A preparation method of tauroursodeoxycholic acid capsules

Abstract

The application discloses a preparation method of tauroursodeoxycholic acid capsules and belongs to the technical field of capsule preparation. The tauroursodeoxyxycholic acid capsules are prepared by using a high-frequency wave vibration device which is precisely driven by a servo motor, and the high-frequency wave vibration device is internally provided with first and second moving blocks which are distributed at intervals and drive a flexible elastic plate to wave and turn over, and a plurality of contact assemblies are uniformly arranged on the elastic plate. In the process of spraying and wetting, particles continuously roll and disperse, water can be rapidly and uniformly distributed on the surfaces of all particles, and the water absorption block can automatically supplement water for dry particles, and will not absorb water from wet particles, so that local over-wetting or over-drying of the particles is effectively avoided. The tauroursodeoxyxycholic acid capsules not only remarkably improve the uniformity of the surface micro-wetting of the particles, and create ideal conditions for efficient coating of the subsequent flow aid, but also combine the high-efficiency airflow disturbance of the fluidized bed mixer, so that the flow aid such as colloidal silicon dioxide is uniformly covered on the surface of the particles, the stickiness of the active ingredient tauroursodeoxycholic acid is reduced, and the flowability of the particles and the consistency of the capsule loading are improved.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of capsules, in particular to a preparation method of tauroursodeoxycholic acid capsules. BACKGROUND

[0002] As an important oral bile acid preparation, tauroursodeoxycholic acid capsules are widely used in the treatment of diseases such as gallstones and cholecystitis. The capsule preparation process generally includes the steps of uniform mixing of the main medicine and various auxiliary materials, wet granulation, drying, granulation, coating, adding lubricant and capsule filling. In order to ensure the accuracy of the capsule filling, the flowability of the granules and the uniformity of the content, a flow aid such as medical grade silicon dioxide is often coated on the surface of the granules to reduce the stickiness of the active ingredient tauroursodeoxycholic acid, improve the flowability of the granules and facilitate large-scale industrial production.

[0003] At present, the commonly used flow aid coating process in industry mainly includes dry direct mixing and simple spray wetting and mixing. However, these traditional processes have many limitations. Firstly, the affinity between the flow aid and the surface of the granules is weak in dry mixing, which easily causes uneven coating, local agglomeration and limited improvement of flowability. Secondly, although simple wetting and mixing can improve the distribution of the flow aid to a certain extent, the uneven distribution of water on the surface of the granules easily leads to over-wetting in some areas and over-drying in some areas, thereby causing incomplete coating of the flow aid or granule sticking and caking. In addition, the existing spray wetting process lacks dynamic fine control of water, and it is difficult to compensate or remove water in real time according to the microenvironment on the surface of the granules, so that the water state of the entire batch of granules is difficult to achieve high consistency, which affects the uniformity of the capsule filling, the flowability and the product consistency, and causes certain difficulties for industrial continuous production.

[0004] Therefore, a preparation method of tauroursodeoxycholic acid capsules is proposed for the above problems. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of tauroursodeoxycholic acid capsules to solve the above problems.

[0006] In order to achieve the above purpose, the technical scheme provided by an embodiment of the present application is as follows:

[0007] A preparation method of tauroursodeoxycholic acid capsules, comprising the following steps:

[0008] S1: passing tauroursodeoxycholic acid through a 150-mesh sieve for standby;

[0009] S2: adding corn starch into purified water at 45-55 DEG C, and adding purified water above 95 DEG C under stirring to prepare a 10% starch slurry;

[0010] S3: mixing and stirring the prescribed amount of tauroursodeoxycholic acid, lactose monohydrate and microcrystalline cellulose uniformly, then adding the starch paste and continuing to stir to form a wet mixture;

[0011] S4: passing the wet mixture through a 16-mesh sieve to obtain wet granules;

[0012] S5: performing drying treatment on the wet granules until the water content of the granules is reduced to below 3%;

[0013] S6: passing the dried granules through a 24-mesh sieve to obtain uniform granules;

[0014] S7: dispersing the dried uniform granules on the surface of a high-frequency wave vibration device driven by a servo motor, uniformly spraying purified water with a mass fraction of 0.3 in a spray manner, the wave frequency is 2 Hz, the mixing time is 5 min, so that the surface of the granules forms a slightly wet state, then the slightly wet granules are collected and transferred to a medical-grade mixing container, 0.1-1% of pharmaceutical-grade colloidal silicon dioxide is added as a glidant, and mechanical mixing is performed using a fluidized bed mixer to uniformly coat the glidant on the surface of the granules;

[0015] S8: adding the prescribed amount of magnesium stearate to the dried uniform granules, mixing uniformly, then filling the granules into empty capsules using a filling rod to obtain tauroursodeoxycholic acid capsules.

[0016] As a further improvement of the present application, the mass percentage ranges of tauroursodeoxycholic acid, lactose, microcrystalline cellulose, corn starch and magnesium stearate are 55%-80%, 5%-15%, 2%-10%, 2%-8% and 0.2%-1%, respectively.

[0017] As a further improvement of the present application, in S1 to S3, tauroursodeoxycholic acid, lactose monohydrate and microcrystalline cellulose are stirred for 10-20 minutes in a mechanical stirring manner to ensure uniformity.

[0018] As a further improvement of the present application, the drying method in S5 is hot air circulation drying, the drying temperature is 40-60°C, the water content of the granules is reduced to below 4% after drying, and the water content is detected periodically during the drying process.

[0019] As a further improvement of the present application, the vibration device in S includes a plurality of first moving blocks and a plurality of second moving blocks, the plurality of first moving blocks and the plurality of second moving blocks are distributed at intervals, the bottom end of the first moving block is fixedly connected with a first upper moving plate, the bottom end of the second moving block is fixedly connected with a second upper moving plate, the first moving block and the second moving block are installed with an elastic plate at the end close to each other, and a plurality of uniformly distributed contact assemblies are installed on the elastic plate.

[0020] As a further improvement of the present application, the first upper moving plate is fixedly connected with a first toothed plate at the bottom end, the second upper moving plate is fixedly connected with a second toothed plate at the bottom end, and a gear is engagedly connected between the first toothed plate and the second toothed plate, and one end of the gear is fixedly connected with a servo motor.

[0021] As a further improvement of the present application, the contact assembly comprises a water-absorbing block, the water-absorbing block is mounted on the elastic plate, the top end of the elastic plate is fixedly connected with a water guide strip, and a plurality of uniformly distributed water guide fibers are mounted outside the water guide strip.

[0022] As a further improvement of the present application, the water-absorbing block, the water guide strip and the water guide fibers are all made of water-absorbing material.

[0023] As a further improvement of the present application, the mechanical mixing in S7 is performed by a fluidized bed mixer for 3-10 minutes.

[0024] As a further improvement of the present application, the magnesium stearate in S8 is added after the dried granules are sieved through a 24-mesh sieve, and the granules are immediately filled after being uniformly mixed, and the mixing time is 2-5 minutes.

[0025] Compared with the prior art, the present application has the following advantages:

[0026] (1) The present application solves the problems of uneven moisture, insufficient flow aid coating and poor batch consistency in the prior art by unique structural design and process innovation. A high-frequency wave vibration device driven by a servo motor is used, and a plurality of first and second moving blocks are arranged at intervals inside the device to jointly drive the flexible elastic plate to make wave-like turning motion. A plurality of contact assemblies are uniformly distributed on the elastic plate, each contact assembly comprises a high water-absorbing water-absorbing block, a hydrophilic water guide strip and a plurality of water guide fibers, and the three components cooperatively build an efficient water-absorbing-water-guiding-balancing network. During the spraying and wetting stage, the particles are continuously in a rolling and dispersing state, and the water sprayed can be quickly and uniformly distributed on the surface of all particles. The water-absorbing block in the system can automatically provide water compensation for the particles with dry surface, and will not absorb water from the particles with wet surface, realizing intelligent dynamic adjustment of water for "dry particles to compensate for water, wet particles to not lose water", and avoiding local particles to be too wet or too dry.

[0027] (2) This scheme not only guarantees the high uniformity of the micro-wet state of the particle surface, creates ideal conditions for subsequent flow agent coating, but also enables the flow agent such as silicon dioxide to be extremely uniformly covered on the surface of each particle through the high-efficiency airflow disturbance of the subsequent fluidized bed mixer, greatly improving the flowability and dispersibility of the particles, avoiding phenomena such as agglomeration, caking, and incomplete local coating, and preparing particle flow agent coating with uniformity, significantly improved flowability, and significantly improved capsule loading consistency, small batch-to-batch quality fluctuation, greatly improved adaptability and product high-quality controllability of industrialized continuous production, and has the advantages of simple structure, controllable operation, and easy industrialization. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 is a preparation scheme of the present application;

[0029] Figure 2 is a three-dimensional structure schematic diagram of the vibration device of the present application;

[0030] Figure 3 is a three-dimensional structure schematic diagram of the elastic plate of the present application;

[0031] Figure 4 is a three-dimensional structure schematic diagram of the contact assembly of the present application;

[0032] Figure 5 is a schematic diagram of the control experiment data of the embodiment of the present application;

[0033] Figure 6 is a schematic diagram of the control experiment data of the embodiment of the present application.

[0034] Explanation of reference numerals in the drawings:

[0035] 2, contact assembly; 11, first moving block; 12, second moving block; 13, first upper moving plate; 14, second upper moving plate; 15, first toothed plate; 16, second toothed plate; 21, elastic plate; 22, water absorbing block; 23, water guide strip; 24, water guide fiber. DETAILED DESCRIPTION

[0036] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application; obviously, the described embodiments are only part of the embodiments of the present application, not all the embodiments; based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application. EMBODIMENT

[0037] Please refer to Figures 1-5 A preparation method of tauroursodeoxycholic acid capsules, comprising the following steps:

[0038] S1: Tauroursodeoxycholic acid is sieved through a 150-mesh screen and is ready for use;

[0039] S2: Corn starch is added to purified water at 45-55°C, and 95°C or higher purified water is added under stirring to prepare a 10% starch slurry;

[0040] S3: The prescribed amount of tauroursodeoxycholic acid, lactose monohydrate, and microcrystalline cellulose are mixed and stirred uniformly, then the starch slurry is added, and stirring is continued to form a wet mixture;

[0041] S4: The wet mixture is sieved through a 16-mesh screen to obtain wet granules;

[0042] S5: The wet granules are subjected to drying treatment until the water content of the granules is reduced to 3% or less;

[0043] S6: The dried granules are sieved through a 24-mesh screen to obtain uniform granules;

[0044] S7: The dried uniform granules are dispersed on the surface of a high-frequency wave vibration device driven by a servo motor, and purified water with a mass fraction of 0.3 is uniformly sprayed in a spray manner, with a wave frequency of 2 Hz and a mixing time of 5 min, so that the surface of the granules forms a slightly wet state. The slightly wet granules are then collected and transferred to a medical-grade mixing container, 0.1-1% pharmaceutical-grade colloidal silicon dioxide flow aid is added, and a fluidized bed mixer is used for mechanical mixing to uniformly coat the flow aid on the surface of the granules;

[0045] S8: The prescribed amount of magnesium stearate is added to the dried uniform granules and mixed uniformly, then the total mixed granules are filled into empty capsules using a filling rod to obtain tauroursodeoxycholic acid capsules.

[0046] The present application solves the problems of uneven moisture of particles, insufficient coating of flow aids and poor batch consistency in the production of tauroursodeoxycholic acid capsules by unique structural design and process innovation. The high-frequency wave vibration device is precisely driven by a servo motor, and the first moving block 11 and the second moving block 12 are arranged at intervals inside the device. The flexible elastic plate 21 is waved to drive the contact assembly 2 arranged on the elastic plate. Each contact assembly includes a superabsorbent water-absorbing block 22, a hydrophilic water guide strip 23 and a water guide fiber 24, which form an efficient water-absorbing-water-guiding-balancing system. During the spraying and moistening process, the particles are continuously rolled and dispersed, and the moisture can be quickly and evenly distributed on the surface of all particles. The water-absorbing block 22 can automatically supplement the moisture for the dry particles, and will not absorb the moisture of the wet particles, realizing the intelligent dynamic adjustment of "dry particle water supplement and wet particle water loss", effectively avoiding the local over-wetting or over-drying of the particles. The structure not only significantly improves the uniformity of the particle surface moisture, but also creates ideal conditions for efficient coating of flow aids. Combined with the high-efficiency airflow disturbance of the fluidized bed mixer, the flow aids such as silicon dioxide are evenly covered on the surface of the particles, greatly improving the flowability of the particles and the consistency of the capsule loading. Experiments prove that the product prepared by the process has stable quality, is suitable for industrial continuous production, and has obvious technical progress and application value.

[0047] The mass percentage ranges of tauroursodeoxycholic acid, lactose, microcrystalline cellulose, corn starch and magnesium stearate are 55%-80%, 5%-15%, 2%-10%, 2%-8% and 0.2%-1% respectively.

[0048] The mass percentage ranges of tauroursodeoxycholic acid, lactose, microcrystalline cellulose, corn starch and magnesium stearate are 55%-80%, 5%-15%, 2%-10%, 2%-8% and 0.2%-1% respectively. The formula ratio is optimized scientifically, which can significantly improve the stability, flowability and industrial production adaptability of the capsule preparation while ensuring the full release of the active ingredients, thereby realizing high quality and high consistency of the capsule product.

[0049] The content of tauroursodeoxycholic acid as the main active ingredient is as high as 55% to 80%, which can ensure that each capsule contains sufficient active ingredients to meet the clinical treatment needs. Lactose, as a commonly used pharmaceutical diluent and filler, plays a role in improving the flowability and filling uniformity of the powder, and has a good regulating effect on the dissolution rate of the main drug. The amount is controlled at 5%-15%, which can ensure the volume and loading of the preparation, and will not affect the disintegration and release of the main drug due to excessive amount.

[0050] Microcrystalline cellulose as a high-efficiency excipient and disintegrant, the mass percentage range is controlled in 2%-10%, effectively improves the particle structure stability and disintegration rate of the capsule content, which is beneficial to the rapid release and absorption of the drug in the digestive tract. Corn starch as a traditional disintegrant and granulating agent, the amount is 2%-8%, which not only helps the smooth progress of the granulation process, but also further improves the disintegration performance of the capsule and promotes the rapid release of the main drug.

[0051] Magnesium stearate as a lubricant, the amount is only 0.2%-1%, which can significantly reduce the friction resistance of the particles in the processes of granulation and filling, reduce the sticking and blocking phenomena in the production process, improve the filling efficiency and the uniformity of the capsule filling, and at the same time will not adversely affect the dissolution behavior of the preparation. The reasonable proportioning of the above ingredients synergizes with each other, which not only ensures the efficacy and safety of the drug preparation, but also improves the controllability of the production process and the consistency of the finished product quality.

[0052] In S1 to S3, tauroursodeoxycholic acid, lactose monohydrate and microcrystalline cellulose are stirred for 10-20 minutes by mechanical stirring to ensure uniformity.

[0053] In S1 to S3, tauroursodeoxycholic acid, lactose monohydrate and microcrystalline cellulose are stirred for 10-20 minutes by mechanical stirring to ensure that the components can be fully and uniformly mixed. Through mechanical stirring, the limitations of manual mixing can be effectively overcome, the mixing efficiency can be improved, the dispersion of the main drug and excipients can be more uniform, local component concentration can be avoided, and the uniformity of the content and the stability of the subsequent granulation process can be improved.

[0054] The stirring time is strictly controlled within the range of 10-20 minutes, which is the best interval determined by process optimization. Within this time, the mixture can achieve ideal uniform distribution, and problems such as particle agglomeration and powder structure damage caused by excessive stirring can be prevented. The uniformly mixed material is helpful for forming a wet mixture with consistent structure when the starch slurry is added subsequently, ensuring the particle forming effect and improving the uniformity of the capsule filling and the uniformity of the dissolution.

[0055] Therefore, by mechanically stirring tauroursodeoxycholic acid, lactose monohydrate and microcrystalline cellulose for 10-20 minutes, the uniform distribution of the formula components can be ensured, and the process controllability of the entire preparation process and the stability of the product quality can be optimized, which is finally beneficial to obtaining tauroursodeoxycholic acid capsule products with definite efficacy and consistent quality.

[0056] The drying method in S5 is hot air circulation drying, the drying temperature is 40℃ to 60℃, and the drying is carried out until the water content of the particles is less than 4%, and the moisture is detected periodically during the drying process.

[0057] In the S5 step, hot air circulation drying is adopted as the drying method, the drying temperature is controlled between 40-60℃, the moisture content of the wet granules is reduced to less than 4%, and the moisture content is detected periodically during the drying process. Hot air circulation drying can provide uniform and stable heat source, so that the water in the granules evaporates uniformly during heating, avoiding local overheating or overdrying, thereby ensuring that the physical properties of the dried granules are consistent and the granule structure is uniform and complete.

[0058] The temperature range of 40-60℃ is selected to balance the effective removal of material moisture and the protection of the physical and chemical stability of the drug and excipients. If the temperature is too low, the drying efficiency will be low and the residual moisture will be too high, affecting the subsequent process and the stability of the preparation. If the temperature is too high, it may cause drug degradation or changes in the properties of the excipients. By strictly controlling the temperature within this range, the quality of the granules and the safety of the finished product are effectively guaranteed.

[0059] During the drying process, periodic sampling and moisture detection can help monitor the dehydration progress of the granules in real time, ensuring that the final moisture content is stable and below 4%. This prevents problems such as granule sticking, poor flowability, or microbial contamination caused by high moisture content. It also avoids excessive drying, which can increase the brittleness of the granules and affect subsequent sieving and filling operations. This process setting not only improves the controllability of the production process, but also optimizes the physical properties and storage stability of the product, contributing to the production of high-quality tauroursodeoxycholic acid capsule preparations.

[0060] The vibration device in S7 includes a plurality of first moving blocks 11 and a plurality of second moving blocks 12. The first moving blocks 11 and the second moving blocks 12 are spaced apart. The first moving blocks 11 are fixedly connected with first upper moving plates 13 at the bottom ends. The second moving blocks 12 are fixedly connected with second upper moving plates 14 at the bottom ends. The first moving blocks 11 and the second moving blocks 12 are installed with elastic plates 21 at the ends close to each other. The elastic plates 21 are installed with a plurality of uniformly distributed contact assemblies 2.

[0061] The first upper moving plates 13 are fixedly connected with first tooth plates 15 at the bottom ends. The second upper moving plates 14 are fixedly connected with second tooth plates 16 at the bottom ends. The first tooth plates 15 and the second tooth plates 16 are meshingly connected with a gear in the middle. One end of the gear is fixedly connected with a servo motor.

[0062] The contact assembly 2 includes a water absorption block 22. The water absorption block 22 is installed on the elastic plate 21. The elastic plate 21 is fixedly connected with a water guide strip 23 at the top end. The water guide strip 23 is installed with a plurality of uniformly distributed water guide fibers 24. The materials of the water absorption block 22, the water guide strip 23, and the water guide fibers 24 are all set as water-absorbing materials.

[0063] The vibration device provided by the present scheme is mainly applied to the micro-wetting treatment stage of drug granules, aiming to achieve high uniformity and controllability of the water content on the surface of the granules, thereby providing an ideal prerequisite for the efficient and uniform coating of the subsequent flow aid

[0064] Specifically, the vibration device includes a plurality of first moving blocks 11 and a plurality of second moving blocks 12, which are arranged in a spaced distribution, and the spaced distribution can avoid particle accumulation or dead angle phenomenon when the particles are dispersed on the surface of the device, and is beneficial to uniform spreading of the particles in the entire device. The bottom end of each first moving block 11 is fixedly connected with a first upper moving plate 13, and the bottom end of each second moving block 12 is fixedly connected with a second upper moving plate 14. Through accurate control of the first upper moving plate 13 and the second upper moving plate 14, the corresponding moving blocks can be driven to move up and down, respectively, to provide a power basis for subsequent undulation of the elastic plate 21.

[0065] At one end of the first moving block 11 and the second moving block 12 close to each other, the elastic plate 21 is fixedly installed together. The elastic plate 21 is made of flexible material and can produce wave-like turning during device movement. The elastic plate 21 is uniformly provided with a plurality of contact assemblies 2, which can fully contact the particles to realize flexible turning and stirring of the particles. The design of the elastic plate 21 not only increases the contact area of the particles with the surface of the device, but also continuously turns and stirs the particles to prevent the particles from agglomerating or being stationary, so that the particles are more uniformly affected by the sprayed water, and the uniformity of the micro-wetting treatment is greatly improved.

[0066] In terms of power transmission, the bottom end of the first upper moving plate 13 is fixedly connected with a first toothed plate 15, and the bottom end of the second upper moving plate 14 is fixedly connected with a second toothed plate 16. The first toothed plate 15 and the second toothed plate 16 are connected by gear meshing in the middle. One end of the gear is fixedly connected with a servo motor. The servo motor can realize precise reciprocating rotation according to the control program, and drive the gear to rotate synchronously. The rotation of the gear further drives the first toothed plate 15 and the second toothed plate 16 to move up and down alternately, and drives each to move up and down alternately on the first upper moving plate 13 and the second upper moving plate 14. Through this mechanical coupling and power transmission mechanism, the elastic plate 21 can continuously produce wave-like turning action to realize flexible and uniform turning and stirring of the particles.

[0067] Each contact assembly 2 includes a water absorption block 22 made of superabsorbent material, which is specially used to absorb excess water during the spraying process to prevent the particles from agglomerating, caking and other adverse phenomena due to excessive water. The water absorption block 22 is installed on the elastic plate 21 and can be in contact with the surface of the particles to the greatest extent during the wave turning of the elastic plate 21 to realize efficient water regulation.

[0068] The water absorption block 22 has a selective adsorption effect: after the particles are sprayed with micro-wet, there are still some particles with dry surfaces and some particles with ideal micro-wet surfaces. When the dry particles contact the water absorption block 22, the water absorption block 22 has a high affinity for water, and the dry particles will preferentially adsorb some purified water from the surface of the water absorption block 22, so that the surface of the dry particles quickly reaches a micro-wet state. When the particles that have reached a micro-wet or wet state contact the water absorption block 22 again, the surface of the particles is close to the saturated water absorption state, and under the action of interfacial tension and material hydrophilicity, the purified water will not further transfer from the surface of the particles to the water absorption block 22, thereby avoiding the particles from drying again due to excessive water loss. This dynamic and reversible adjustment mechanism of water helps to achieve uniformity of the micro-wetness of the entire batch of particles.

[0069] In addition, the top end of the elastic plate 21 is also fixedly connected with a water guide strip 23 made of a hydrophilic material, which is used to further collect and conduct the excess water absorbed by the water absorption block 22. The outer layer of the water guide strip 23 is uniformly surrounded by a plurality of water guide fibers 24, which are superfine hydrophilic fibers or sponge-like materials that can disperse and store the water conducted by the water guide strip 23, further improving the water absorption efficiency and capacity of the whole. The water absorption block 22, the water guide strip 23 and the water guide fibers 24 cooperate with each other to form a complete water absorption and water guide network structure, which can realize timely and sufficient removal of excess water, preventing water loss control during the micro-wet treatment of the particles.

[0070] Through the above structure and mechanism, not only can the water distribution between the particles be automatically adjusted to achieve the intelligent dynamic balance of "dry particles supplementing water and wet particles not losing water", but also can ensure the high uniformity of the water on the surface of the particles, providing ideal surface conditions for the uniform coating of the flow aid, greatly improving the stability of the preparation process and the consistency of the product. In actual use, first, the dry and uniform particles are uniformly dispersed on the surface of the elastic plate 21 of the vibration device, then purified water with a mass fraction of 0.1-0.5% is uniformly sprayed in a spraying manner to make the particle surfaces obtain a moderate micro-wet state. During the operation of the device, the elastic plate 21 continuously waves and turns over, driving the particles to constantly roll and disperse, and in this process, the micro-wet water can be uniformly distributed to all particle surfaces, while the excess water is preferentially absorbed by the water absorption block 22 on the elastic plate 21 and further conducted, dispersed and stored by the water guide strip 23 and the water guide fibers 24, ensuring that the particle surfaces always maintain an ideal micro-wet state.

[0071] The granules are fully stirred and uniformly distributed, which significantly improves the uniformity of the spray water treatment. Secondly, the water absorption function of the water absorption block 22, the water guide strip 23 and the water guide fiber 24 effectively prevents the agglomeration and caking of the granules due to excessive moisture, so that each granule can obtain a controllable slightly wet surface. Thirdly, the wave turning of the elastic plate 21 realizes the flexible treatment of the granules, which not only avoids the damage to the structure of the granules, but also enhances the dispersion effect between the granules. Finally, the device provides an ideal pretreatment basis for subsequent uniform coating of the flow aid, which helps to improve the uniformity of the flow aid distribution, the flowability of the granules and the consistency of the capsule loading, and ensures the stability and controllability of the preparation quality.

[0072] After the slightly wet treatment is completed, the granules with slightly wet surface treated by the vibration device are collected and transferred to a medical-grade mixing container. Then, 0.1-1% of pharmaceutical-grade silicon dioxide flow aid is added to the container. In the specific operation process, a fluidized bed mixer is preferably used for mechanical mixing. The fluidized bed mixer makes the granules suspended and in a fluidized state by introducing a certain flow rate of gas into the container, and the flow aid such as silicon dioxide is uniformly dispersed between the gas flow and the granules. The device can realize efficient tumbling, dispersion and collision of the granules, so that the flow aid is fully and uniformly coated on the surface of each granule.

[0073] Firstly, after the surface of the granules is treated by the slightly wet treatment, the surface has a certain extremely thin water film or a short-term polarity enhancement effect, which can improve the physical adsorption capacity of the silicon dioxide flow aid on the surface of the granules. Secondly, the efficient gas flow disturbance in the fluidized bed mixer and the mutual collision between the granules accelerate the dispersion rate and uniformity of the flow aid, avoiding the risk of agglomeration or local overload of the flow aid. Thirdly, under the fluidized state, the flow aid repeatedly contacts the surface of the granules for multiple times, which significantly improves the integrity and compactness of the powder coating.

[0074] In S8, the magnesium stearate is added after the dry granules are sieved through a 24-mesh sieve, and is immediately filled after being uniformly mixed with the total granules. The mixing time is 2-5 minutes.

[0075] In S7, the selected hollow capsule is a No. 1 pharmaceutical hollow capsule. The volume of the No. 1 capsule is moderate, which is convenient for industrialized automatic filling, can meet the demand of tauroursodeoxycholic acid granule loading, and is helpful to ensure the convenience of drug taking and the compliance of patients. The use of standardized No. 1 pharmaceutical hollow capsule is also conducive to controlling the consistency of product quality, meeting the requirements of various packaging and circulation links, and improving the market applicability and safety of the preparation.

[0076] In addition, in step S8, the addition process of magnesium stearate is optimized: after the dried granules are sized through a 24-mesh sieve, the prescribed amount of magnesium stearate is immediately added and mixed uniformly with the granules, and the mixing time is controlled within 2-5 minutes, which can ensure that the magnesium stearate fully wraps the surface of the granules, significantly improves the flowability and lubricity of the granules, effectively reduces the friction and adhesion of the granules to the equipment during the filling process, and improves the filling efficiency and charge uniformity.

[0077] At the same time, the mixing time is controlled between 2-5 minutes, which not only ensures the uniform distribution of the lubricant, but also prevents the granule structure from being damaged or the lubricant from being wrapped too much to affect the subsequent dissolution behavior, thereby optimizing the process performance and product quality of the capsules.

[0078] Therefore, multiple embodiments are used for experiments, so as to obtain the influence of different amounts of purified water on the uniformity of the flow aid coating, and the specific operation is as follows:

[0079] Material formula:

[0080] Tauroursodeoxycholic acid: 65%;

[0081] Lactose monohydrate: 10%;

[0082] Microcrystalline cellulose: 7%;

[0083] Corn starch: 5%;

[0084] Magnesium stearate: 0.5%;

[0085] Pharmaceutical-grade silicon dioxide: 0.5%;

[0086] Purified water: 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% group experiments;

[0087] Key equipment and parameters:

[0088] Mechanical stirrer: used in step S3, rotation speed 60 rpm, stirring time 15 min.

[0089] Hot air circulating drying oven: step S5, temperature setting 50°C, air speed 1.5 m / s, drying to a moisture content <4%, sampling every 30 min for moisture detection.

[0090] Vibration device:

[0091] Servo motor: rated power 400W, rated speed 3000 rpm, control accuracy ±0.1°.

[0092] Gear ratio: 1:10, driving the first tooth plate 15 and the second tooth plate 16 to realize up-down alternating motion.

[0093] Elastic plate 21: wave motion frequency 2 Hz, amplitude 10 mm.

[0094] Water absorption block 22, water guide strip 23, water guide fiber 24: high molecular hydrophilic material, single water absorption block water absorption 0.5 g / 10 min.

[0095] Fluidized bed mixer: empty wind speed 0.6 m / s, charging amount 1 kg, mixing time 5 min.

[0096] Process steps

[0097] S1-S6: raw material sieving, slurry preparation, mixing, granulation, drying, and granulation, all according to the formula and the above device parameters;

[0098] S7: disperse 1 kg of evenly dried granules on the surface of the elastic plate 21 of the vibration device, start the servo motor, control the wave turning frequency to 2 Hz, and continue for 10 min;

[0099] Uniformly spray different mass fractions of purified water 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% using a super-micro atomizing nozzle, and record the data of each group;

[0100] During the operation of the vibration device, the water absorption block 22, water guide strip 23, and water guide fiber 24 work together to remove excess water, ensuring that the surface of the granules is only slightly wet.

[0101] Collect the slightly wet granules and transfer them to the fluidized bed mixer, add 0.5% medical grade silicon dioxide, and air mix for 5 min to achieve uniform coating of the glidant.

[0102] S8: After sieving through a 24-mesh sieve, add 0.5% magnesium stearate, mix for 3 min, load into capsules, and complete the preparation of the preparation.

[0103] Detection method and results

[0104] 1. Glidant coating uniformity detection method:

[0105] Scanning electron microscope SEM and energy dispersive spectroscopy EDS: observe the distribution pattern and content of silicon dioxide on the surface of 20 sampled granules to determine the uniformity of coating.

[0106] Flowability determination: measure the repose angle and falling time of the granules to indirectly reflect the consistency of glidant distribution.

[0107] Capsule loading consistency: take 20 capsules, weigh them, and calculate the RSD.

[0108] Results are as follows Figure 5As shown, when the purified water dosage is 0.3%, the particle surface silica distribution is the most uniform under SEM, the coefficient of variation of Si content is the lowest in EDS analysis, the particle flowability and capsule loading consistency are the best, and lower than 0.2%, the coating is not complete; higher than 0.4%, the risk of agglomeration and caking increases.

[0109] The high-frequency wave vibration device driven by a servo motor is matched with 0.3% purified water spraying, so that the particle surface can be ideally slightly wet, the flow aid can be uniformly coated through mechanical mixing in the fluidized bed, and finally the tauroursodeoxycholic acid capsules with excellent flowability and high loading consistency are obtained. The detection results show that the process parameters of the application are preferably selected as follows: the spraying purified water dosage is 0.3%, the wave frequency is 2 Hz, and the mixing time is 5 min, so that the uniformity of the flow aid coating is the best.

[0110] At the same time, in order to aim at the differences between the existing traditional dry mixing and simple spraying wetting process and the process of the application in the uniformity of the flow aid coating, the particle flowability and the capsule loading consistency, the following experimental methods are designed:

[0111] The formula is uniform (mass percentage):

[0112] Tauroursodeoxycholic acid: 65%;

[0113] Lactose monohydrate: 10%;

[0114] Microcrystalline cellulose: 7%;

[0115] Corn starch: 5%;

[0116] Magnesium stearate: 0.5%;

[0117] Pharmaceutical grade silicon dioxide: 0.5%;

[0118] Batch: 1 kg per group;

[0119] Raw material pretreatment (the same for all groups):

[0120] Tauroursodeoxycholic acid is passed through a 150-mesh sieve, lactose and microcrystalline cellulose are passed through a 100-mesh sieve.

[0121] Corn starch is prepared into 10% starch slurry (45-55℃ water dissolution→95℃ hot water gelatinization).

[0122] Mix the main drug, lactose and microcrystalline cellulose for 15 min→add starch slurry→wet granulation (16-mesh sieve).

[0123] Hot air circulation drying (50℃, air speed 1.5 m / s) until the water content is less than 4%.

[0124] After drying, pass through a 24-mesh sieve to obtain uniform particles.

[0125] Three groups of process treatment:

[0126] Traditional dry mixing group includes: 1 kg of dry particles are put into a V-type mixer; 0.5% of silicon dioxide is added, mixed for 10 minutes; sieved through a 24-mesh sieve; 0.5% of magnesium stearate is added, and mixed for 3 minutes in total; and loaded into a No. 1 hollow capsule.

[0127] Simple spray wetting group includes:

[0128] 1 kg of dry particles are spread on a stainless steel tray, and 0.3% of purified water is atomized and sprayed using a sprayer at a spraying rate of 10 mL / min for about 2 minutes; the particles are manually stirred while spraying to make the surface of the particles slightly wet; the particles are immediately transferred into a V-type mixer, 0.5% of silicon dioxide is added, and mixed for 10 minutes; sieved through a 24-mesh sieve→0.5% of magnesium stearate is added, and mixed for 3 minutes in total; and loaded into a No. 1 hollow capsule.

[0129] The present application scheme group includes: 1 kg of dry particles are evenly dispersed on the surface of an elastic plate of a wave vibration device; a servo motor is started, and the wave frequency is set to 2 Hz and the amplitude is set to 10 mm; 0.3% of purified water is sprayed using an ultramicro atomizing nozzle at a spraying rate of 10 mL / min for 2-3 minutes; the water absorption block / water guide fiber network is operated for 10 minutes to automatically balance the moisture on the surface of the particles; the particles are collected and transferred into a fluidized bed mixer, 0.5% of silicon dioxide is added, and mixed for 5 minutes at an air flow speed of 0.6 m / s; sieved through a 24-mesh sieve→0.5% of magnesium stearate is added, and mixed for 3 minutes in total; and loaded into a No. 1 hollow capsule.

[0130] The three groups are detected, including:

[0131] Glidant coating uniformity method: scanning electron microscopy (SEM) + energy dispersive spectroscopy (EDS), 20 particles are sampled, the surface Si content distribution is detected, and the coefficient of variation (CV%) is calculated.

[0132] Particle flowability method: angle of repose determination: the particles are allowed to freely fall, and the angle of repose is taken.

[0133] Fall time: the time for 100 g of particles to pass through a fixed hopper.

[0134] Capsule loading consistency method: 20 capsules are randomly taken and weighed, and the average loading and relative standard deviation (RSD%) are calculated.

[0135] Agglomeration and caking method: sieved through a 24-mesh sieve, and the passing rate and visual agglomeration are recorded.

[0136] By Figure 6The contrast experiment can show that: the traditional dry mixing group has obvious uneven distribution of flow aid, serious particle agglomeration, poor flowability and insufficient capsule loading consistency; the simple spray wetting group improves the distribution of flow aid to a certain extent, but due to uneven moisture control, there are still local over-wetting or over-drying, limited improvement of particle flowability and loading consistency, and after using the process of the application, the dynamic balance of particle surface moisture is realized by means of the wave type vibration device and the water absorption network, so that the flow aid can be highly uniformly coated, the particle flowability is significantly enhanced, the capsule loading consistency reaches the best level, and there is almost no agglomeration phenomenon, which fully proves the significant superiority and industrial application value of the application in technical effect.

[0137] It will be apparent to those skilled in the art that the application is not limited to the details of the above-exemplified embodiments and that the application can be implemented in other particular forms without departing from the spirit or essential characteristics of the application. The embodiments should therefore be considered in all respects as illustrative and not restrictive, the scope of the application being defined by the appended claims rather than by the above description, and it is therefore intended that all changes that come within the meaning and range of equivalency of the claims are resolvable position the application. Any reference signs in the claims should not be construed as limiting the claims to the figures in which the reference signs are used.

[0138] Furthermore, it should be understood that, although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the description of the specification is only for the sake of clarity, and those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that those skilled in the art can understand.

Claims

1. A process for the preparation of tauroursodeoxycholic acid capsule characterized by: It comprises the following steps: S1: Tauroursodeoxycholic acid is sieved through a 150-mesh sieve for standby; S2: Corn starch is added to purified water at 45-55°C, and then purified water at above 95°C is added under stirring to prepare a 10% starch slurry; S3: A prescribed amount of tauroursodeoxycholic acid, lactose monohydrate, and microcrystalline cellulose are mixed and stirred uniformly, and then the starch slurry is added, and stirring is continued to form a wet mixture; S4: The wet mixture is sieved through a 16-mesh sieve to obtain wet granules; S5: The wet granules are subjected to drying treatment until the water content of the granules is reduced to below 3%; S6: The dried granules are sieved through a 24-mesh sieve to obtain uniform granules; S7: The dried uniform granules are dispersed on the surface of a high-frequency wave vibration device driven by a servo motor, and purified water with a mass fraction of 0.3% is uniformly sprayed in a spraying manner, the wave frequency is 2 Hz, and the mixing time is 5 min, so that the surface of the granules forms a slightly wet state, and then the slightly wet granules are collected and transferred to a medical-grade mixing container, medical-grade colloidal silicon dioxide glidant with a mass fraction of 0.1%-1% is added, and a fluidized bed mixer is used for mechanical mixing to uniformly coat the glidant on the surface of the granules; S8: A prescribed amount of magnesium stearate is added to the dried uniform granules and mixed uniformly, and then a filling rod is used to fill the mixed granules into empty capsules to obtain tauroursodeoxycholic acid capsules; The vibration device in S7 comprises a plurality of first moving blocks (11) and a plurality of second moving blocks (12), the plurality of first moving blocks (11) and the plurality of second moving blocks (12) are distributed at intervals, the bottom end of each first moving block (11) is fixedly connected with a first upper moving plate (13), the bottom end of each second moving block (12) is fixedly connected with a second upper moving plate (14), and the first moving blocks (11) and the second moving blocks (12) are installed with elastic plates (21) at the ends close to each other, and a plurality of uniformly distributed contact assemblies (2) are installed on each elastic plate (21); The bottom end of each first upper moving plate (13) is fixedly connected with a first toothed plate (15), the bottom end of each second upper moving plate (14) is fixedly connected with a second toothed plate (16), and a gear is meshingly connected between the first toothed plate (15) and the second toothed plate (16), and one end of the gear is fixedly connected with a servo motor; The contact assembly (2) comprises a water absorption block (22), the water absorption block (22) is installed on the elastic plate (21), the top end of the elastic plate (21) is fixedly connected with a water guide strip (23), and a plurality of uniformly distributed water guide fibers (24) are installed outside the water guide strip (23); The materials of the water absorption block (22), the water guide strip (23), and the water guide fibers (24) are all set to water-absorbing materials.

2. A process for the preparation of a tauroursodeoxycholic acid capsule as claimed in claim 1, wherein: The mass percentage ranges of tauroursodeoxycholic acid, lactose, microcrystalline cellulose, corn starch, and magnesium stearate are 55%-80%, 5%-15%, 2%-10%, 2%-8%, and 0.2%-1%, respectively.

3. A process for the preparation of a tauroursodeoxycholic acid capsule as claimed in claim 1, wherein: In S3, tauroursodeoxycholic acid, lactose monohydrate, and microcrystalline cellulose are stirred for 10-20 minutes in a mechanical stirring manner to ensure uniformity.

4. A process for the preparation of a tauroursodeoxycholic acid capsule as claimed in claim 1, wherein: The drying method in S5 is hot air circulation drying, the drying temperature is 40-60℃, the drying is until the moisture content of the granules is less than 4%, and the moisture is detected by periodic sampling during the drying.

5. A process for the preparation of a tauroursodeoxycholic acid capsule as claimed in claim 1, wherein: The mechanical mixing in S7 is performed by a fluidized bed mixer for 3-10 minutes.

6. A process for the preparation of a tauroursodeoxycholic acid capsule as claimed in claim 1, wherein: The magnesium stearate in S8 is added after the dried granules are sieved through a 24-mesh sieve, and the granules are immediately filled after being uniformly mixed, and the mixing time is 2-5 minutes.

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