An oral preparation of berberine tannate and its preparation method

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to an oral preparation of berberine tannate and a preparation method thereof. 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 carboxymethyl cellulose sodium and cross-linked polyvinylpyrrolidone. Each auxiliary material of the oral preparation of berberine tannate cooperates synergistically, effectively improving the fluidity and compressibility of the powder, and obtaining a final preparation product with excellent stability and dissolution property and high bioavailability; in addition, the preparation process of the oral preparation is simple and suitable for large-scale production.

Description

Technical Field

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

[0002] Berberine tannate, also known as coptisine, is an important alkaloid that can be extracted from plants such as Coptis chinensis, Phellodendron amurense, and Berberis vulgaris. It has antibacterial, anti-inflammatory, antiviral, and antioxidant effects and is commonly used to treat diseases such as intestinal infections, sores, and inflammations. As a drug for gastrointestinal diseases, berberine tannate decomposes into berberine and tannic acid in the intestine. The former has antibacterial effects and can inhibit a variety of Gram-positive and Gram-negative bacteria in vitro. Among them, it has strong inhibitory effects on hemolytic streptococcus, Staphylococcus aureus, Vibrio cholerae, Neisseria meningitidis, Shigella, Salmonella typhi, Corynebacterium diphtheriae, etc.; the latter has astringent effects. In addition, in vitro tests have confirmed that berberine can enhance the phagocytic ability of white blood cells and the reticuloendothelial system of the liver.

[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 problems such as difficulty in swallowing for children, poor medication compliance, and inconvenience in taking small doses. Liquid suspensions have disadvantages such as large volume, inconvenient storage and transportation, and poor drug stability.

[0004] Chinese Patent Application CN115212172A discloses a pediatric berberine tannate suspension granule 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 shaking with water, solving the problem of inconvenient medication for children; however, its dissolution rate only reaches the minimum limit specified in the "Chinese Pharmacopoeia Inspection Standard Operating Specification", which affects the efficacy of the drug to a certain extent.

[0005] During the research and development of oral preparations, the stability, dissolution rate, and bioavailability of the preparation are the main aspects that researchers need to focus on. 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, and stability of the active ingredient, etc.; on the other hand, they also affect the processing performance of the preparation such as powder fluidity, 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 rate of the preparation through excipients. Summary of the Invention

[0006] In view of the problems existing in the prior art, the present invention provides an oral preparation of berberine tannate and a preparation method thereof. In the research of this oral preparation, by utilizing the properties of various excipients and their mutual cooperation, as well as the optimization of the preparation process, the stability, dissolution characteristics and bioavailability of the preparation are effectively improved, and the preparation process is simple and suitable for large-scale production.

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

[0008] The present invention provides an oral preparation of berberine tannate, and the oral preparation includes: 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 carboxymethyl cellulose sodium and cross-linked polyvinylpyrrolidone.

[0009] Further, by weight, it includes: 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] Still further, by weight, it includes: 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] Further, 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 polyvinylpyrrolidone.

[0013] The present invention also provides a preparation method of the oral preparation of berberine tannate according to any one of the above, including the following steps:

[0014] (1) Mix berberine tannate with the filler and carry out micronization treatment to obtain a mixed powder;

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

[0016] (3) Add the mixed powder into solution A, prepare soft materials and granulate;

[0017] (4) After granulation, add the disintegrant and the wetting agent, mix evenly and press into tablets to obtain the product.

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

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

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

[0021] Further, the amount of the mixed powder added for the first time accounts for 30 - 50% of the total mass of the mixed powder; 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 silica as fillers. In the presence of colloidal silica, pregelatinized starch can significantly improve the fluidity and compressibility of the preparation. Microcrystalline cellulose has strong water absorption and swelling properties, which can promote the entry of water into the interior of the preparation and play a role in rapid disintegration. The three cooperate with each other to effectively disperse the API; combined with a specific disintegrant to further accelerate disintegration, making the preparation have both compressibility and rapid dissolution characteristics;

[0024] (2) In the preparation of the present invention, the synergistic effect of the excipient filler and the binder is significant, 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 the smooth progress of tabletting, and can effectively avoid problems such as disintegration and poor dissolution of the preparation caused by too long tabletting time;

[0026] (4) The present invention further optimizes the preparation process, especially the micronization treatment of the API, filler, and binder, and the adjustment of their addition methods, which also improves the fluidity and compressibility of the preparation, laying a foundation for the improvement of the stability and dissolution of the preparation. Specific Embodiments

[0027] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention. Those not specified in the examples are carried out under conventional conditions. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0028] Example 1

[0029] An oral berberine tannate preparation, consisting of: 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 carboxymethylcellulose sodium, and 1 part of sodium stearyl fumarate.

[0030] The preparation method is as follows:

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

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

[0033] (3) (By mass) Take 30% of the mixed powder and add it to the hydroxypropyl methylcellulose solution, heat up to 80 °C, and mix evenly; after cooling to room temperature, add the remaining mixed powder and continue to mix evenly to prepare a soft material, sieve to obtain wet granules, and granulate after drying;

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

[0035] Example 2

[0036] An oral berberine tannate preparation, consisting of: 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 carboxymethylcellulose sodium, and 1.5 parts of magnesium stearate.

[0037] The preparation method is as follows:

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

[0039] [[ID=3 / 4]](2) Dissolve ethyl cellulose in water to prepare an ethyl cellulose solution with a mass concentration of 5%;

[0040] (3) (By mass) Take 30% of the mixed powder and add it to the ethyl cellulose solution, heat up to 80 °C, and mix evenly; after cooling to room temperature, add the remaining mixed powder and continue to mix evenly to prepare a soft material, sieve to obtain wet granules, and granulate after drying;

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

[0042] Example 3

[0043] An oral preparation of berberine tannate, with the composition: 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 polyvinylpyrrolidone, and 0.5 part of polyvinylpyrrolidone.

[0044] The preparation method is as follows:

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

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

[0047] (3) (By mass) Take 50% of the mixed powder and add it to the ethyl cellulose solution, heat up to 80 °C, mix evenly; after cooling to room temperature, add the remaining mixed powder, continue to mix evenly to prepare a soft material, sieve to obtain wet granules, and granulate after drying;

[0048] (4) After granulating, add cross-linked polyvinylpyrrolidone and polyvinylpyrrolidone, mix evenly, and press tablets to obtain the product.

[0049] Example 4

[0050] An oral preparation of berberine tannate, with the composition: 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) Take berberine tannate, pregelatinized starch, microcrystalline cellulose, and colloidal silicon dioxide and add them to a jet mill for ultrafine grinding to obtain a mixed powder (particle size about 0.05 μm);

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

[0054] (3) (By mass) Take 30% of the mixed powder and add it to the hydroxypropyl methylcellulose solution, heat up to 80 °C, mix evenly; after cooling to room temperature, add the remaining mixed powder, continue to mix evenly to prepare a soft material, sieve to obtain wet granules, and granulate after drying;

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

[0056] Example 5

[0057] An oral berberine tannate preparation, the composition of which is as follows: 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) Take berberine tannate, pregelatinized starch, microcrystalline cellulose, and colloidal silicon dioxide, add them to a fluid energy mill for ultrafine grinding to obtain a mixed powder (particle size about 0.05 μm);

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

[0061] (3) (By mass) Take 30% of the mixed powder and add it to the hydroxypropyl methylcellulose solution, heat up to 80 °C, mix evenly; after cooling to room temperature, add the remaining mixed powder, continue to mix evenly to prepare a soft material, pass through a sieve to obtain wet granules, and granulate after drying;

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

[0063] Comparative Example 1

[0064] An oral berberine tannate preparation, which is only different from Example 1 in composition, and uses an equal amount of lactose to replace 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] An oral berberine tannate preparation, which is only different from Example 1 in 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 carboxymethyl cellulose sodium, and 1 part of sodium stearyl fumarate.

[0067] Comparative Example 3

[0068] An oral berberine tannate preparation, which is only different from Example 1 in 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 carboxymethyl cellulose sodium, and 1 part of sodium stearyl fumarate.

[0069] Comparative Example 4

[0070] A berberine tannate oral preparation, which is only different from Example 1 in 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 carboxymethylcellulose sodium, and 1 part of sodium stearyl fumarate.

[0071] Comparative Example 5

[0072] A berberine tannate oral preparation, which is only different from Example 1 in 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 carboxymethylcellulose sodium, and 1 part of sodium stearyl fumarate.

[0073] Comparative Example 6

[0074] A berberine tannate oral preparation, which is only different from Example 1 in composition and 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 carboxymethylcellulose sodium, and 1 part of sodium stearyl fumarate.

[0075] Comparative Example 7

[0076] A berberine tannate oral preparation, which is only different from Example 1 in the preparation method, specifically:

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

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

[0079] (3) Add the mixed powder to the hydroxypropyl methylcellulose solution, mix evenly, prepare soft materials, sieve to obtain wet granules, and granulate after drying;

[0080] (4) After granulation, add cross-linked carboxymethylcellulose sodium and sodium stearyl fumarate, mix evenly and press tablets to obtain.

[0081] Comparative Example 8

[0082] A berberine tannate oral preparation, which is only different from Example 1 in the preparation method, specifically:

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

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

[0085] (3) Take 30% of the mixed powder (by mass) and add it to the hydroxypropyl methylcellulose solution, mix evenly; add the remaining mixed powder, continue to mix evenly to prepare soft materials, pass through a sieve to obtain wet granules, and size the granules after drying;

[0086] (4) After sizing, add sodium croscarmellose and sodium stearyl fumarate, mix evenly, and press tablets to obtain the product.

[0087] Comparative Example 9

[0088] The berberine tannate tablets prepared by using the formulation and preparation process of Example 1 of Patent ZL200910136682.8 have the following prescription composition: 50 parts of berberine tannate, 5 parts of low-substituted hydroxypropyl cellulose, 4 parts of sodium carboxymethyl starch, 20 parts of pregelatinized starch sodium, 106 parts of mannitol, 5.6 parts of colloidal silicon dioxide, 6 parts of talc powder, 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 evenly, and pass through a 100-mesh sieve;

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

[0092] (3) Mix the raw materials in steps (1) and (2), pass through a 100-mesh sieve, and press tablets to obtain the product.

[0093] Test Example 1: Forming performance of the preparation

[0094] In accordance with the General Principles 9001 Guidelines for the Stability Testing of Active Pharmaceutical Ingredients and Dosage Forms and the Method for the Examination of Friability of Tablets 0923 in the Fourth Part of the Chinese Pharmacopoeia 2020 Edition, the hardness and friability of the oral preparations prepared in the above examples and comparative examples were detected, and the results are shown in Table 1.

[0095] Table 1 Detection results of the forming performance of berberine tannate oral preparations

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

[0097] As can be seen from the above table, the preparation of berberine tannate in Examples 1-5 was smooth, with the hardness between 6.3-7.0 kg and the friability between 0.35-0.42, all meeting the requirements; in Comparative Examples 1-8, there was sieve sticking to varying degrees. In Comparative Examples 2-4 and 8, the berberine tannate prepared had lower hardness and 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 formability of the preparation; in addition, if the temperature during the wet granulation process does not meet the requirements, it will be difficult to form tablets during tabletting; since the formability of the preparations in Comparative Examples 2-4 and 8 cannot meet the requirements, subsequent stability, dissolution, and bioavailability tests will no longer be carried out on them.

[0098] Test Example 2: Stability Test

[0099] In accordance with the General Principles for the Stability Testing of Bulk Drugs and Preparations 9001 in the Fourth Part of the Chinese Pharmacopoeia (2020 Edition), the oral preparations prepared in the above Examples and Comparative Examples were placed under accelerated conditions of 40±2°C and relative humidity of 75±5% RH for 6 months, and their stability was evaluated with the change of related substances as the index. 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, after 6 months of acceleration, the maximum single impurity of the berberine tannate oral preparations prepared in Examples 1-5 did not exceed 0.075%, and the total impurities did not exceed 0.10%. After 6 months of acceleration in the Examples, the change of impurities did not exceed 5%, and the preparation stability was better; after acceleration in Comparative Example 1, the maximum single impurity and total impurities increased rapidly. It can be seen that when the filler does not contain colloidal silicon dioxide, it will have a certain impact on the preparation stability. Secondly, for Comparative Examples 5 and 6, which are preparations made only with filler and only with binder respectively, after 6 months of acceleration, the maximum single impurity and total impurities increased by more than one time, indicating that the filler and binder of the present invention play a synergistic role in improving the preparation stability. Compared with Example 1, in Comparative Example 7, during the wet granulation process, adding the mixed powder all at once will lead to uneven mixing. After 3 months of acceleration, the maximum single impurity and total impurities both increased by about 1 time, and after 6 months of acceleration, the maximum single impurity and total impurities both increased by about 2 times, and the stability decreased significantly. The addition method of the mixed powder also has a great impact on the preparation stability. Finally, after 6 months of acceleration, the maximum single impurity and total impurities of the berberine tannate dispersible tablets prepared in Comparative Example 9 both increased by more than 1 time, and the stability was also poor.

[0103] Test Example 3: Disintegration Time Limit and Dissolution Test

[0104] The disintegration time limit and dissolution rate of the oral preparations prepared in the above examples and comparative examples were detected in accordance with the disintegration time limit inspection method in General Principles 0921 and the dissolution and release determination method in General Principles 0931 of the Fourth Part of Chinese Pharmacopoeia (2020 Edition). The results are shown in Table 3 and Table 4.

[0105] Table 3 Results of Disintegration Time Limit 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 Results of Dissolution Rate of Berberine Tannate Oral Preparation

[0108] 5 min 10 min 15 min 20 min 30 min 60 min 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] As can be seen from the above table, the disintegration time of the berberine tannate oral preparations prepared in Examples 1-5 of the present invention is within 20 s, and the fastest can reach 15 s; the cumulative dissolution rate at 15 min is above 85%, and the highest reaches above 90%, meeting the requirements. Compared with Example 1, the type of filler in Comparative Example 1 is different, and the disintegration time is significantly prolonged, which may be related to the large hardness of the preparation. The dissolution rate in the early stage (before 10 min) is much slower than that in Example 1. As time prolongs, the dissolution level close to that in Example 1 can be reached at 60 min; the disintegration time of the berberine tannate oral preparations prepared in Comparative Examples 5 and 6 is above 30 s, and the cumulative dissolution rate at 15 min is below 75%. Compared with Example 1, both the dissolution rate and dissolution degree are poor. It can be seen that with the combination of the filler and binder of the present invention, the continuous and stable dissolution of the preparation can be ensured; the disintegration time and the dissolution rate in the early stage (before 15 min) of Comparative Example 7 are only slightly worse than those in Example 1, and only the dissolution in the later stage is greatly limited. It can be seen that insufficient mixing will affect the full dissolution of the active ingredient of the preparation, thereby affecting its utilization rate; the disintegration time of the dispersible tablets of berberine tannate prepared in Comparative Example 9 is short, comparable to the level of the oral preparations of the present invention; the cumulative dissolution rate at 60 min can reach above 90%, but the dissolution rate at 15 min is less than 85%, not meeting the requirements.

[0110] Test Example 4: Blood Drug Concentration Test

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

[0112] Table 5 Results of the changes in plasma drug 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] Note: * p < 0.05, compared with Example 1, there was a significant difference; ** p < 0.01, compared with Example 1, there was a highly significant difference.

[0115] As can be seen from the above table, the berberine tannate oral preparations prepared in Examples 1-5 of the present invention have relatively high absorption rate and absorption degree in rats. Compared with Example 1, in Comparative Example 1, the type of filler is different, and C max , AUC 0-48 both decreased, but there was no significant difference. T max was significantly prolonged. It can be seen that the present invention can significantly improve the absorption rate of drugs and to a certain extent improve the absorption degree by selecting fillers; compared with Example 1, there was a significant difference in T max in Comparative Example 5, but there was no significant difference in C max and AUC 0-48 ; there were significant differences in C max , T max and AUC 0-48 in Comparative Example 6, indicating that the filler and the binder act synergistically to improve the absorption of the preparation in rats; finally, in the preparation of the berberine tannate oral preparation in Comparative Example 7, the mixed powder was added to the binder solution at one time. Compared with Example 1, C max , T max and AUC 0-48 all had significant differences, indicating 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 absorption degree of the drug. Finally, compared with the berberine tannate preparation of Example 1 of the present invention, the berberine tannate dispersible tablets prepared in Comparative Example 9 had a slow absorption rate and a low absorption degree, and there were significant differences.

[0116] Generally speaking, compared with the prior art, the berberine tannate preparations prepared by the present invention have made remarkable progress in terms of preparation stability, disintegration and dissolution characteristics, and bioavailability, and have more 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 limiting the protection scope of the present invention. Any simple modification or equivalent replacement made by those of ordinary skill in the art to the technical solution of the present invention shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. An oral preparation of berberine tannate, characterized in that, The oral preparation includes: berberine tannate, filler, disintegrant, binder and wetting agent; the filler is pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide; the binder is ethyl cellulose or hydroxypropyl methylcellulose; the disintegrant is one or both of sodium carboxymethylcellulose cross-linked and polyvinylpyrrolidone cross-linked; By weight, it includes: 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; The preparation method of the oral preparation includes the following steps: (1) Mix berberine tannate with the filler and conduct micronization treatment to obtain a mixed powder; (2) Dissolve the binder in water to obtain solution A; (3) Add the mixed powder to solution A, prepare soft materials, and granulate; (4) After granulation, add the disintegrant and wetting agent, mix evenly and press tablets to obtain the product; In step (3), the mixed powder is added in 2 times. The first time is added when the temperature is raised to 60 - 80 °C, and the second time is added at room temperature.

2. The berberine tannate oral preparation according to claim 1, wherein By weight, it includes: 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.

3. 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).

4. The berberine tannate oral preparation according to claim 1, wherein The wetting agent is selected from one or more of magnesium stearate, sodium stearyl fumarate and polyvinylpyrrolidone.

5. The preparation method of the berberine tannate oral preparation according to any one of claims 1-4, characterized in that, It includes the following steps: (1) Mix berberine tannate with the filler and conduct micronization treatment to obtain a mixed powder; (2) Dissolve the binder in water to obtain solution A; (3) Add the mixed powder to solution A, prepare soft materials, and granulate; (4) After granulation, add the disintegrant and wetting agent, mix evenly and press tablets to obtain the product; In step (3), the mixed powder is added in 2 times. The first time is added when the temperature is raised to 60 - 80 °C, and the second time is added at room temperature.

6. The preparation method according to claim 5, wherein In step (1), the particle range of the mixed powder after micronization treatment is 0.04 - 0.08 μm.

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

8. The preparation method according to claim 5, characterized in that, The addition amount of the first mixed powder accounts for 30 - 50% of the total mass of the mixed powder; the addition amount of the second mixed powder accounts for 50 - 70% of the total mass of the mixed powder.

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