Glycocholic acid sustained release preparation and production process thereof

Abstract

The invention discloses a glycocholic acid sustained release preparation and a production process thereof. The glycocholic acid sustained-release preparation comprises glycocholic acid sustained-release pellets, and the preparation method of the glycocholic acid sustained-release preparation comprises the following steps: firstly, preparing glycocholic acid and auxiliary materials into a drug-containing pellet core according to a formula, then coating the drug-containing pellet core with a sustained-release material to obtain the sustained-release pellets, and finally, filling the sustained-release pellets into capsules to obtain the glycocholic acid sustained-release preparation. The preparation method comprises the following steps: carrying out wet granulation-extrusion rolling to obtain wet pills, drying, and coating with a fluidized bed to obtain the glycocholic acid sustained-release pellets. The quality of the drug-loaded pellet is controlled according to indexes such as roundness, bulk density, yield and the like, the drug release effect of the sustained-release pellet is evaluated according to the dissolution rate, and the release mechanism and the initial stability of the glycocholic acid sustained-release pellet are investigated. The invention has the advantages of favorable sustained-release effect, reduced medication frequency, simple and feasible preparation process, favorable reproducibility and favorable drug stability, is suitable for industrial production, aims at supporting the research and development of the compound sustained-release drug, and has obvious social and economic benefits.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutics, in particular to a glycocholic acid sustained-release preparation. The present invention also relates to a production process of the sustained-release preparation. Background Art

[0002] Glycocholic acid (GCA) is a conjugated bile acid with the following structural formula:

[0003]

[0004] The chemical name is 3α,7α,12α-trihydroxy-5β-24-cholanoyl-N-glycine, chemical formula: C 26 H 43 NO6, molecular weight: 465.62.

[0005] Glycocholic acid is a conjugated bile acid in which the carboxyl group of bile acid and the amino group of glycine are connected by an amide bond. It is a compound with a steroid nucleus structure and is mainly extracted from animal bile. It is a white crystalline powder. Glycocholic acid is an endogenous substance in animals. Its structure contains both hydrophilic hydroxyl and carboxyl groups and hydrophobic hydrocarbon cores and methyl groups. This makes glycocholic acid have strong interfacial activity, which can reduce the surface tension between oil and water phases, promote lipid emulsification, and expand the contact surface between fat and lipase, accelerate the digestion of lipids, and can be used as an excipient and absorption promoter for drugs in clinical practice. In recent years, it has also been found that glycocholic acid has certain anti-inflammatory, antioxidant, and humoral immunity and non-specific immunity enhancement functions.

[0006] Clinically, glycocholic acid is the main bile acid component in serum during late pregnancy. In normal pregnancy, the level of glycocholic acid in maternal serum gradually increases with gestational age. Pathological increase is common in liver diseases, such as acute hepatitis, moderate chronic hepatitis, primary liver cancer, cirrhosis, etc. Gallbladder diseases, such as cholecystitis, gallstones, biliary ascariasis, etc.

[0007] At present, the research on glycocholic acid is mainly reflected in the pharmacokinetics and pharmacological effects, and there is no report on its development into a preparation. Some literature shows that glycocholic acid is absorbed quickly in rats and is prone to "peak and valley" phenomenon, resulting in low bioavailability; and there is also a document CN109620832B showing that glycocholic acid can be used as an effective active ingredient in the preparation of anti-mammary hyperplasia drugs, so it is urgent to prepare a sustained-release preparation of glycocholic acid.

[0008] Micropellets are a multi-unit oral dosage form, with a diameter generally ranging from 0.5 to 2.5 mm. Each dose can be composed of dozens to hundreds of spherical pellets, which are easy to coat and package, and can be directly made into capsules, tablets or other forms of drugs. The drug release rate is relatively stable, and the gastrointestinal transit is not restricted by the food delivery rhythm and gastric emptying. It has the advantages of large distribution area in the gastrointestinal tract, small local irritation, and high bioavailability. Therefore, making glycocholic acid into a sustained-release preparation can avoid the "peak and valley" phenomenon of the drug in the body, and the blood drug concentration is stable; compared with the powder, the fluidity and stability are significantly improved, which not only makes up for the lack of preparations, but also improves the bioavailability of the drug and promotes the development and utilization of the drug.

[0009] Therefore, there is a need in the art to develop a glycocholic acid sustained-release preparation that has simple prescription and preparation process and excellent therapeutic effect.

[0010] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the invention

[0011] The purpose of the present invention is to provide a glycocholic acid sustained-release preparation and a production process of the sustained-release preparation.

[0012] The glycocholic acid sustained-release preparation provided by the present invention has a structure from inside to outside of: a drug-loaded micro-pellet core and a sustained-release coating layer.

[0013] The present invention fully considers the roundness, friability, yield, theoretical loading, physical and chemical characteristics of glycocholic acid itself and the characteristics of the diluent, and the drug loading (%) = glycocholic acid mass / glycocholic acid micropill mass × 100% = 10% to 45%, preferably 20% to 40%.

[0014] In one embodiment of the present invention, in the drug-loaded micropellet core: the drug-loaded micropellet core components include the following material components in mass parts: 5 parts to 23 parts of glycocholic acid, 28 parts to 45 parts of diluent; preferably include the following material components in mass parts: 10 parts to 20 parts of glycocholic acid, 30 parts to 40 parts of diluent.

[0015] Furthermore, the diluent is microcrystalline cellulose (MCC) or a combination of microcrystalline cellulose and corn starch or a combination of microcrystalline cellulose and lactose, preferably microcrystalline cellulose.

[0016] The contents of glycocholic acid and diluent are calculated based on the total weight of glycocholic acid and diluent.

[0017] In one embodiment of the present invention, in the sustained-release layer:

[0018] The coating material is NE 30D.

[0019] The weight of the coating layer is 1-3% of the weight of the pellet core, preferably 1.1-2.3%, and more preferably 1.2-1.8%.

[0020] The present invention also provides a production process of the above-mentioned glycocholic acid sustained-release preparation, comprising the following steps:

[0021] (1) Weigh the materials according to the specified amount;

[0022] (2) Preparation of drug-loaded micropellet cores: Glycocholic acid and diluent were sieved in sequence, mixed evenly, and then added to the water-made soft material and mixed for 24 to 36 minutes;

[0023] (3) putting the prepared glycocholic acid soft material into an extruder of an extrusion spheronization machine, starting the extruder, and extruding the soft material into strips with uniform length and thickness; then putting the strips into a spheronization machine in batches for spheronization to prepare wet micropellets with uniform particle size and round shape; discharging the material, putting the micropellets into a drying oven for drying, and screening qualified micropellets;

[0024] (4) Preparation of sustained-release micropellets: Weigh the formulated amount of sustained-release coating material, dilute with water to an appropriate concentration, stir evenly and sieve to prepare a sustained-release coating solution; place the prepared drug-loaded micropellet cores into a fluidized bed, adjust the various parameters of the fluidized bed, and use a peristaltic pump to coat the coating solution in a bottom spraying manner to increase the weight to a desired weight, take out, put into a drying oven for drying, and screen qualified sustained-release micropellets;

[0025] (5) Capsule filling: The sustained-release micropellets obtained in step (4) are filled into capsules to obtain a glycocholic acid sustained-release preparation.

[0026] In a specific embodiment of the present invention, the method for the release of glycocholic acid sustained-release preparation is constructed: the second method of the release determination device (General Rules 0931 of the Fourth Part of the 2020 Edition of the Chinese Pharmacopoeia) is adopted. Rotation speed: 100 rpm; release medium: 900 mL pH 6.8 phosphate buffer; temperature: 37 ° C ± 0.5 ° C, operate according to the law, take 5 mL of the solution for filtration at different times, and add 5 mL of fresh isothermal dissolution medium to the dissolution cup in time, and use high performance liquid chromatography, chromatographic column: medium spectrum blue RX-C18 (4.6 mm × 150 mm, 5 μm); mobile phase: 10 mmol / L ammonium acetate: acetonitrile = 67: 33, flow rate: 0.5 mL / min; injection volume: 8 μ L; column temperature: 30 ° C; detection wavelength: 210 nm, calculate the cumulative release of each capsule at different times by external standard method.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] (1) The present invention provides a sustained-release preparation of glycocholic acid. The sustained-release preparation uses microcrystalline cellulose as a diluent in the drug-carrying layer, which greatly improves the quality of the micropills compared with other excipients. As a sustained-release material, NE 30D has the characteristics of low permeability, no need to add additional plasticizers, good film flexibility, and no influence of ions and pH. The present invention can achieve a good sustained-release effect through the selection of coating weight gain. It not only makes up for the lack of preparations, but also improves the bioavailability of glycocholic acid drugs and promotes the development and utilization of drugs.

[0029] (2) The glycocholic acid sustained-release preparation of the present invention reduces the number of medication times for patients and improves patient compliance; it has a stable blood drug concentration and is safer to take; and compared with drug powder, it has improved fluidity and stability and is easy to use and store.

[0030] (3) In summary, the glycocholic acid sustained-release preparation of the present invention obtains a glycocholic acid sustained-release preparation with good sustained-release performance and excellent stability by reasonably setting the drug-carrying layer and the sustained-release layer structure and selecting the type and amount of each excipient. The production process is simple, the materials used are relatively cheap, and the cost is low, so it is easy to implement and apply on a large scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the technical solutions in the examples of this application and to more completely understand the application and its beneficial effects, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the application, and those skilled in the art can obtain other drawings based on these drawings without creative work.

[0032] Figure 1 .Process flow chart of glycocholic acid sustained-release preparation;

[0033] Figure 2 . Release curves of glycocholic acid sustained-release pellets with different coating weight gains in pH 6.8 buffer;

[0034] Figure 3 . Release curves of glycocholic acid sustained-release pellets with different coating weight gains in distilled water;

[0035] Figure 4 . Release curves of glycocholic acid sustained-release micropellets with different coating weight gains in pH 4.5 buffer;

[0036] Figure 5 . Release curves of three batches of glycocholic acid sustained-release pellets;

[0037] Figure 6 .High temperature test release curve;

[0038] Figure 7 .High humidity test release curve;

[0039] Figure 8 .Release curve of strong light test;

[0040] Fig. 9 . Accelerated test release curve; DETAILED DESCRIPTION

[0041] The embodiments described below with reference to the accompanying drawings are exemplary and are intended to be used to explain the present invention, but should not be construed as limiting the present invention.

[0042] It should be understood that the terms or words used in the specification and claims should not be understood as having the meaning defined in the dictionary, but should be understood as having the meaning consistent with their meaning in the context of the present invention based on the following principle: the concept of the term can be appropriately defined by the inventor for the best explanation of the present invention.

[0043] The production process of the glycocholic acid sustained-release preparation in the following embodiments comprises:

[0044] (1) Weigh the materials according to the specified amount;

[0045] (2) Preparation of drug-loaded micropellet cores: Weigh glycocholic acid and diluent, sieve them in sequence, mix them evenly, add water to make a soft material, and mix for 24 to 36 minutes;

[0046] (3) putting the prepared glycocholic acid soft material into the extruder of the extrusion spheronization machine, starting the extruder, adjusting the extrusion speed to 21.5 Hz, and extruding the soft material into strips of uniform length and thickness; then putting the strips into the spheronization machine in batches for spheronization, with a spheronization speed of 34 Hz ​​and a spheronization time of 8 to 10 min to prepare wet micropellets with uniform particle size and round shape; taking out, placing in a 40° C. oven to dry for 4 h, and screening the drug-loaded micropellet cores of 20 to 32 mesh;

[0047] (4) Preparation of sustained-release micropellets: Weigh the formula amount of sustained-release coating material, add water to dilute to an appropriate concentration, stir evenly and sieve to prepare a sustained-release coating solution; put the prepared drug-loaded micropellet cores into a fluidized bed, with an inlet air temperature of 22°C to 28°C, preheat for 5 to 10 min, and use a bottom spray coating method at a blast flow rate of 32 to 35 Hz, an atomization pressure of 0.1 MPa, and a spray rate of 0.8 to 1.2 mL / min to achieve the desired weight gain, take out, put in a 40°C drying oven for aging for 24 h, and screen to obtain sustained-release micropellets with a mesh size of 20 to 32;

[0048] (5) Preparation of glycocholic acid sustained-release capsules: The glycocholic acid sustained-release micropellets obtained in step (4) are divided into gelatin hollow capsules to prepare hard capsules to obtain a glycocholic acid sustained-release preparation with a specification of 50 mg.

[0049] The preparation process of its glycocholic acid sustained-release preparation is as follows: Figure 1 shown.

[0050] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0051] Examples 1-3: Investigate the effects of different diluents on the quality of glycocholic acid micropellets.

[0052] The formula and evaluation indexes are shown in Table 1 below:

[0053] Table 1:

[0054]

[0055] Comparative Example 1: The same as Example 1, except that the diluent is replaced by 233 g of lactose.

[0056] Comparative Example 2: The same as Example 1, except that the diluent is replaced by 233g corn starch.

[0057] From the above, it can be seen that the cores of the drug-loaded micropellets prepared by the extrusion spheronization method after a slight adjustment of the auxiliary materials in Examples 1 to 3 are smooth, round and relatively uniform in appearance. Different types of diluents were used in the above examples, and the yield and roundness of the qualified drug-loaded micropellets obtained in Example 1 were better than those of the other groups of examples, indicating that the preferred prescription process of Example 1 is reasonable and feasible. Comparative Examples 1 and 2, under the same pill making conditions, could not obtain the above-mentioned shaped micropellets. Only under specific diluents and ratios could micropellets with roundness and yield that met the requirements be obtained, proving that the above prescriptions and ratios are not obvious.

[0058] Examples 4-7: Investigating the effect of different drug loadings on the quality of glycocholic acid pellets

[0059] The formula and evaluation indexes are shown in Table 2 below:

[0060] Table 2:

[0061]

[0062] From the above, it can be seen that: in Examples 4 to 7, the drug loading of the pellet core is adjusted. Under the same conditions, the larger the drug loading of the pellets, the easier it is for the pellets to stick together, the roundness and yield are reduced, and the particle size distribution range of the pellets becomes larger; on the contrary, the smaller the drug loading, the smoother the pelleting and the easier it is to form, but the dosage is large and the patient compliance is poor. Compared with the other groups of examples, Example 6 has appropriate roundness and yield, and high patient compliance.

[0063] Investigate the reproducibility of the preparation of glycocholic acid drug-loaded micropellets:

[0064] Three batches of glycocholic acid drug-loaded micropellets were produced according to the optimal process recipe, with batch numbers G1, G2, and G3. The powder quality and release rate of the three batches of glycocholic acid micropellets were checked. The results are shown in Table 3:

[0065] Table 3:

[0066]

[0067] The results in Table 3 show that the powder quality of the three batches of glycocholic acid drug-loaded micropellets is stable, the preparation method of glycocholic acid micropellets has good reproducibility, and the release results of the three batches of glycocholic acid micropellets in buffer solution show that the micropellets have no sustained-release effect, which provides a material basis and guarantee for the subsequent coating method.

[0068] Release determination method of glycocholic acid sustained-release preparation: the second method of release determination device (General Rules 0931 of Part Four of the 2020 edition of the Chinese Pharmacopoeia) was used. Rotation speed: 100 rpm; release medium: 900 mL pH 6.8 phosphate buffer; temperature: 37 ° C ± 0.5 ° C, operate according to the law, take 5 mL of solution for filtration at different times, and add 5 mL of fresh isothermal dissolution medium to the dissolution cup in time, and use high performance liquid chromatography, chromatographic column: medium spectrum blue RX-C18 (4.6 mm × 150 mm, 5 μm); mobile phase: 10 mmol / L ammonium acetate: acetonitrile = 67: 33, flow rate: 0.5 mL / min; injection volume: 8 μ L; column temperature: 30 ° C; detection wavelength: 210 nm, calculate the cumulative release of each capsule at different times by external standard method. The release amount of each tablet of this product in 2, 4, 8 and 12 hours should be less than 40%, 40%-60%, 70-90% and more than 90% of the labeled amount respectively. According to the general rules of the fourth part of the Chinese Pharmacopoeia 2020 edition, 0931 release rate and release rate inspection method, it should meet the requirements.

[0069] Example 8: Investigating the effects of different coating formulations

[0070] Comparative Example 3: Same as Example 8, except that 144 g of sustained-release material is used. replace.

[0071] The glycocholic acid drug-loaded micropellets with sustained-release layer prepared according to the above optimal process prescription have a specific formula as shown in Table 4 below, and the release results are shown in Table 5 below:

[0072] Table 4:

[0073]

[0074] Table 5:

[0075]

[0076] In the above examples, cellulose is selected from common coating materials. and acrylic resins ( NE 30D), and no additional plasticizer is required for the two coating materials. Without adding other materials, the release is investigated. From the above results, it can be seen that the release value of Example 8 is in the middle value, and the release in each time period is in the high-quality range. In contrast, under the same coating weight gain conditions, Comparative Example 3 cannot achieve the purpose of sustained release. It can be seen from the experiment that not all prescriptions can achieve the above effects, indicating that the coating prescription of Example 8 is reasonable and feasible.

[0077] Examples 9-13: Investigating the effects of different coating weight gain:

[0078] The specific weight gain level and release results are shown in Table 6 below:

[0079] Table 6:

[0080]

[0081] From the above, it can be seen that the in vitro release rate of glycocholic acid sustained-release pellets has obvious differences. As the weight gain of the pellet coating increases, the drug release rate slows down; conversely, as the coating weight gain decreases, the drug release rate accelerates. Considering the release rate standard comprehensively, 1.2-1.4% is preferred.

[0082] Examples 14-19: Investigating the effects of different aging conditions:

[0083] The specific aging conditions and release results are shown in Table 7 below:

[0084] Table 7:

[0085]

[0086] From the above results, it can be seen that there is no significant difference in the drug release of microcapsules under aging conditions of 40℃ and 50℃, indicating that the microcapsule coating can be completely healed at 40℃. At 60℃, the drug release rate of the microcapsules slows down, so it is recommended to age at 40℃. The longer the aging time at 40℃, the slower the drug release of the microcapsules. When the aging time exceeds 24h, the drug release rate has no significant change. Do not over-dry. Too little water content in the coating will make the coating brittle, which may affect the release of the preparation.

[0087] Investigate the stability and repeatability of coating process:

[0088] The method of Example 8 was repeated to prepare three batches of glycocholic acid sustained-release pellets, which were labeled as G1, G2, and G3, respectively. The release rates of the three batches of glycocholic acid sustained-release pellets were measured. The results are as follows: Figure 5 .

[0089] Study on the drug release rate of glycocholic acid sustained-release micropellets:

[0090] The cumulative release data of the glycocholic acid sustained-release micropellets prepared in Example 8 at different time points, i.e., 1, 2, 4, 6, 8, 10, and 12 h, were fitted with zero-order, first-order, Higuchi, and Ritger-Peppas release equations using Origin 2021 software. The zero-order release equation was: Q = a1 + b1 t; the first-order release equation was: Q = a2 (1-e -b 2 t ); Higuchi: Q = a3 + b3 t 1 / 2 ; Ritger-Peppas: Q = kt n ; In the above formula, Q is the cumulative drug release, t is the sampling time, a1, a2, a3 are all constants, b1, b2, b3 and k are all drug release constants. The drug release equation fitting results are shown in Table 8:

[0091] Table 8:

[0092]

[0093] As shown in Table 8, the degree of fitting of the in vitro release model of glycocholic acid sustained-release pellets is as follows: Fist-order model > Ritger-Peppas model > Higuchi model > Zero-order model. The release rate is best fitted with the first-order release equation, R 2 The value is the largest, which is 0.99419. It can be inferred that the release mechanism of the coated micropellets in the dissolution medium is closer to the first-order release. The release characteristic index n in the Ritger-Peppas equation release curve is significant: when n≤0.45, the drug release mechanism is mainly Fick diffusion; when 0.45<n<0.89, the drug release mechanism is non-Fick diffusion, that is, the drug diffusion and skeleton dissolution work together; when n≥0.89, the drug release mechanism is skeleton dissolution. The fitting result n value is 0.70802, so it is inferred that the release process of the coated micropellets is a process of drug diffusion and skeleton dissolution.

[0094] Study on the stability of glycocholic acid sustained-release micropellets:

[0095] High temperature test: The glycocholic acid sustained-release micropellets prepared in Example 8 were placed in a constant temperature and humidity incubator at 60°C for 10 days for high temperature test. The test results showed that the sustained-release micropellets released faster on the 5th and 10th days than on the 0th day. It may be that under high temperature conditions, the moisture content of the coating film decreased, causing the coating film to become brittle, which in turn led to faster release. Therefore, it is shown that temperature has an impact on the quality of micropellets, and high temperatures should be avoided during storage.

[0096] Table 9: High temperature test results (n=3)

[0097]

[0098] High humidity test: The glycocholic acid sustained-release micropellets prepared in Example 8 were placed in a dryer in a constant temperature and humidity incubator, and the temperature of the incubator was set to 25°C and the humidity was set to 92.5%. The humidity of 92.5% was maintained with a saturated KNO3 solution in the dryer, and a high humidity test was conducted. The test results show that the content of the sustained-release micropellets will decrease slightly after the 5th and 10th days of placement. This shows that humidity has a certain effect on the quality of the micropellets, and it is recommended to store them in a cool and dry place.

[0099] Table 10: High humidity test results (n=3)

[0100]

[0101] Strong light test: The glycocholic acid sustained-release micropellets prepared in Example 8 were placed in a constant temperature and humidity incubator, and the illumination was set to 4500±500lx for 10 days. The test results showed that all inspection items met the requirements, indicating that light had no effect on the quality of the micropellets.

[0102] Table 11: Strong light test results (n=3)

[0103]

[0104] Accelerated test: The glycocholic acid sustained-release capsules prepared in Example 8 were placed in an environment of 40°C and 75% humidity for 6 months, and samples were taken at 0, 1, 2, 3, and 6 months, respectively, and compared with the sample at time 0. The test results showed that the content and release rate of the sustained-release capsules did not change significantly in the first two months (subsequent tests are still ongoing), indicating that they have good stability under this condition.

[0105] Table 12:

[0106]

[0107] The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. All equivalent embodiments or changes made without departing from the spirit of the present invention should be included in the scope of protection of the present invention.

[0108] The prescription production process created by the present invention is only applicable to glycocholic acid drugs, not to other drugs, and is not a simple replacement. The glycocholic acid sustained-release preparation and production process established thereby are not obvious to those skilled in the art, and require creative labor by the inventor to obtain.

Claims

1. A glycocholic acid sustained-release preparation, characterized in that: The structure of the glycocholic acid sustained-release preparation from inside to outside is: a drug-loaded micro-pellet core and a sustained-release coating layer. The drug-loaded micro-pellet core comprises glycocholic acid and a diluent; and the drug loading is 10% to 45%.

2. The glycocholic acid sustained-release preparation according to claim 1, characterized in that: The drug loading is 20% to 40%.

3. The glycocholic acid sustained-release preparation according to claim 1, characterized in that: The core components of the drug-loaded micropellets include the following substances in parts by weight: 5 to 23 parts of glycocholic acid and 28 to 45 parts of a diluent.

4. The glycocholic acid sustained-release preparation according to claim 1, characterized in that: The core components of the drug-loaded micro-pellets include the following substances in parts by weight: 10 to 20 parts of glycocholic acid and 30 to 40 parts of a diluent.

5. The glycocholic acid sustained-release preparation according to claim 1, characterized in that: The diluent is microcrystalline cellulose or a combination of microcrystalline cellulose and corn starch or a combination of microcrystalline cellulose and lactose.

6. The glycocholic acid sustained-release preparation according to claim 1, characterized in that: The coating material is NE 30D.

7. The sustained-release preparation of glycocholic acid according to claim 1, characterized in that: The weight of the coating layer is 1-3% of the weight of the pellet core.

8. The production process of a glycocholic acid sustained-release preparation according to claim 1, characterized in that: The following steps are involved: (1) Weigh the materials according to the specified amount; (2) Preparation of drug-loaded micropellet cores: sieve glycocholic acid and diluent in sequence, mix them evenly, add water-made soft material, and mix; (3) putting the prepared glycocholic acid soft material into an extruder of an extrusion spheronization machine to extrude strips of uniform length and thickness; then putting the strips into a spheronization machine for spheronization to prepare wet micropellets with uniform particle size and round shape; discharging the material, drying the wet micropellets, and screening qualified micropellets; (4) Preparation of sustained-release pellets: Weigh the formulated amount of sustained-release coating material, dilute with water to an appropriate concentration, stir evenly and sieve to prepare a sustained-release coating solution; place the prepared drug-loaded pellet cores into a fluidized bed, adjust the parameters, coat and increase the weight to the required weight, take out and dry, and screen qualified sustained-release pellets; (5) Capsule filling: The sustained-release micropellets obtained in step (4) are filled into capsules to obtain a glycocholic acid sustained-release preparation.

9. The production process of a glycocholic acid sustained-release preparation according to claim 8, characterized in that: The mixing time of step (2) is 24 to 36 minutes.

10. The method for constructing the release rate of the glycocholic acid sustained-release preparation according to claim 1, characterized in that: Rotation speed: 100rpm; release medium: 900mL pH6.8 phosphate buffer; temperature: 37℃±0.5℃. Operate according to the law, take 5mL of the solution for filtration at different times, and add 5mL of fresh isothermal dissolution medium to the dissolution cup in time. Use high performance liquid chromatography, chromatographic column: Medium Spectrum Blue RX-C18 (4.6mm×150mm, 5μm); mobile phase: 10mmol / L ammonium acetate: acetonitrile = 67:33, flow rate: 0.5mL / min; injection volume: 8μL; column temperature: 30℃; detection wavelength: 210nm, calculate the cumulative release of each capsule at different times by the external standard method.

Images