Berberine tannate oral preparation and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a berberine tannate oral preparation and a preparation method thereof. The oral preparation comprises berberine tannate, a filling agent, a disintegrating agent, an adhesive and a wetting agent, the filling agent is pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide; the disintegrating agent is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone. The auxiliary materials of the berberine tannate oral preparation cooperate with one another, so that the flowability and compressibility of the powder are effectively improved, and the obtained final preparation product is excellent in stability and dissolution property and high in bioavailability; in addition, the oral preparation is simple in preparation process and suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to an oral berberine tannate preparation and a preparation method thereof. Background Art

[0002] Berberine tannate, also known as coptis chinensis, is an important alkaloid that can be extracted from plants such as coptis chinensis, phellodendron chinense, and trifoliate needles. It has antibacterial, anti-inflammatory, antiviral and antioxidant effects and is often used to treat intestinal infections, sores and inflammation. Berberine tannate, a drug for gastrointestinal diseases, decomposes into berberine and tannic acid in the intestines. The former has antibacterial effects and has inhibitory effects on a variety of Gram-positive and Gram-negative bacteria in vitro, including hemolytic streptococci, Staphylococcus aureus, Vibrio cholerae, meningococci, Shigella, Salmonella typhi, and Corynebacterium diphtheriae; the latter has an astringent effect. In addition, in vitro experiments have confirmed that berberine can enhance the phagocytic ability of white blood cells and the liver reticuloendothelial system.

[0003] Berberine tannate is slightly soluble in water, and easily soluble in solvents such as alcohol, ether and chloroform. There are generally stability problems in the preparation process of the preparation. The main dosage forms of berberine tannate are tablets or liquid suspensions. Tablets have the problems of difficulty in swallowing for children, poor medication compliance and inconvenience in taking small doses. Liquid suspensions have the disadvantages of large size, inconvenient carrying and storage, and poor drug stability.

[0004] Chinese invention patent application CN115212172A discloses a berberine tannate suspension granule for children and a preparation method thereof. Berberine tannate with poor water solubility is made into a suspension granule with a filler, a suspending agent, and a flavoring agent. When taken, it can be dispersed into a uniform suspension by adding water and shaking, thus solving the problem of inconvenience in taking medicine for children. However, its solubility only reaches the minimum limit specified in the "Chinese Pharmacopoeia Inspection Standard Operation Specification", which affects the efficacy of the medicine to a certain extent.

[0005] In the process of oral preparation development, preparation stability, dissolution and bioavailability are the main aspects that R&D personnel need to pay attention to. These properties are not only related to the preparation process, but also closely related to the selection of excipients. On the one hand, excipients affect the content uniformity, disintegration and dissolution performance of active ingredients, and the stability of active ingredients; on the other hand, they also affect the processing performance of preparations such as powder flowability, compressibility, granulation performance and uniformity. In the research of berberine tannate oral preparations, there is still a technical gap in improving the stability and dissolution of preparations through excipients. Summary of the invention

[0006] In view of the problems existing in the prior art, the present invention provides an oral berberine tannate preparation and a preparation method thereof. In the study of the oral preparation, the properties of various auxiliary materials and their mutual coordination, as well as the optimization of the preparation process, are utilized to effectively improve the stability, dissolution characteristics and bioavailability of the preparation, and the preparation process is simple and suitable for large-scale production.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] The present invention provides an oral preparation of berberine tannate, which comprises: berberine tannate, a filler, a binder, a wetting agent and a disintegrant; the filler is pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide; the disintegrant is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinyl pyrrolidone.

[0009] Furthermore, the composition comprises, by weight: 0.5-25 parts of berberine tannate, 25-60 parts of pregelatinized starch, 10-35 parts of microcrystalline cellulose, 1-10 parts of colloidal silicon dioxide, 1-5 parts of disintegrant, 1-15 parts of binder and 0.5-1.5 parts of wetting agent.

[0010] Furthermore, the composition comprises, by weight: 5-15 parts of berberine tannate, 40-60 parts of pregelatinized starch, 15-20 parts of microcrystalline cellulose, 1-5 parts of colloidal silicon dioxide, 3-5 parts of disintegrant, 8-15 parts of binder and 0.5-1 part of wetting agent.

[0011] Furthermore, the mass ratio of the pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide is 1:(0.2-1):(0.01-0.06).

[0012] The binder is selected from one or more of ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; the wetting agent is selected from one or more of magnesium stearate, sodium stearyl fumarate and povidone.

[0013] The present invention also provides a method for preparing any of the above-mentioned berberine tannate oral preparations, comprising the following steps:

[0014] (1) mixing berberine tannate and a filler and performing a micronization treatment to obtain a mixed powder;

[0015] (2) dissolving the binder in water to obtain solution A;

[0016] (3) Adding the mixed powder to solution A to prepare a soft material, and granulating it;

[0017] (4) After granulation, add disintegrant and wetting agent, mix well, and press into tablets.

[0018] Furthermore, in step (1), the particle size of the mixed powder after micronization is in the range of 0.04-0.08 μm.

[0019] Furthermore, the mass concentration of the binder in the solution A is 5-20%.

[0020] Furthermore, in step (3), the mixed powder is added in two times, the first time the temperature is raised to 60-80°C and the second time the temperature is room temperature.

[0021] Furthermore, the amount of the mixed powder added for the first time accounts for 30-50% of the total mass of the mixed powder; and the amount of the mixed powder added for the second time accounts for 50-70% of the total mass of the mixed powder.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) The berberine tannate oral preparation of the present invention uses pregelatinized starch, microcrystalline cellulose, and colloidal silicon dioxide as fillers. Pregelatinized starch can significantly improve the fluidity and compressibility of the preparation in the presence of colloidal silicon dioxide. Microcrystalline cellulose has strong water absorption and swelling properties, which promotes the entry of water into the preparation and plays a role in rapid disintegration. The three cooperate with each other to effectively disperse the API. The specific disintegrant is then used to further accelerate the disintegration, so that the preparation has both compressibility and rapid dissolution characteristics.

[0024] (2) The auxiliary filler and the binder in the preparation of the present invention have a significant synergistic effect, which not only improves the formability of the preparation, but also improves the stability and disintegration of the preparation;

[0025] (3) In addition, the wetting agent selected in the present invention has strong compatibility, ensures smooth tableting, and can effectively avoid problems such as disintegration of the preparation and poor dissolution caused by too long tableting time;

[0026] (4) The present invention further improves the fluidity and compressibility of the preparation by optimizing the preparation process, especially the micronization of API, filler and binder, and the adjustment of their addition methods, thus laying a foundation for improving the stability and solubility of the preparation. DETAILED DESCRIPTION

[0027] To make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention is clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the art without creative work are within the scope of protection of the present invention. If the specific conditions are not specified in the examples, they are carried out under normal conditions. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0028] Example 1

[0029] A berberine tannate oral preparation comprises: 8 parts of berberine tannate, 50 parts of pregelatinized starch, 20 parts of microcrystalline cellulose, 3 parts of colloidal silicon dioxide, 8 parts of hydroxypropyl methylcellulose, 3 parts of cross-linked carboxymethyl cellulose sodium and 1 part of sodium stearyl fumarate.

[0030] The preparation method is as follows:

[0031] (1) adding berberine tannate, pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide to a jet mill for ultrafine grinding to obtain a mixed powder (particle size of about 0.05 μm);

[0032] (2) dissolving hydroxypropyl methylcellulose in water to prepare a hydroxypropyl methylcellulose solution with a mass concentration of 8%;

[0033] (3) (by mass) adding 30% of the mixed powder to the hydroxypropyl methylcellulose solution, heating to 80° C., and mixing uniformly; cooling to room temperature, adding the remaining mixed powder, and continuing to mix uniformly to prepare a soft material, sieving to obtain wet granules, and drying to obtain whole granules;

[0034] (4) After granulation, add cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, mix well, and press into tablets to obtain the product.

[0035] Example 2

[0036] A berberine tannate oral preparation comprises: 15 parts of berberine tannate, 60 parts of pregelatinized starch, 10 parts of microcrystalline cellulose, 1 part of colloidal silicon dioxide, 15 parts of ethyl cellulose, 1 part of cross-linked sodium carboxymethyl cellulose and 1.5 parts of magnesium stearate.

[0037] The preparation method is as follows:

[0038] (1) adding berberine tannate, pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide to a jet mill for ultrafine grinding to obtain a mixed powder (particle size of about 0.04 μm);

[0039] (2) dissolving ethyl cellulose in water to prepare a 5% ethyl cellulose solution;

[0040] (3) (by mass) 30% of the mixed powder is added to the ethyl cellulose solution, the temperature is raised to 80°C, and the mixture is mixed uniformly; after the mixture is cooled to room temperature, the remaining mixed powder is added, and the mixture is mixed uniformly to prepare a soft material, which is sieved to obtain wet granules, and then dried to obtain granules;

[0041] (4) After granulation, add cross-linked sodium carboxymethyl cellulose and magnesium stearate, mix well, and press into tablets to obtain the product.

[0042] Example 3

[0043] A berberine tannate oral preparation comprises: 5 parts of berberine tannate, 25 parts of pregelatinized starch, 35 parts of microcrystalline cellulose, 10 parts of colloidal silicon dioxide, 1 part of ethyl cellulose, 5 parts of cross-linked polyvinyl pyrrolidone and 0.5 parts of povidone.

[0044] The preparation method is as follows:

[0045] (1) adding berberine tannate, pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide to a jet mill for ultrafine grinding to obtain a mixed powder (particle size of about 0.07 μm);

[0046] (2) dissolving ethyl cellulose in water to prepare an ethyl cellulose solution with a mass concentration of 15%;

[0047] (3) (by mass) adding 50% of the mixed powder to the ethyl cellulose solution, heating to 80°C, and mixing uniformly; cooling to room temperature, adding the remaining mixed powder, and continuing to mix uniformly to prepare a soft material, sieving to obtain wet granules, and drying to obtain granules;

[0048] (4) After granulation, add cross-linked polyvinyl pyrrolidone and povidone, mix well, and press into tablets to obtain the product.

[0049] Example 4

[0050] A berberine tannate oral preparation comprises: 8 parts of berberine tannate, 30 parts of pregelatinized starch, 35 parts of microcrystalline cellulose, 8 parts of colloidal silicon dioxide, 8 parts of hydroxypropyl methylcellulose, 3 parts of cross-linked carboxymethyl cellulose sodium and 1 part of sodium stearyl fumarate.

[0051] The preparation method is as follows:

[0052] (1) adding berberine tannate, pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide to a jet mill for ultrafine grinding to obtain a mixed powder (particle size of about 0.05 μm);

[0053] (2) dissolving hydroxypropyl methylcellulose in water to prepare a hydroxypropyl methylcellulose solution with a mass concentration of 8%;

[0054] (3) (by mass) adding 30% of the mixed powder to the hydroxypropyl methylcellulose solution, heating to 80° C., and mixing uniformly; cooling to room temperature, adding the remaining mixed powder, and continuing to mix uniformly to prepare a soft material, sieving to obtain wet granules, and drying to obtain whole granules;

[0055] (4) After granulation, add cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, mix well, and press into tablets to obtain the product.

[0056] Example 5

[0057] A berberine tannate oral preparation comprises: 8 parts of berberine tannate, 60 parts of pregelatinized starch, 10 parts of microcrystalline cellulose, 3 parts of colloidal silicon dioxide, 8 parts of hydroxypropyl methylcellulose, 3 parts of cross-linked carboxymethyl cellulose sodium and 1 part of sodium stearyl fumarate.

[0058] The preparation method is as follows:

[0059] (1) adding berberine tannate, pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide to a jet mill for ultrafine grinding to obtain a mixed powder (particle size of about 0.05 μm);

[0060] (2) dissolving hydroxypropyl methylcellulose in water to prepare a hydroxypropyl methylcellulose solution with a mass concentration of 8%;

[0061] (3) (by mass) adding 30% of the mixed powder to the hydroxypropyl methylcellulose solution, heating to 80° C., and mixing uniformly; cooling to room temperature, adding the remaining mixed powder, and continuing to mix uniformly to prepare a soft material, sieving to obtain wet granules, and drying to obtain whole granules;

[0062] (4) After granulation, add cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, mix well, and press into tablets to obtain the product.

[0063] Comparative Example 1

[0064] A berberine tannate oral preparation, which differs from Example 1 only in that the composition is different, and an equal amount of lactose is used instead of pregelatinized starch; specifically: 8 parts of berberine tannate, 50 parts of lactose, 20 parts of microcrystalline cellulose, 3 parts of colloidal silicon dioxide, 8 parts of hydroxypropyl methylcellulose, 3 parts of cross-linked carboxymethyl cellulose sodium and 1 part of sodium stearyl fumarate.

[0065] Comparative Example 2

[0066] A berberine tannate oral preparation, which differs from Example 1 only in the composition and does not contain colloidal silicon dioxide; specifically: 8 parts of berberine tannate, 52.15 parts of pregelatinized starch, 20.85 parts of microcrystalline cellulose, 8 parts of hydroxypropyl methylcellulose, 3 parts of cross-linked sodium carboxymethyl cellulose and 1 part of sodium stearyl fumarate.

[0067] Comparative Example 3

[0068] A berberine tannate oral preparation, which differs from Example 1 only in the composition and does not contain pregelatinized starch; specifically: 8 parts of berberine tannate, 63.5 parts of microcrystalline cellulose, 9.5 parts of colloidal silicon dioxide, 8 parts of hydroxypropyl methylcellulose, 3 parts of cross-linked sodium carboxymethyl cellulose and 1 part of sodium stearyl fumarate.

[0069] Comparative Example 4

[0070] A berberine tannate oral preparation, which differs from Example 1 only in the composition and does not contain microcrystalline cellulose; specifically: 8 parts of berberine tannate, 69 parts of pregelatinized starch, 4 parts of colloidal silicon dioxide, 8 parts of hydroxypropyl methylcellulose, 3 parts of cross-linked sodium carboxymethyl cellulose and 1 part of sodium stearyl fumarate.

[0071] Comparative Example 5

[0072] A berberine tannate oral preparation, which differs from Example 1 only in the composition and does not contain hydroxypropyl methylcellulose; specifically: 8 parts of berberine tannate, 55.5 parts of pregelatinized starch, 22.2 parts of microcrystalline cellulose, 3.3 parts of colloidal silicon dioxide, 3 parts of cross-linked sodium carboxymethyl cellulose and 1 part of sodium stearyl fumarate.

[0073] Comparative Example 6

[0074] A berberine tannate oral preparation, which differs from Example 1 only in the composition, does not contain pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide; specifically: 8 parts of berberine tannate, 81 parts of hydroxypropyl methylcellulose, 3 parts of cross-linked sodium carboxymethyl cellulose and 1 part of sodium stearyl fumarate.

[0075] Comparative Example 7

[0076] An oral preparation of berberine tannate, which differs from Example 1 only in the preparation method, specifically:

[0077] (1) adding berberine tannate, pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide to a jet mill for ultrafine grinding to obtain a mixed powder (particle size of about 0.05 μm);

[0078] (2) dissolving hydroxypropyl methylcellulose in water to prepare a hydroxypropyl methylcellulose solution with a mass concentration of 8%;

[0079] (3) adding the mixed powder to the hydroxypropyl methylcellulose solution and mixing evenly to prepare a soft material, sieving to obtain wet granules, and drying to obtain granules;

[0080] (4) After granulation, add cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, mix well, and press into tablets to obtain the product.

[0081] Comparative Example 8

[0082] An oral preparation of berberine tannate, which differs from Example 1 only in the preparation method, specifically:

[0083] (1) adding berberine tannate, pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide to a jet mill for ultrafine grinding to obtain a mixed powder (particle size of about 0.05 μm);

[0084] (2) dissolving hydroxypropyl methylcellulose in water to prepare a hydroxypropyl methylcellulose solution with a mass concentration of 8%;

[0085] (3) (by mass) adding 30% of the mixed powder to the hydroxypropyl methylcellulose solution and mixing evenly; adding the remaining mixed powder and continuing to mix evenly to prepare a soft material, sieving to obtain wet granules, and drying to obtain whole granules;

[0086] (4) After granulation, add cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, mix well, and press into tablets to obtain the product.

[0087] Comparative Example 9

[0088] The berberine tannate tablets prepared by the formulation and preparation process of Example 1 of Patent ZL200910136682.8 have a prescription composition of: 50 parts of berberine tannate, 5 parts of low-substituted hydroxypropyl cellulose, 4 parts of sodium hydroxymethyl starch, 20 parts of pregelatin sodium starch, 106 parts of mannitol, 5.6 parts of micropowder silica gel, 6 parts of talc, 3 parts of magnesium stearate, and 0.4 parts of sodium saccharin.

[0089] The preparation method is as follows:

[0090] (1) Weigh berberine tannate and mannitol according to the prescription amount, mix well, and pass through a 100-mesh sieve;

[0091] (2) Weigh the amount of Qiyu excipients according to the prescription, mix well, and pass through a 100-mesh sieve;

[0092] (3) The raw materials of step (1) and step (2) are mixed, passed through a 100-mesh sieve, and pressed into tablets.

[0093] Test Example 1: Formulation Performance

[0094] According to the general rules 9001 Guidelines for stability testing of raw materials and preparations and 0923 Tablet friability test method of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the hardness and friability of the oral preparations prepared in the above embodiments and comparative examples were tested, and the results are shown in Table 1.

[0095] Table 1 Test results of molding properties of berberine tannate oral preparations

[0096] Preparation Hardness(kg) Friability (%) Example 1 Preparation goes smoothly 6.5 0.39 Example 2 Preparation goes smoothly 6.3 0.42 Example 3 Preparation goes smoothly 6.6 0.37 Example 4 Preparation goes smoothly 6.8 0.36 Example 5 Preparation goes smoothly 7.0 0.35 Comparative Example 1 Slightly sticky 7.8 0.30 Comparative Example 2 Moderate sticky screen 5.4 0.73 Comparative Example 3 Moderate sticky screen 5.2 0.75 Comparative Example 4 Moderate sticky screen 5.6 0.85 Comparative Example 5 Slightly sticky 6.8 0.52 Comparative Example 6 Slightly sticky 8.7 0.21 Comparative Example 7 Slightly sticky 8.9 0.18 Comparative Example 8 Severe sticking 3.1 1.05 Comparative Example 9 Preparation goes smoothly 6.1 0.45

[0097] As can be seen from the above table, the berberine tannate in Examples 1-5 was prepared smoothly, with a hardness between 6.3-7.0 kg and a friability between 0.35-0.42, all meeting the requirements; Comparative Examples 1-8 all showed varying degrees of sticking to the sieve, and the berberine tannate prepared in Comparative Examples 2-4 and Comparative Example 8 had a lower hardness, a higher friability, and poor molding performance. It can be seen that the lack of any one of pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide in the filler will have a great impact on the molding of the preparation; in addition, the temperature during the wet granulation process did not meet the requirements, which would make it difficult to mold during tableting; since the molding of the preparations of Comparative Examples 2-4 and Comparative Example 8 could not meet the requirements, they would no longer be tested for stability, dissolution and bioavailability.

[0098] Test Example 2: Stability Test

[0099] In accordance with the guidelines for stability testing of raw materials and preparations in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the oral preparations prepared in the above embodiments and comparative examples were placed under accelerated conditions of temperature 40±2°C and relative humidity 75±5%RH for 6 months, and the changes in related substances were used as indicators to evaluate their stability. The results are shown in Table 2.

[0100] Table 2 Stability results of berberine tannate oral preparations under accelerated conditions

[0101]

[0102] As can be seen from the above table, the maximum single impurity of the berberine tannate oral preparation prepared in Examples 1-5 does not exceed 0.075% and the total impurity does not exceed 0.10% after 6 months of acceleration. The changes in impurities in the examples after 6 months of acceleration do not exceed 5%, and the stability of the preparation is better; after acceleration, the maximum single impurity and total impurity of Comparative Example 1 increase rapidly, which shows that when the filler does not contain colloidal silica, it will have a certain impact on the stability of the preparation. Secondly, the maximum single impurity and total impurity of the preparations prepared in Comparative Examples 5 and 6, respectively, increased by more than double after 6 months of acceleration, indicating that the filler and the binder of the present invention play a synergistic role in improving the stability of the preparation. Compared with Example 1, in the wet granulation process of Comparative Example 7, the one-time addition of the mixed powder will lead to uneven mixing. The maximum single impurity and total impurity increase by about 1 times after 3 months of acceleration, and the maximum single impurity and total impurity increase by about 2 times after 6 months of acceleration, and the stability is greatly reduced. The addition method of the mixed powder also has a great influence on the stability of the preparation. Finally, the maximum single impurity and total impurity of the berberine tannate dispersible tablets prepared in Comparative Example 9 increased by more than 1 times after accelerated growth for 6 months, and the stability was also poor.

[0103] Test Example 3: Disintegration time and dissolution test

[0104] According to the general rule 0921 disintegration time test method and general rule 0931 dissolution and release determination method of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the disintegration time and dissolution of the oral preparations prepared in the comparative examples of the above embodiments were tested, and the results are shown in Tables 3 and 4.

[0105] Table 3 Disintegration time results of berberine tannate oral preparation

[0106] Disintegration time(s) Example 1 15 Example 2 1 8 Example 3 20 Example 4 16 Example 5 15 Comparative Example 1 48 Comparative Example 5 33 Comparative Example 6 45 Comparative Example 7 25 Comparative Example 9 19

[0107] Table 4 Dissolution results of berberine tannate oral preparation

[0108] 5min 10min 15min 20min 30min 60min Example 1 68.54 79.33 89.45 92.14 95.87 99.85 Example 2 64.28 76.54 86.49 91.17 94.84 98.15 Example 3 65.11 75.36 85.97 90.24 93.33 97.20 Example 4 66.34 78.42 90.01 92.47 96.03 99.47 Example 5 69.81 79.03 88.52 92.08 94.57 99.18 Comparative Example 1 38.29 42.34 48.99 60.50 75.25 96.37 Comparative Example 5 45.12 54.54 62.17 72.11 83.93 86.10 Comparative Example 6 47.51 56.69 66.33 75.24 85.50 88.87 Comparative Example 7 66.37 74.52 83.42 84.13 87.42 89.10 Comparative Example 9 35.22 58.49 69.32 80.21 83.44 93.58

[0109] It can be seen from the above table that the disintegration time of the berberine tannate oral preparations prepared in Examples 1-5 of the present invention is within 20 seconds, and the fastest can reach 15 seconds; the cumulative dissolution rate at 15 mmin is all above 85%, and the highest is above 90%; it meets the requirements. Compared with Example 1, the type of filler in Comparative Example 1 is different, and the disintegration time is significantly prolonged. This may be related to the high hardness of the preparation. The dissolution rate in the early stage (before 10 minutes) is much slower than that in Example 1. As time goes on, it can reach a dissolution level close to that of Example 1 at 60 mmin; the disintegration time of the berberine tannate oral preparations prepared in Comparative Examples 5 and 6 is more than 30 seconds, and the cumulative dissolution rate at 15 mmin is less than 75%. Compared with Example 1, the dissolution rate and dissolution degree are both poor. It can be seen that the filler and the binder of the present invention are different. With the cooperation of, the preparation can be guaranteed to dissolve continuously and stably; the disintegration time and the early (before 15mmin) dissolution of comparative example 7 are only slightly worse than those of example 1, and only the later dissolution is greatly limited. It can be seen that insufficient mixing will affect the sufficient dissolution of the active ingredients of the preparation, and then affect its utilization rate; the disintegration time of berberine tannate dispersible tablets prepared in comparative example 9 is relatively short, which is equivalent to the level of the oral preparation of the present invention; the cumulative dissolution in 60min can reach more than 90%, but the dissolution in 15min is less than 85%, which does not meet the requirements.

[0110] Test Example 4: Blood drug concentration test

[0111] This experiment investigated the changes in blood concentration of berberine tannate oral preparations prepared in the comparative examples of the above-mentioned embodiments. Thirty-nine SD rats, half male and half female, weighing 140±10g, were randomly divided into 13 groups, 3 rats in each group, and given the berberine tannate oral preparations prepared in Examples 1-5 and Comparative Examples 1-8 (dosage 20mg / kg), respectively. About 300μL of whole blood was collected from the retro-orbital venous plexus of the rats in a heparinized EP tube before administration (0h) and 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 36h, and 48h after administration, and the plasma was collected by centrifugation; the plasma samples of each group were subjected to HPLC detection, the blood concentration of berberine tannate was quantitatively analyzed, and the peak concentration (Cmax and peak time (T max ) and the area under the drug-time curve (AUC) were statistically analyzed and the results are shown in Table 5.

[0112] Table 5 Results of changes in blood concentration of berberine tannate oral preparations

[0113] <![CDATA[C max (ng / mL)]]> <![CDATA[T max (h)]]> <![CDATA[AUC 0-48 (ng·h / mL)]]> Example 1 25.14±2.47 2.41±0.14 145.50±25.12 Example 2 22.37±2.05 3.04±0.58 135.25±18.33 Example 3 24.66±2.40 2.71±0.42 142.18±28.15 Example 4 20.41±3.12 3.15±0.44 140.57±19.47 Example 5 21.36±2.28 2.97±0.23 138.24±20.06 Comparative Example 1 <![CDATA[18.25±1.51 * ]]> <![CDATA[8.46±2.22 * ]]> <![CDATA[120.51±14.85 * ]]> Comparative Example 5 19.42±0.75 <![CDATA[15.45±0.84 * ]]> 136.24±19.90 Comparative Example 6 <![CDATA[12.36±1.38 ** ]]> <![CDATA[9.26±2.14 * ]]> <![CDATA[111.40±13.32 * ]]> Comparative Example 7 <![CDATA[10.42±1.24 ** ]]> <![CDATA[15.25±2.87 ** ]]> <![CDATA[105.45±18.59 ** ]]> Comparative Example 9 <![CDATA[16.66±1.28 * ]]> <![CDATA[10.31±2.45 * ]]> <![CDATA[118.35±12.25 * ]]>

[0114] Remark: * p<0.05, compared with Example 1, there is a significant difference; ** p<0.01, which is significantly different from Example 1.

[0115] As can be seen from the above table, the berberine tannate oral preparations prepared in Examples 1-5 of the present invention have higher absorption rates and absorption degrees in rats. Compared with Example 1, Comparative Example 1 has different filler types, and C max , AUC 0-48 Both decreased, but there was no significant difference. max The T of Comparative Example 5 is significantly prolonged, which shows that the present invention can significantly improve the absorption rate of the drug through the selection of the filler, and improve the absorption degree of the drug to a certain extent; compared with Example 1, the T of Comparative Example 5 is max There is a significant difference, but C max and AUC 0-48 There is no significant difference; C of Comparative Example 6 max , T max and AUC 0-48 There are significant differences, indicating that the filler and the binder work synergistically to improve the absorption of the preparation in rats; Finally, in the preparation process of the berberine tannate oral preparation of Comparative Example 7, the mixed powder is added to the binder solution at one time. Compared with Example 1, C max , T max and AUC 0-48 There are significant differences, which can explain that during the mixing process of the mixed powder of the active ingredient and the filler with the binder solution, the addition method will directly affect the mixing uniformity of the preparation and indirectly affect the absorption rate and degree of the drug. Finally, the berberine tannate dispersible tablets prepared in Comparative Example 9 have a slow absorption rate and a low absorption degree compared with the berberine tannate preparation of Example 1 of the present invention, and there are significant differences.

[0116] In general, compared with the prior art, the berberine tannate preparation prepared by the present invention has made significant progress in terms of preparation stability, disintegration and dissolution characteristics, and bioavailability, and has greater application value.

[0117] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A berberine tannate oral preparation, characterized in that: The oral preparation comprises: berberine tannate, a filler, a disintegrant, a binder and a wetting agent; the filler is pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide; the disintegrant is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinyl pyrrolidone.

2. The berberine tannate oral preparation according to claim 1, characterized in that: The invention comprises, by weight: 0.5-25 parts of berberine tannate, 25-60 parts of pregelatinized starch, 10-35 parts of microcrystalline cellulose, 1-10 parts of colloidal silicon dioxide, 1-5 parts of disintegrant, 1-15 parts of binder and 0.5-1.5 parts of wetting agent.

3. The berberine tannate oral preparation according to claim 2, characterized in that: The invention comprises, by weight: 5-15 parts of berberine tannate, 40-60 parts of pregelatinized starch, 15-20 parts of microcrystalline cellulose, 1-5 parts of colloidal silicon dioxide, 3-5 parts of disintegrant, 8-15 parts of binder and 0.5-1 part of wetting agent.

4. The berberine tannate oral preparation according to claim 1, characterized in that: The mass ratio of the pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide is 1:(0.2-1):(0.01-0.06).

5. The berberine tannate oral preparation according to claim 1, characterized in that: The binder is selected from one or more of ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; the wetting agent is selected from one or more of magnesium stearate, sodium stearyl fumarate and povidone.

6. The method for preparing the berberine tannate oral preparation according to any one of claims 1 to 5, characterized in that: The following steps are involved: (1) mixing berberine tannate and a filler and performing a micronization treatment to obtain a mixed powder; (2) dissolving the binder in water to obtain solution A; (3) Adding the mixed powder to solution A to prepare a soft material, and granulating it; (4) After granulation, add disintegrant and wetting agent, mix well, and press into tablets.

7. The preparation method according to claim 6, characterized in that: In step (1), the particle size of the mixed powder after micronization is in the range of 0.04-0.08 μm.

8. The preparation method according to claim 6, characterized in that: The mass concentration of the binder in the solution A is 5-20%.

9. The preparation method according to claim 6, characterized in that: In step (3), the mixed powder is added in two times, the first time the temperature is raised to 60-80°C and the second time it is added at room temperature.

10. The preparation method according to claim 9, characterized in that: The amount of powder added in the first mixing accounts for 30-50% of the total mass of the mixed powder; the amount of powder added in the second mixing accounts for 50-70% of the total mass of the mixed powder.

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