof in the pH = 6.8 phosphate buffer solution is only 80.29%, and the release of berberine is not complete.

[0088] In Comparative Example 5, the microwave energy is 437 J, and the encapsulation rate of berberine is significantly lower than that of Example 1, indicating that the input of microwave energy also affects the encapsulation rate and release behavior of berberine.

[0089] The results of the examples of the present application show that the combination of "starch gelatinization-rejuvenation" and the biomimetic mineralization method has a synergistic effect of improving the encapsulation rate of berberine and resisting gastric acid.

Claims

1. A method for preparing a pregelatinized starch / calcium-containing mineral-berberine complex, characterized by, The method comprises the following steps: (1) mixing inorganic acid salt, starch and water, and treating by microwave to obtain a colloidal solution of starch-salt; (2) mixing calcium salt, berberine and ethanol to obtain an ethanol solution containing berberine and calcium salt; (3) adding the colloidal solution of starch-salt prepared in step (1) into the ethanol solution containing berberine and calcium salt prepared in step (2), stirring and reacting, and then performing reslurry treatment, centrifugation, precipitation, drying to obtain pregelatinized starch / calcium-containing mineral-berberine complex; The inorganic acid salt is at least one of carbonates; The mass ratio of the inorganic acid salt, starch and water is 0.52~4.24:2:30; The mass ratio of the calcium salt, berberine and ethanol is 0.43~4.44:0.25:50; In the microwave treatment, the time and frequency of microwave treatment are adjusted so that the microwave energy value obtained per gram of starch is 1310J~4370J; The starch is one or more of corn starch or cassava starch.

2. The process for the preparation of pregelatinized starch / calcium-containing mineral-berberine complexes according to claim 1, characterized in that: In step (1), the inorganic acid salt is sodium carbonate or potassium carbonate.

3. The process for the preparation of pregelatinized starch / calcium containing mineral-berberine complex according to claim 1, characterized by: In step (2), the calcium salt is one or more of calcium chloride, calcium nitrate or calcium acetate.

4. A pregelatinized starch / calcium-containing mineral-berberine complex prepared by the preparation method of any one of claims 1-3.

5. The pregelatinized starch / calcium-containing mineral-berberine complex according to claim 4, characterized in that, The mass ratio of the starch and the calcium-containing mineral in the pregelatinized starch / calcium-containing mineral-berberine complex is 1:0.25~2; and the calcium-containing mineral is calcium carbonate.

6. Use of the pregelatinized starch / calcium-containing mineral-berberine complex of claim 4 in the preparation of a drug for treating intestinal infection, conjunctivitis or suppurative otitis media.

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