Ursodeoxycholic acid capsule and preparation method thereof

Abstract

The present invention discloses an ursodeoxycholic acid capsule and a preparation method thereof. The ursodeoxycholic acid capsule is composed of contents and a capsule shell, wherein the contents include ursodeoxycholic acid, a filler, a binder and a lubricant, wherein the filler is microcrystalline cellulose and lactose, the binder is povidone K30, and the lubricant is magnesium stearate and silicon dioxide. The present invention adopts ursodeoxycholic acid raw material, obtains it by mechanical crushing, does not require micronized raw material, and has a simple and controllable process. By optimizing the type and amount of filler and lubricant and optimizing the one-step granulation process parameters, the prepared ursodeoxycholic acid capsule product has good dissolution, small batch-to-batch variation, and stable quality. In five different media, namely, pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, pH 7.2 phosphate buffer, and pH 7.5 phosphate buffer, the ursodeoxycholic acid capsule has the same dissolution behavior as the reference preparation Ursof.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an ursodeoxycholic acid capsule and a preparation method thereof. Background Art

[0002] Ursodeoxycholic acid (UDCA), the main component of bear bile, is chemically known as (3α,7β)-dihydroxy-5β-cholanoic acid, the 7-hydroxy diastereomer of chenodeoxycholic acid. Since its discovery in the 1980s as an effective cholesterol gallstone dissolver, new research has consistently demonstrated its positive effects in choleresis and liver protection. In recent years, international reports have shown that UDCA is not only effective in treating primary biliary cirrhosis, primary sclerosing cholangitis, and chronic active hepatitis, but is also useful in treating chronic hepatitis and post-liver transplant rejection. Ursodeoxycholic acid increases bile acid secretion, increasing its content in bile and promoting choleretic activity. It also inhibits hepatic cholesterol synthesis, reduces the molecular weight and saturation index of cholesterol in bile, improves cholesterol solubility in gallstones, and reduces the likelihood of gallstone formation. In addition, ursodeoxycholic acid can reduce liver fat, increase the activity of liver catalase, and improve the liver's detoxification and detoxification capabilities. Therefore, ursodeoxycholic acid is widely used in the clinical treatment of various liver diseases and has achieved good results.

[0003] Currently, ursodeoxycholic acid is primarily used clinically to treat various liver, gallbladder, and digestive tract diseases. With the continuous advancement of molecular biology and basic and clinical research on ursodeoxycholic acid, it has been found that ursodeoxycholic acid also has positive effects in promoting immune regulation and treating coronary heart disease.

[0004] Currently, the most common ursodeoxycholic acid preparation on the market is tablets, which are mainly used to treat liver and gallbladder diseases. However, ursodeoxycholic acid tastes bitter, so it is not suitable for people who are afraid of bitterness, such as young children. Capsules can better improve the compliance of taking the medicine.

[0005] Research results from the Guangdong Provincial Food and Drug Inspection Institute show that there are significant differences in the intrinsic quality of ursodeoxycholic acid tablets produced by many domestic companies. The similarity between different companies is low, and even the uniformity of products in different batches or within batches of the same company is inconsistent. Such significant differences in dissolution at different time points may cause uneven drug efficacy, thereby affecting the clinical efficacy of ursodeoxycholic acid tablets.

[0006] The market for ursodeoxycholic acid preparations has seen significant growth, with the vast majority of sales coming from imported Ursofalk, a German pharmaceutical company. Sales of domestically produced ursodeoxycholic acid preparations have been declining for nearly a decade, reaching a low point in 2012. While there has been some recovery in the past two years, the market share remains below 3%. Given the limited availability of Ursofalk's formulation and manufacturing process, its high price and the significant financial burden on patients, the development of ursodeoxycholic acid capsules with a different formulation than Ursofalk has become an urgent issue.

[0007] Existing patent CN109568288A discloses ursodeoxycholic acid capsules. The raw materials, by weight, include: 3-9 parts ursodeoxycholic acid, 0.01-4 parts pregelatinized starch, 0.02-4 parts starch, 0.1-0.2 parts magnesium stearate, 0.05-0.5 parts colloidal silicon dioxide, and 0.05-1 parts hydropropyl methylcellulose. The ursodeoxycholic acid is micronized to a particle size D90 <40 μm. Micronized raw materials are used, and micronization of these raw materials requires high equipment and processes. Micronized raw materials also exhibit strong agglomeration and metal adhesion, making the process challenging for current pharmaceutical processing lines that primarily utilize metal equipment. The use of starch as a binder in this formulation requires the preparation of a starch slurry during production, requiring high-temperature boiling or boiling water slurry flushing. This process carries the risk of burns. Furthermore, variations in starch slurry preparation significantly affect its viscosity, leading to batch-to-batch variability in the resulting product. In addition, traditional high-efficiency wet granulators produce the required granules through high-speed shearing and stirring, which has problems such as high granule hardness, high granule strength, and difficulty in granulation. Summary of the Invention

[0008] The present invention aims to overcome the shortcomings of the prior art and provide an ursodeoxycholic acid capsule and a preparation method thereof. The ursodeoxycholic acid capsule of the present invention has a reasonable formulation, good dissolution, readily available materials, a simple and controllable preparation process, small batch-to-batch variability, stable product quality, and its dissolution performance is similar to that of the reference reagent Ursofara.

[0009] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0010] An ursodeoxycholic acid capsule is composed of contents and a capsule shell. The contents include ursodeoxycholic acid, a filler, a binder, and a lubricant. The filler is microcrystalline cellulose and lactose, the binder is povidone K30, and the lubricant is magnesium stearate and silicon dioxide. The contents specifically include the following components in parts by weight: 225-275 parts of ursodeoxycholic acid, 12-20 parts of povidone K30, 25-35 parts of lactose, 25-35 parts of microcrystalline cellulose, 0.66-1.66 parts of magnesium stearate, and 1.66-2.66 parts of silicon dioxide.

[0011] Different drugs have strict selectivity for the particle size of raw materials, and are also selective for the types of excipients and their dosage. The ursodeoxycholic acid of the ursodeoxycholic acid capsules of the present invention is obtained by mechanical crushing, and does not require micronization treatment to avoid agglomeration of the micronized raw materials, which is not conducive to process operation. The preferred raw material particle size range of the present invention is: 18μm≤d50≤50μm, 80μm≤d90≤250μm. The ursodeoxycholic acid capsules of the present invention do not use starch as a binder and disintegrant, but select hydrophilic lactose and hydrophobic microcrystalline cellulose as a filler excipient composition, and are prepared with polyvidone K30, a high-efficiency binder commonly used in current pharmaceutical processes. Povidone K30 is dissolved at room temperature, and does not require high-temperature slurry boiling or boiling water slurrying. Magnesium stearate and silicon dioxide are selected as lubricants, and the dissolution of the prepared ursodeoxycholic acid capsule product is more similar to the dissolution of the original formulation of Ursof.

[0012] The ursodeoxycholic acid capsules prepared by the present invention have small intra-batch and inter-batch differences, excellent uniformity and controllability in product quality, and consistent dissolution curve behavior and stability with Ursofara. While ensuring product safety and effectiveness, the product price can be further reduced, giving patients more choices.

[0013] The present invention also provides a method for preparing the aforementioned ursodeoxycholic acid capsules, which are prepared through a one-step granulation, mixing, and filling process. The present invention utilizes a more efficient one-step granulation process, where dry mixing, wet mixing, stirring, granulation, and drying are all completed within the same fluidized bed apparatus, eliminating numerous operational steps, saving production time, and improving production efficiency. The granules produced by the one-step granulation process are uniform in size, easily controllable in size, and exhibit excellent flowability and compression molding properties, resulting in less batch-to-batch variability and more stable quality.

[0014] Preferably, the preparation method of the ursodeoxycholic acid capsules specifically comprises the following steps:

[0015] (1) Add ethanol, purified water, and povidone K30 in proportion, stir and dissolve completely to obtain an adhesive solution, which is set aside;

[0016] (2) obtaining ursodeoxycholic acid that meets the particle size requirements, and passing ursodeoxycholic acid, microcrystalline cellulose, and lactose through a 20-40 mesh sieve for later use;

[0017] (3) adding ursodeoxycholic acid, microcrystalline cellulose and lactose in step (2) into a boiling granulator, spraying the binder solution into the granulator, performing one-step granulation to obtain wet granules, and drying to obtain intermediate 1;

[0018] (4) adding silicon dioxide and magnesium stearate to the intermediate 1 and mixing them uniformly in a mixer to obtain the intermediate 2;

[0019] (5) According to the product specifications, the intermediate 2 is filled into the capsule shell to obtain ursodeoxycholic acid capsules.

[0020] Preferably, in step (1), the weight ratio of ethanol to purified water is 1:10-1:5.

[0021] Preferably, in step (3), the process parameters of the one-step granulation are: inlet air temperature: 30-45°C, the spraying frequency is adjusted to spray the binder solution, and the material temperature is controlled to be maintained at 20°C-35°C to obtain wet granules; and the material is dried at 55°C-65°C until the moisture content of the material does not exceed 3.0%. By optimizing the one-step granulation process parameters, the particles after drying are uniform in size and have good dissolution performance.

[0022] Preferably, in step (4), the intermediate 1 is sieved through a 20-40 mesh sieve, and the magnesium stearate and silicon dioxide are sieved through a 20-40 mesh sieve.

[0023] Preferably, in step (4), the sieved magnesium stearate and silicon dioxide are mixed evenly, and then added to the sieved intermediate 1 and mixed for 5-10 minutes.

[0024] Preferably, in step (5), the intermediate 2 is filled into a capsule shell by a fully automatic capsule filling machine.

[0025] Following oral administration, drug absorption depends on the dissolution or release of the drug from the formulation and its permeation or transport through the gastrointestinal tract under physiological conditions. Drug dissolution or release has a significant impact on drug absorption. The consistency of in vitro dissolution behavior can be assessed by comparing the dissolution curve similarity factor (f2) and the dissolution curve difference factor (f1). f2 should be greater than 50, and f1 should be between 0 and 15.

[0026] The similarity factor f2 is calculated as follows:

[0027]

[0028] R t and T t Represents the cumulative dissolution of the two preparations at the nth sampling point

[0029] The calculation formula of the difference factor f1 is as follows:

[0030]

[0031] R t and T t Represents the cumulative dissolution of the two preparations at the nth sampling point.

[0032] Pharmacokinetic data for ursodeoxycholic acid capsules show that after oral administration, the drug is rapidly absorbed through passive transport in the jejunum and anterior ileum, and through active transport in the terminal ileum. Generally, 60% to 80% of the drug is absorbed. After absorption, nearly all bile acids are conjugated to glycine and taurine in the liver and then secreted with bile. The first-pass clearance rate in the liver can reach 60%. In the intestine, a portion is degraded by bacteria into 7-ketocholic acid and cholic acid. Cholic acid is hepatotoxic and can cause damage to hepatocytes in some animal species. In humans, only a small portion is absorbed and detoxified in hepatocytes through sulfation, secreted with bile, and ultimately excreted in the feces. The half-life of ursodeoxycholic acid is 3.5 to 5.8 days.

[0033] Ursodeoxycholic acid capsules are pH-dependent preparations. In pH 1.2 hydrochloric acid solution, water, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer, dissolution differences between preparations of different qualities were not significant, and therefore could not be used to effectively differentiate product quality. However, in pH 7.2 phosphate buffer, the dissolution behavior of different preparations differed significantly, effectively enabling differentiation of product dissolution behavior and providing a discriminating dissolution condition for ursodeoxycholic acid capsules.

[0034] The ursodeoxycholic acid capsules of the present invention not only have the same dissolution as the reference preparation in four conventional media, namely pH 1.2 hydrochloric acid solution, water, pH 4.5 acetate buffer and pH 6.8 phosphate buffer, but also have the same dissolution as the reference preparation in pH 7.2 phosphate buffer and pH 7.5 phosphate buffer, which are media with higher discrimination power for ursodeoxycholic acid.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] (1) The present invention uses common ursodeoxycholic acid raw materials, which are conventional and easily available and do not require micronization treatment, thereby avoiding the agglomeration of the micronized raw materials and reducing metal adhesion. For current pharmaceutical processing lines that are mainly equipped with metal equipment, the process difficulty is reduced.

[0037] (2) The present invention does not use starch as a binder and disintegrant, but instead selects hydrophilic lactose and hydrophobic microcrystalline cellulose as a filler excipient composition, which is prepared by combining it with povidone K30, a highly effective binder commonly used in current pharmaceutical processes. Povidone K30 is dissolved at room temperature. Combined with a one-step granulation process, the dry mixing, wet mixing, stirring, granulation, and drying of the materials are all completed in the same fluidized bed equipment, simplifying the process operation, saving production time, and improving production efficiency. The granules produced by the one-step granulation process have uniform particle size, good fluidity and compression forming properties, and are easy to control, resulting in smaller batch-to-batch quality differences and more stable quality.

[0038] (3) Compared with tablets, ursodeoxycholic acid capsules are multi-particle dispersion systems, which disperse quickly in gastrointestinal fluid, are well absorbed, have high bioavailability, and can mask the bitter taste of the drug, thereby improving patient compliance.

[0039] (4) The ursodeoxycholic acid capsules prepared by the present invention have stable quality, simple preparation process and low production cost, and are suitable for large-scale industrial production. The in vitro dissolution curve of the ursodeoxycholic acid capsules prepared by the present invention was tested, and the consistency between batches was good, the quality was stable and controllable, and the dissolution behavior was the same as that of the original preparation Ursof in five different media, namely pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, pH 7.2 phosphate buffer and pH 7.5 phosphate buffer. The present invention can break the monopoly of foreign products, further reduce product prices while ensuring product safety and effectiveness, and provide patients with more choices. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The dissolution curves of different batches of ursodeoxycholic acid capsule preparations and the reference preparation in pH 1.2 hydrochloric acid solution in Example 6 are shown;

[0041] Figure 2 The dissolution curves of different batches of ursodeoxycholic acid capsule preparations and the reference preparation in pH 4.5 acetate buffer solution of Example 6 are shown;

[0042] Figure 3 The dissolution curves of different batches of ursodeoxycholic acid capsule preparations and the reference preparation in pH 6.8 phosphate buffer solution in Example 6 are shown;

[0043] Figure 4 The dissolution curves of different batches of ursodeoxycholic acid capsule preparations and the reference preparation in pH 7.2 phosphate buffer solution of Example 6 are shown;

[0044] Figure 5 These are the dissolution curves of different batches of ursodeoxycholic acid capsule preparations and the reference preparation in pH 7.5 phosphate buffer solution in Example 6. DETAILED DESCRIPTION

[0045] To better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. Those skilled in the art should understand that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0046] In the examples, the experimental methods used are conventional methods unless otherwise specified, and the materials and reagents used are commercially available unless otherwise specified. The reference reagent of the present invention is Ursofol produced by Fokker Pharma GmbH in Germany.

[0047] Example 1 Effect of different processes on product dissolution

[0048] In this example, the effects of different production processes on product dissolution were studied with the same components and dosages of ursodeoxycholic acid capsules. The specific process parameters are shown in Table 1.

[0049] Table 1 List of different granulation process parameters

[0050]

[0051] The dissolution curves of ursodeoxycholic acid capsules prepared according to the above granulation process and the reference preparation Ursofara were measured and evaluated using the similarity factor f2. The results are shown in Table 2.

[0052] Table 2 Dissolution curve data of different production processes

[0053]

[0054] Result analysis:

[0055] Direct powder mixing: The density of the contents is relatively low, and 00# capsules must be used for filling. The capsules are too large to be swallowed, and the dissolution curve is not similar to that of the reference preparation.

[0056] High-speed stirring wet granulation: During the granulation process, static electricity was obvious, and the fine powder was adsorbed on the pot wall and became sticky after being squeezed and sheared by the stirring paddle. After drying, the particle size was uneven, and the large particles were hard. No dissolution curve study was conducted.

[0057] One-step granulation: The dry granules produced are relatively uniform in size, good in particle size, appropriate in proportion, and have a dissolution curve similar to that of the reference preparation.

[0058] In summary, the present invention prefers a one-step granulation process, in which dry mixing, wet mixing, stirring, granulation forming, and drying of the materials are all completed in the same fluidized bed equipment, which simplifies the process operation and ensures uniform granule size, good fluidity and compression forming properties, and more stable quality.

[0059] Example 2 Effect of different raw material particle sizes on product dissolution

[0060] In this example, the effects of different raw material particle sizes on product dissolution were studied with the same components and dosages of ursodeoxycholic acid capsules. The specific raw material particle size parameters are shown in Table 3.

[0061] Table 3 List of different raw material particle sizes

[0062]

[0063] The preparation method of the ursodeoxycholic acid capsules of this embodiment comprises the following steps:

[0064] (1) Add ethanol to purified water, mix, add povidone K30, and stir until the povidone K30 is completely dissolved and the solution is clear to obtain an adhesive solution for later use;

[0065] (2) ursodeoxycholic acid raw material is passed through a 20-mesh sieve, and microcrystalline cellulose and lactose are passed through a 40-mesh sieve and set aside;

[0066] (3) adding the sieved material from step (2) to a boiling granulator, setting the air inlet temperature to 30-45°C, adjusting the spray frequency to spray the binder solution, and controlling the material temperature to be maintained within the range of 25-35°C to obtain wet granules of ursodeoxycholic acid capsules; drying the wet granules at 55-65°C until the moisture content of the granules does not exceed 3.0%, thereby obtaining intermediate 1;

[0067] (4) sieve the intermediate 1 through a 20-40 mesh sieve to form particles, sieve the silicon dioxide and magnesium stearate through a 40 mesh sieve and mix them, add the magnesium stearate and silicon dioxide mixture and the sieved intermediate 1 into a mixer and mix for 10 minutes to obtain intermediate 2;

[0068] (5) According to the product specifications, the intermediate 2 is filled into capsule shells by a fully automatic capsule filling machine to obtain ursodeoxycholic acid capsules.

[0069] The dissolution curves of ursodeoxycholic acid capsules prepared using the above-mentioned raw materials with different particle sizes and the reference preparation Ursofara were measured, and the dissolution curve similarity factor f2 and difference factor f1 were used to compare them. The results are shown in Table 4.

[0070] Table 4 Dissolution curves of samples prepared from raw materials with different particle sizes in pH 7.2 medium

[0071]

[0072] The above results show that the particle size distribution of the raw material has a significant effect on the dissolution rate of the preparation. As the particle size of the raw material increases, the dissolution rate tends to decrease. When its d50 is 14.6μm and the corresponding d90 is 51.4μm, the dissolution is too fast due to the small raw material particle size, and the dissolution curve in the pH7.2 medium is not similar to that of the reference product. When the particle size distribution range of the raw material is approximately 18μm≤d50≤50μm, 80μm≤d90≤250μm, the dissolution curve of the prepared sample in the pH7.2 medium is similar to that of the reference product. When its d50>50μm, d90>250μm, the dissolution is slow due to the large raw material particle size, and the dissolution curve in the pH7.2 medium is not similar to that of the reference product, and the mixing effect in the product is not good. Therefore, the preferred particle size of the raw material in this application is: 18μm≤d50≤50μm, 80μm≤d90≤250μm.

[0073] Example 3 Effect of different fillers on product dissolution

[0074] The effects of different fillers on product dissolution were studied. The specific formulation of the contents of ursodeoxycholic acid capsules is shown in Table 5.

[0075] Table 5 Prescription list of different fillers

[0076]

[0077]

[0078] The preparation method of ursodeoxycholic acid capsules with different fillers in this embodiment comprises the following steps:

[0079] (1) Add ethanol to purified water, mix, add povidone K30, and stir until the povidone K30 is completely dissolved and the solution is clear to obtain an adhesive solution for later use;

[0080] (2) Ursodeoxycholic acid raw materials with a diameter of 18 μm ≤ d50 ≤ 50 μm and a diameter of 80 μm ≤ d90 ≤ 250 μm were sieved through a 20-mesh sieve, and the lactose in recipe 6, the microcrystalline cellulose and lactose mixture in recipe 7, and the microcrystalline cellulose in recipe 8 were sieved through a 40-mesh sieve and set aside;

[0081] (3) adding the sieved material from step (2) to a boiling granulator, setting the air inlet temperature to 30-45°C, adjusting the spray frequency to spray the binder solution, and controlling the material temperature to be maintained within the range of 25-35°C to obtain wet granules of ursodeoxycholic acid capsules; drying the wet granules at 55-65°C until the moisture content of the granules does not exceed 3.0%, thereby obtaining intermediate 1;

[0082] (4) sieve the intermediate 1 through a 20-40 mesh sieve to form particles, sieve the silicon dioxide and magnesium stearate through a 40 mesh sieve and mix them, add the magnesium stearate and silicon dioxide mixture and the sieved intermediate 1 into a mixer and mix for 10 minutes to obtain intermediate 2;

[0083] (5) According to the product specifications, the intermediate 2 is filled into capsule shells by a fully automatic capsule filling machine to obtain ursodeoxycholic acid capsules.

[0084] The dissolution curves of ursodeoxycholic acid capsules prepared using the above-mentioned fillers and the reference preparation Ursofara in a pH 7.2 medium were measured and compared using the dissolution curve similarity factor f2 and difference factor f1. The results are shown in Table 6.

[0085] Table 6

[0086]

[0087] Result analysis:

[0088] Prescription 6 uses only lactose as filler, which has good hydrophilicity, but its particle disintegration effect is not as good as that of microcrystalline cellulose, resulting in low product dissolution.

[0089] Prescription 7 uses only microcrystalline cellulose as the filler. The ursodeoxycholic acid raw material is hydrophobic in nature. Adding only hydrophobic microcrystalline cellulose to the filler cannot promote the wetting of the ursodeoxycholic acid raw material, which will result in low dissolution of the product.

[0090] The filler of prescription 8 uses a combination of microcrystalline cellulose and lactose. Microcrystalline cellulose promotes the disintegration of particles, and lactose increases the wetting of particles. The combination of the two results in good dissolution of the product, which is similar to the dissolution curve of the reference preparation.

[0091] In summary, the filler of the present invention is preferably a combination of microcrystalline cellulose and lactose.

[0092] Example 4 Effect of different ratios of lubricants on product dissolution

[0093] The effects of different proportions of lubricants on product dissolution were studied. The specific formulation of the contents of ursodeoxycholic acid capsules is shown in Table 7.

[0094] Table 7 List of lubricants with different ratios

[0095]

[0096] The method for preparing ursodeoxycholic acid capsules with different ratios of lubricants in this embodiment comprises the following steps:

[0097] (1) Add ethanol to purified water, mix, add povidone K30, and stir until the povidone K30 is completely dissolved and the solution is clear to obtain an adhesive solution for later use;

[0098] (2) Ursodeoxycholic acid raw materials with 18 μm ≤ d50 ≤ 50 μm and 80 μm ≤ d90 ≤ 250 μm are sieved through a 20-mesh sieve, and microcrystalline cellulose and lactose are sieved through a 40-mesh sieve and set aside;

[0099] (3) adding the sieved material from step (2) to a boiling granulator, setting the air inlet temperature to 30-45°C, adjusting the spray frequency to spray the binder solution, and controlling the material temperature to be maintained within the range of 25-35°C to obtain wet granules of ursodeoxycholic acid capsules; drying the wet granules at 55-65°C until the moisture content of the granules does not exceed 3.0%, thereby obtaining intermediate 1;

[0100] (4) sieve the intermediate 1 through a 20-40 mesh sieve to form particles, sieve the silicon dioxide and magnesium stearate through a 40 mesh sieve and mix them, add the magnesium stearate and silicon dioxide mixture and the sieved intermediate 1 into a mixer and mix for 10 minutes to obtain intermediate 2;

[0101] (5) According to the product specifications, the intermediate 2 is filled into capsule shells by a fully automatic capsule filling machine to obtain ursodeoxycholic acid capsules.

[0102] The dissolution curves of the ursodeoxycholic acid capsules prepared above and the reference preparation Ursofara in a pH 7.2 medium were measured and compared using the dissolution curve similarity factor f2 and difference factor f1. The results are shown in Table 8.

[0103] Table 8 Dissolution curves of samples prepared with different ratios of lubricants in pH 7.2 medium

[0104]

[0105] Conclusion analysis:

[0106] When the lubricant of Prescription 9 consisted of 2.66 parts of magnesium stearate and 0.66 parts of silicon dioxide, the production process went smoothly, but the product dissolution was slow and different from that of the reference preparation.

[0107] When the lubricant of prescription 10 consisted of 1.66 parts of magnesium stearate and 1.66 parts of silicon dioxide, the production process went smoothly and the dissolution of the product was similar to that of the reference preparation.

[0108] When the lubricant of prescription 11 consisted of 0.66 parts of magnesium stearate and 2.66 parts of silicon dioxide, the production process went smoothly and the dissolution of the product was similar to that of the reference preparation.

[0109] It can be seen that the ratio of magnesium stearate to silicon dioxide in the lubricant affects the dissolution performance of the product. To obtain an ursodeoxycholic acid capsule product with a dissolution profile consistent with that of Ursoflav, the lubricant of the present invention comprises 0.66-1.66 parts of magnesium stearate and 1.66-2.66 parts of silicon dioxide. When the magnesium stearate is less than 0.66 parts and the silicon dioxide is greater than 2.66 parts, while the dissolution performance of the product is not affected, it can adversely affect the flowability of Intermediate 2, preventing the product from being smoothly filled into the capsule.

[0110] Example 5 Effect of One-Step Granulation Process Parameters on Product Dissolution

[0111] In this example, the effect of lubricants with different one-step granulation process parameters on product dissolution was studied with other conditions being the same.

[0112] The preparation method of ursodeoxycholic acid capsules of this embodiment comprises the following steps:

[0113] (1) Add ethanol to purified water in a weight ratio of 1:10 to 1:5, add povidone K30 after mixing, and stir until the povidone K30 is completely dissolved and the solution is clear, thereby obtaining an adhesive solution for later use;

[0114] (2) Ursodeoxycholic acid raw materials with 18 μm ≤ d50 ≤ 50 μm and 80 μm ≤ d90 ≤ 250 μm are sieved through a 20-mesh sieve, and microcrystalline cellulose and lactose are sieved through a 40-mesh sieve and set aside;

[0115] (3) The sieved material from step (2) was added to a boiling granulator, the air inlet temperature was set to 30-45°C, and the spraying frequency was adjusted to spray the binder solution, as shown in Table 9, to obtain ursodeoxycholic acid capsule wet granules; the wet granules were dried at 55-65°C until the moisture content of the granules did not exceed 3.0%, to obtain intermediate 1;

[0116] (4) sieve the intermediate 1 through a 20-mesh sieve to form particles, sieve the silicon dioxide and magnesium stearate through a 40-mesh sieve and mix them, add the magnesium stearate and silicon dioxide mixture and the sieved intermediate 1 into a mixer and mix for 10 minutes to obtain intermediate 2;

[0117] (5) According to the product specifications, the intermediate 2 is filled into capsule shells by a fully automatic capsule filling machine to obtain ursodeoxycholic acid capsules.

[0118] Table 9 One-step granulation process parameters

[0119]

[0120] The dissolution curves of ursodeoxycholic acid capsules prepared by the above method and the reference preparation Ursofara in pH 7.2 medium were measured and compared using the dissolution curve similarity factor f2 and difference factor f1. The results are shown in Table 10.

[0121] Table 10 Dissolution curves of samples prepared by one-step granulation in pH 7.2 medium (n=12)

[0122]

[0123] Result analysis:

[0124] As the material temperature decreases, the proportion of particles that can pass through a 24-mesh sieve before granulation decreases, the particle density increases, the dissolution rate decreases, and the similarity factor approaches the lower limit.

[0125] The dissolution curve of the product prepared when the material temperature was controlled at 20-35°C was similar to that of the reference preparation and met the requirements.

[0126] Example 6 Production scale batch prescription

[0127] Three batches were produced in the workshop according to the determined prescription, and the prescription of the contents is shown in Table 11.

[0128] The dissolution and stability of the product are consistent with those of the reference preparation.

[0129] Table 11 Sample capsule contents components

[0130]

[0131] The preparation method of ursodeoxycholic acid capsules of this embodiment comprises the following steps:

[0132] (1) Add ethanol to purified water, mix, add povidone K30, and stir until the povidone K30 is completely dissolved and the solution is clear to obtain an adhesive solution for later use;

[0133] (2) Ursodeoxycholic acid raw materials with 18 μm ≤ d50 ≤ 50 μm and 80 μm ≤ d90 ≤ 250 μm are sieved through a 20-mesh sieve, and microcrystalline cellulose and lactose are sieved through a 40-mesh sieve and set aside;

[0134] (3) adding the sieved material from step (2) to a boiling granulator, setting the air inlet temperature to 30-45°C, adjusting the spray frequency to spray the binder solution, and controlling the material temperature to be maintained within the range of 25-35°C to obtain wet granules of ursodeoxycholic acid capsules; drying the wet granules at 55-65°C until the moisture content of the granules does not exceed 3.0%, thereby obtaining intermediate 1;

[0135] (4) sieve the intermediate 1 through a 20-mesh sieve to form particles, sieve the silicon dioxide and magnesium stearate through a 40-mesh sieve and mix them, add the magnesium stearate and silicon dioxide mixture and the sieved intermediate 1 into a mixer and mix for 10 minutes to obtain intermediate 2;

[0136] (5) According to the product specifications, the intermediate 2 is filled into capsule shells by a fully automatic capsule filling machine to obtain ursodeoxycholic acid capsules.

[0137] Using 15K11254L, 16B18318L, and 13I27710L batches of Ursofarad as reference reagents, the dissolution rates of the three batches of Ursofarad in five common media, namely, pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, pH 7.2 phosphate buffer, and pH 7.5 phosphate buffer, were determined, and the dissolution curves were drawn. The results are shown in Figure 2. Figure 1-5 shown.

[0138] Depend on Figure 1-5 The results show that the dissolution and stability of the products produced in the above three batches are consistent with those of the reference preparation, indicating that the ursodeoxycholic acid capsule preparation prepared according to the process of the present invention has small batch differences and the product quality has excellent uniformity and controllability.

[0139] Compared with the existing ursodeoxycholic acid preparation process that requires the use of micronized raw materials, the preparation method of the ursodeoxycholic acid capsules of the present invention only requires the use of ursodeoxycholic acid raw materials and mechanically crushing to obtain the product, without the need for micronized raw materials. The process is simple, and by optimizing the type and ratio of the filler and the proportion of the lubricant, and adopting an efficient one-step granulation process, the product has the same dissolution behavior in five different media, namely, pH 1.2 hydrochloric acid, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and pH 7.2 phosphate buffer and pH 7.5 phosphate buffer, which are the distinguishing media for ursodeoxycholic acid capsules, and can effectively reflect the absorption law of the human body.

[0140] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for preparing ursodeoxycholic acid capsules, characterized in that: The specific steps include: (1) Add 9.8 parts of ethanol, 83.35 parts of purified water, and 8.1 parts of povidone K30, and stir to dissolve completely to obtain an adhesive solution for later use; (2) Obtain 125 parts of ursodeoxycholic acid with a particle size range of 18 µm ≤ d50 ≤ 50 µm and 80 µm ≤ d90 ≤ 250 µm and pass it through a 20-mesh sieve. Take 15.13 parts of microcrystalline cellulose and 15.13 parts of lactose and pass them through a 40-mesh sieve for later use. (3) Add ursodeoxycholic acid, microcrystalline cellulose and lactose in step (2) into a boiling granulator, set the air inlet temperature to 30-45°C, adjust the spray frequency to spray the binder solution, and control the material temperature to be maintained at 25°C-35°C to obtain wet granules, and then dry at 55°C-65°C until the moisture content of the material does not exceed 3.0%, thereby obtaining intermediate 1; (4) The intermediate 1 was sieved through a 20-mesh sieve to obtain a granule, 1.33 parts of silicon dioxide and 0.33 parts of magnesium stearate were sieved through a 40-mesh sieve and mixed, and the intermediate 1 and the mixture of silicon dioxide and magnesium stearate were mixed in a mixer for 10 minutes to obtain intermediate 2; (5) According to the product specifications, the intermediate 2 is filled into the capsule shell to obtain ursodeoxycholic acid capsules.

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