Ursodeoxycholic acid capsule formulation for litholysis after biliary stent placement.

Abstract

This invention discloses an ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement, belonging to the field of pharmaceutical technology. The capsule formulation comprises, by weight, 250 parts ursodeoxycholic acid, 40 parts pentaerythritol, 30 parts hydroxypropyl methylcellulose acetosuccinate, 15 parts microcrystalline cellulose, 35 parts starch, 5 parts colloidal silica, 2 parts magnesium stearate, and 120 parts purified water. It is prepared by co-preparing ursodeoxycholic acid with pentaerythritol and hydroxypropyl methylcellulose acetosuccinate into a ternary solid dispersion, allowing ursodeoxycholic acid to exist in an amorphous form. This dispersion is then granulated into capsules using a three-step wet granulation process, achieving a balance between rapid release and long-term storage stability. The pentaerythritol may also include a combination of low-crystallinity and high-crystallinity pentaerythritol, achieving a dual-phase release of both immediate and sustained-release components, further prolonging the duration of effective drug concentration. This formulation is suitable for the needs of patients after biliary stent placement for rapid onset of action and long-term treatment.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to an ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement. Background Technology

[0002] Common bile duct stones are a common biliary system disease, with a high incidence in the Yangtze River basin, southeastern coastal areas, southwest China, and southern China. Currently, endoscopic retrograde cholangiopancreatography (ERCP) combined with endoscopic sphincterotomy is the main treatment for common bile duct stones, which can be removed using a basket or balloon. However, for refractory common bile duct stones such as large stones (diameter > 1.5 cm), multiple stones (≥ 3), or stones complicated by bile duct stenosis or papillary structural abnormalities, complete stone removal in a single procedure is difficult. Often, a biliary stent is placed first, followed by a second endoscopic retrograde cholangiopancreatography (ERCP) for stone removal 3-6 months later.

[0003] Ursodeoxycholic acid (UDCA) is a widely used litholytic drug in clinical practice. Its mechanism of action involves inhibiting cholesterol synthesis in the liver and reducing cholesterol saturation in bile, thus facilitating the gradual dissolution of cholesterol in gallstones. Clinical studies have confirmed that combining UDCA with biliary stent placement significantly improves the success rate of secondary stone removal in refractory common bile duct stones. However, UDCA is almost insoluble in water, classifying it as a poorly soluble drug. The dissolution rate of its oral formulation is a key factor affecting its absorption in vivo and its concentration in bile. Currently, UDCA capsules exist primarily in a crystalline state, resulting in a slow dissolution rate in the gastrointestinal tract. This leads to a prolonged time required to reach an effective litholytic concentration in bile, which is insufficient to meet the clinical need for rapid onset of action and early establishment of effective litholytic concentrations after biliary stent placement. Furthermore, existing formulations are susceptible to environmental humidity during storage, exhibiting poor stability.

[0004] Therefore, developing an ursodeoxycholic acid capsule formulation that can achieve rapid dissolution of ursodeoxycholic acid, reach an effective litholytic concentration in the early postoperative period after biliary stenting, and has good storage stability is of great clinical significance and application value. Summary of the Invention

[0005] This application provides an ursodeoxycholic acid capsule formulation for dissolving stones after biliary stenting, which solves the technical defects of existing oral ursodeoxycholic acid formulations, where ursodeoxycholic acid exists in a crystalline state, resulting in a slow dissolution rate and inability to achieve an effective stone-dissolving concentration in the early postoperative period, as well as the insufficient storage stability and susceptibility to moisture absorption and deterioration of existing formulations.

[0006] This application provides an ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement, comprising the following raw and excipient materials by weight: 230-270 parts ursodeoxycholic acid, 20-60 parts pentaerythritol, 10-50 parts hydroxypropyl methylcellulose acetosuccinate, 10-20 parts microcrystalline cellulose, 25-45 parts starch, 4-6 parts colloidal silica, 1-3 parts magnesium stearate, and 100-140 parts purified water.

[0007] Furthermore, the pentaerythritol has a particle size D90 ≤ 50 μm; the hydroxypropyl methylcellulose acetosuccinate is a micronized grade AS-MF type with an average particle size D50 ≤ 3 μm.

[0008] Furthermore, by weight, it contains the following raw and auxiliary materials: 250 parts ursodeoxycholic acid, 40 parts pentaerythritol, 30 parts hydroxypropyl methylcellulose acetosuccinate, 15 parts microcrystalline cellulose, 35 parts starch, 5 parts colloidal silica, 2 parts magnesium stearate, and 120 parts purified water.

[0009] Furthermore, the pentaerythritol comprises low-crystallinity pentaerythritol and high-crystallinity pentaerythritol, wherein the residual crystallinity of low-crystallinity pentaerythritol is ≤2%, the residual crystallinity of high-crystallinity pentaerythritol is 5%-10%, and the weight ratio of low-crystallinity pentaerythritol to high-crystallinity pentaerythritol is 3:1.

[0010] The preparation method of the ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement includes the following steps: Step 1: Pass pentaerythritol through a 100-mesh sieve and collect the sieve residue for later use; hydroxypropyl methylcellulose acetosuccinate can be used directly; Step 2: Ursodeoxycholic acid, pentaerythritol and hydroxypropyl methylcellulose acetosuccinate were added to anhydrous ethanol at a weight ratio of 1:15. The mixture was stirred until completely dissolved and then rotary evaporated at 50°C and -0.09 MPa vacuum until the ethanol was completely evaporated. The mixture was then dried for 10 hours at 45°C and -0.09 MPa vacuum. The powder was then pulverized through an 80-mesh sieve to obtain a ternary solid dispersion powder. Step 3: Add the ternary solid dispersion powder obtained in Step 2, microcrystalline cellulose and 28 parts of starch into a mixer and mix for 10 minutes at a mixing speed of 10 rpm; Step 4: Take 108 parts of purified water and heat it to 85℃. Keep it warm for 10 minutes. Slowly add the remaining 7 parts of starch to the insulated container and stir to gelatinize the starch. Cool down to 68℃ to obtain starch slurry. Step 5: Add the premixed material from Step 3 to a wet granulator, premix for 60 seconds at a stirring speed of 80 rpm and a cutter speed of 2000 rpm; spray 9.6 parts of purified water onto the surface of the material, granulate for 180 seconds at a stirring speed of 120 rpm and a cutter speed of 2000 rpm for the first granulation; add the starch slurry obtained in Step 4 to the material while it is still hot, granulate for 180 seconds at a stirring speed of 180 rpm and a cutter speed of 2000 rpm for the second granulation; add 3.2 parts of purified water, granulate for 180 seconds at a stirring speed of 120 rpm and a cutter speed of 2000 rpm for the third granulation; discharge the material and granulate it through a 20-mesh sieve to obtain wet granules; Step 6: Place the wet granules in a fluidized bed for drying, with an inlet air temperature of 60℃ and the material temperature controlled below 45℃, until the moisture content is ≤2%; Step 7: Sieve the dried granules through a 2.0mm sieve to form larger granules, add colloidal silica and magnesium stearate, and mix for 10 minutes at a mixing speed of 10 rpm; Step 8: Fill the shell with the mixed granules to obtain ursodeoxycholic acid capsule formulation.

[0011] Furthermore, the pentaerythritol mentioned in step 2 includes low-crystallinity pentaerythritol and high-crystallinity pentaerythritol. The residual crystallinity of low-crystallinity pentaerythritol is ≤2%, and the residual crystallinity of high-crystallinity pentaerythritol is 5%-10%. The weight ratio of low-crystallinity pentaerythritol to high-crystallinity pentaerythritol is 3:1.

[0012] Furthermore, step 2 further includes preparing a low-crystallinity pentaerythritol solid dispersion and a high-crystallinity pentaerythritol solid dispersion, respectively: The preparation method of the low crystallinity pentaerythritol solid dispersion is as follows: 250 parts of ursodeoxycholic acid, 30 parts of low crystallinity pentaerythritol and 30 parts of hydroxypropyl methylcellulose acetosuccinate are added to anhydrous ethanol, with the weight ratio of ursodeoxycholic acid to anhydrous ethanol being 1:15. The mixture is stirred until completely dissolved, and then rotary evaporated under a water bath temperature of 45℃ and a vacuum degree of -0.09MPa. At the same time, a rapid cooling method using an ice bath is adopted to ensure a cooling rate of ≥20℃ / min. After the ethanol is completely evaporated, the mixture is dried for 9 hours under a temperature of 43℃ and a vacuum degree of -0.09MPa, and then pulverized through an 80-mesh sieve. The preparation method of the highly crystalline pentaerythritol solid dispersion is as follows: 250 parts of ursodeoxycholic acid, 10 parts of highly crystalline pentaerythritol, and 30 parts of hydroxypropyl methylcellulose acetosuccinate are added to anhydrous ethanol, with the weight ratio of ursodeoxycholic acid to anhydrous ethanol being 1:15. The mixture is stirred until completely dissolved, and then rotary evaporated at a water bath temperature of 55℃ and a vacuum degree of -0.09MPa, while using natural cooling to keep the cooling rate ≤1℃ / min. After the ethanol is completely evaporated, the mixture is dried for another 5 hours at a temperature of 47℃ and a vacuum degree of -0.09MPa, and then pulverized through an 80-mesh sieve.

[0013] Further, the premixing in step 3 is as follows: 30 parts of low-crystallinity pentaerythritol solid dispersion powder, 10 parts of high-crystallinity pentaerythritol solid dispersion powder, 15 parts of microcrystalline cellulose and 28 parts of starch are added to a mixer and mixed for 15 minutes at a mixing speed of 10 rpm.

[0014] One or more technical solutions provided in the embodiments of this application have at least the following technical effects or advantages: By utilizing the intermolecular hydrogen bond network formed by the four hydroxymethyl groups of pentaerythritol with the carboxyl and hydroxyl groups of ursodeoxycholic acid, ursodeoxycholic acid is anchored in the pentaerythritol carrier, inhibiting the rearrangement and crystallization of ursodeoxycholic acid molecules. This allows the drug to be stably dispersed in an amorphous form, significantly improving the dissolution rate of ursodeoxycholic acid in the biliary environment. This can meet the clinical need for patients after biliary stent placement to quickly establish an effective litholytic concentration in the early postoperative period.

[0015] By utilizing the competitive hydrogen bond formed between the carboxyl group on the HPMCAS molecular chain and the hydroxymethyl group of pentaerythritol, some of the active hydroxyl groups of pentaerythritol are consumed, reducing the probability of esterification reaction between the hydroxyl groups of pentaerythritol and the carboxyl groups of ursodeoxycholic acid, and effectively inhibiting the formation of ester impurities. At the same time, the hydrophobic acetyl group of HPMCAS forms a hydrophobic barrier on the surface of the solid dispersion, effectively inhibiting the recrystallization of ursodeoxycholic acid caused by the hygroscopicity of pentaerythritol, thus giving the formulation good long-term storage stability.

[0016] Pentaerythritol and HPMCAS exhibit a synergistic effect. Pentaerythritol anchors ursodeoxycholic acid in an amorphous form for rapid release, while HPMCAS protects this amorphous form from degradation. Through a ternary hydrogen bond network, they work synergistically to achieve both anchoring and protection, ensuring that ursodeoxycholic acid maintains rapid dissolution while possessing good storage stability and low ester impurity content, making it suitable for long-term medication needs of patients after biliary stent placement.

[0017] By combining pentaerythritol in a specific ratio with low-crystallinity and high-crystallinity pentaerythritol, the low-crystallinity pentaerythritol dissolves rapidly for immediate release, while the high-crystallinity pentaerythritol dissolves slowly due to its higher lattice energy barrier. This continuous replenishment of ursodeoxycholic acid into the system achieves a dual-phase release of both immediate and sustained-release, effectively prolonging the effective concentration maintenance time of ursodeoxycholic acid in bile and better meeting the clinical needs of patients undergoing continuous litholytic therapy after biliary stent placement. Detailed Implementation

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to limit the invention; the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0019] Example 1: This example provides an ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement. A pentaerythritol-HPMCAS-ursodeoxycholic acid ternary solid dispersion is prepared by introducing pentaerythritol and hydroxypropyl methylcellulose acetosuccinate (HPMCAS) into ursodeoxycholic acid. The resulting solid dispersion is then further prepared into a capsule formulation. The specific technical solution is as follows.

[0020] The amounts of each raw material and excipient in the formula, by weight, are as follows: 250 parts ursodeoxycholic acid, 40 parts pentaerythritol, 30 parts hydroxypropyl methylcellulose acetosuccinate, 15 parts microcrystalline cellulose, 35 parts starch, 5 parts colloidal silica, 2 parts magnesium stearate, and 120 parts purified water.

[0021] Among them, pentaerythritol has a particle size D90≤50μm; hydroxypropyl methylcellulose acetosuccinate is micronized grade AS-MF type with an average particle size D50≤3μm.

[0022] The preparation method of the ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement includes the following steps: Step 1: Pretreatment of pentaerythritol with HPMCAS; Pass pentaerythritol through a 100-mesh sieve and collect the sieve-passing material for later use. HPMCAS uses micronized grade AS-MF, which can be used directly without further pulverization.

[0023] Step 2: Preparation of pentaerythritol-HPMCAS-ursodeoxycholic acid ternary solid dispersion; 250 parts of ursodeoxycholic acid, 40 parts of pentaerythritol, and 30 parts of HPMCAS were added to anhydrous ethanol at a weight ratio of 1:15. The mixture was stirred until completely dissolved to obtain a clear solution. The solution was then placed in a rotary evaporator and evaporated at a water bath temperature of 50°C and a vacuum of -0.09 MPa until the ethanol was completely evaporated, yielding a solid, foamy dispersion. The resulting solid dispersion was placed in a vacuum drying oven and dried for 10 hours at 45°C and a vacuum of -0.09 MPa until constant weight was achieved. The dried solid dispersion was then pulverized and passed through an 80-mesh sieve to obtain a pentaerythritol-HPMCAS-ursodeoxycholic acid ternary solid dispersion powder.

[0024] Step 3: Premix; Add the ternary solid dispersion powder obtained in step 2, 15 parts of microcrystalline cellulose and 28 parts of starch to a mixer and mix for 10 minutes at a mixing speed of 10 rpm.

[0025] Step 4: Prepare the pulp; Take 108 parts of purified water and heat it to 85℃. Keep it warm for 10 minutes. Slowly add the remaining 7 parts of starch to the insulated container and stir to gelatinize the starch. Then cool it down to 68℃ to obtain starch slurry.

[0026] Step 5: Wet granulation; Add the premixed material from step 3 to the wet granulator, start the machine and premix for 60 seconds at a stirring speed of 80 rpm and a cutter speed of 2000 rpm. After premixing, spray 9.6 parts of purified water onto the surface of the material, set the time to 180 seconds, the stirring speed to 120 rpm, and the cutter speed to 2000 rpm for the first granulation.

[0027] After the first granulation is completed, open the feeding port and add the starch slurry obtained in step 4 to the material while it is still hot. Set the time to 180s, the stirring speed to 180rpm, and the cutter speed to 2000rpm for the second granulation.

[0028] After the second granulation, add 3.2 parts of purified water through the feeding port, set the time to 180s, the stirring speed to 120rpm, and the cutter speed to 2000rpm for the third granulation.

[0029] After granulation, open the discharge valve to discharge the wet granules and granulate them through a granulator with a screen mesh of 20 mesh.

[0030] Step 6: Drying; Wet particles are added to a fluidized bed for drying. The inlet air temperature is 60℃, the material temperature is controlled below 45℃, and drying is stopped when the material moisture content is reduced to below 2%. The material is then discharged.

[0031] Step 7: Granulation and blending; The pulverizer and granulator are equipped with a 2.0mm screen and the rotation speed is set to 800rpm. After the dried particles are passed through the pulverizer and granulator, they are transferred to the mixer. 5 parts of colloidal silica and 2 parts of magnesium stearate are added and mixed for 10 minutes at a mixing speed of 10rpm.

[0032] Step 8: Capsule filling; The mixed granules were filled into No. 0 capsule shells, with a filling volume of 330 mg, to obtain ursodeoxycholic acid capsule formulation.

[0033] Experiments were conducted for this embodiment to verify the effects of the introduction of pentaerythritol and hydroxypropyl methylcellulose acetosuccinate (HPMCAS) in Example 1 on the performance of ursodeoxycholic acid capsule formulation. Each experimental group contained 250 parts ursodeoxycholic acid, 15 parts microcrystalline cellulose, 35 parts starch, 5 parts colloidal silica, 2 parts magnesium stearate, and 120 parts purified water. Seven experimental groups were set up according to Table 1, differing only in the amount of pentaerythritol and HPMCAS added.

[0034] Table 1 Experimental Grouping in Example 1

[0035] Experiment 1 served as the control group, without the addition of pentaerythritol and HPMCAS. The preparation method was the same as in Example 1, but steps 1 and 2 were omitted. Ursodeoxycholic acid powder was directly mixed with excipients and then proceeded to step 3. The remaining steps were the same as in Example 1.

[0036] Experiment 2 involved the addition of only 40 parts of pentaerythritol, without the addition of HPMCAS. The preparation method was the same as in Example 1, but the HPMCAS pretreatment in step 1 was omitted. In step 2, only ursodeoxycholic acid and pentaerythritol were dissolved in anhydrous ethanol, without the addition of HPMCAS. The remaining steps were the same as in Example 1.

[0037] Experiment 3 involved the addition of only 30 parts of HPMCAS, without the addition of pentaerythritol. The preparation method was the same as in Example 1, except that in step 2, only ursodeoxycholic acid and HPMCAS were dissolved in anhydrous ethanol, without the addition of pentaerythritol. The remaining steps were the same as in Example 1.

[0038] Experiments 4 through 7 were conducted according to the formulation and preparation method of Example 1, with the only difference being the amount of pentaerythritol and HPMCAS added.

[0039] Performance testing methods: 1. Dissolution rate determination shall be performed in accordance with Method II (paddle method) of General Chapter 0931, Part IV, Chinese Pharmacopoeia 2020 Edition.

[0040] Dissolution conditions: 900 ml of phosphate buffer (made by mixing equal volumes of 0.03 mol / L potassium dihydrogen phosphate solution and 0.12 mol / L disodium hydrogen phosphate solution, and adjusting the pH to 7.5 with 1 mol / L sodium hydroxide solution) was used as the dissolution medium. The dissolution speed was 75 rpm, and the temperature was 37.5℃ ± 0.5℃. The procedure was followed, and samples were taken at 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min.

[0041] Test solution: Take an appropriate amount of the dissolution solution, filter it, and take the filtrate.

[0042] Reference solution: Weigh an appropriate amount of ursodeoxycholic acid reference standard accurately, dissolve it in 1.4 ml of 1 mol / L sodium hydroxide solution, and quantitatively dilute it with a dissolution medium to prepare a solution containing approximately 0.28 mg per ml.

[0043] Detection method: High performance liquid chromatography (HPLC) was used. The injection volume was 50 μl. The cumulative dissolution rate per particle was calculated based on the peak area using the external standard method. Six particles were measured in each group, and the average value was taken.

[0044] 2. Accelerated stability tests (ester impurity content and hygroscopic weight gain) were conducted in accordance with General Chapters 9001 and 9103 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0045] Experimental conditions: Approximately 2g of the contents of each sample capsule was accurately weighed and placed evenly in a pre-weighed weighing bottle. The bottle was then placed in a constant temperature and humidity chamber at 60℃±2℃ and 75%±5% relative humidity for 7 days. After 7 days, the contents were removed, accurately weighed, and the percentage increase in weight due to moisture absorption was calculated. Moisture absorption weight gain (%) = (Weight after moisture absorption - Weight before moisture absorption) / Weight before moisture absorption × 100%.

[0046] Determination of ester impurities: High performance liquid chromatography (HPLC) was used to determine the content of ursodeoxycholic acid-pentaerythritol ester impurities according to General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia. The percentage of the peak area of ​​ester impurities was calculated with the peak area of ​​ursodeoxycholic acid as 100%. Three samples were measured for each group, and the average value was taken.

[0047] 3. Electrostatic assessment and particle flowability measurement: Electrostatic assessment: The degree of electrostatic charge during the wet granulation process is visually assessed and classified into three levels: strong, medium, and weak.

[0048] Particle flowability determination: The angle of repose of the dried particles was measured using the fixed funnel method to evaluate particle flowability. Each group was measured three times, and the average value was taken.

[0049] The test results are shown in Tables 2 and 3 below: Table 2 Results of Dissolution Test

[0050] Table 3 Results of Accelerated Stability Test, Electrostatic Assessment and Particle Flowability Measurement in Example 1

[0051] Experimental results showed that the dissolution rate reached 86.4% at 515 min and 98.5% at 60 min. While achieving rapid release of ursodeoxycholic acid, the ester impurity content was only 0.5%, and the hygroscopic weight gain was only 5.1%, which was significantly better than Experiment 2 with only pentaerythritol and Experiment 3 with only HPMCAS. This confirmed a clear synergistic effect between pentaerythritol and HPMCAS. Pentaerythritol anchors ursodeoxycholic acid to an amorphous form through intermolecular hydrogen bonds, thereby achieving rapid release. HPMCAS, on the other hand, competitively consumes the active hydroxyl groups of pentaerythritol to inhibit esterification reaction, while using hydrophobic acetyl groups to form a barrier and reduce hygroscopicity. The division of labor and synergy between the two enabled Example 1 to effectively solve the problem of poor stability when pentaerythritol is used alone while maintaining the advantage of rapid dissolution. Furthermore, when the amount of pentaerythritol and HPMCAS was increased to 60 parts and 50 parts or 80 parts and 70 parts, the performance indicators did not improve significantly. On the contrary, the dissolution rate decreased due to the increase in the viscosity of the solid dispersion.

[0052] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages: The purpose of introducing pentaerythritol in this embodiment is to solve the problem that the original formulation has a slow dissolution rate of crystalline ursodeoxycholic acid, which cannot achieve an effective litholytic concentration in the early stage after biliary stenting. The purpose of introducing hydroxypropyl methylcellulose acetosuccinate is to solve the problem that when pentaerythritol is used alone, its hydroxyl groups react with the carboxyl groups of ursodeoxycholic acid under humid and hot conditions to generate impurities, and that the amorphous ursodeoxycholic acid in pentaerythritol loses its rapid release effect due to recrystallization during storage because of its strong hygroscopicity.

[0053] This embodiment prepares a ternary solid dispersion by introducing pentaerythritol and HPMCAS into ursodeoxycholic acid, achieving the following technical effects: Pentaerythritol contains four hydroxymethyl groups, which can form an intermolecular hydrogen bond network with the carboxyl and hydroxyl groups in ursodeoxycholic acid molecules. This anchors the ursodeoxycholic acid molecules in the pentaerythritol carrier, inhibits the rearrangement and crystallization of ursodeoxycholic acid molecules, and allows the drug to be stably dispersed in an amorphous form, thereby significantly improving the dissolution rate of ursodeoxycholic acid in the biliary environment.

[0054] The carboxyl groups on the HPMCAS molecular chain form intermolecular hydrogen bonds with the hydroxymethyl groups of pentaerythritol, causing the HPMCAS polymer chains to wrap around the pentaerythritol-ursodeoxycholic acid aggregate, forming a polymer protective cage. The hydrophobic acetyl groups of HPMCAS are arranged outwards on the surface of the solid dispersion, forming a hydrophobic barrier that prevents environmental moisture from penetrating into the solid dispersion, thus inhibiting the recrystallization of ursodeoxycholic acid caused by pentaerythritol hygroscopicity. Simultaneously, the carboxyl groups of HPMCAS form competitive hydrogen bonds with the hydroxymethyl groups of pentaerythritol, consuming some of the active hydroxyl groups of pentaerythritol, reducing the probability of esterification reactions between the pentaerythritol hydroxyl groups and the ursodeoxycholic acid carboxyl groups, and inhibiting the formation of ester impurities.

[0055] Pentaerythritol and HPMCAS work synergistically through a ternary hydrogen bond network. Pentaerythritol anchors ursodeoxycholic acid in an amorphous form, while HPMCAS protects this amorphous form from destruction. Together, they achieve the dual functions of anchoring and protection, enabling ursodeoxycholic acid to maintain rapid dissolution while possessing good storage stability and low ester impurity content, making it suitable for the long-term medication needs of patients after biliary stent placement.

[0056] Example 2: This example is a further improvement upon Example 1. While the technical solution described in Example 1 achieves rapid dissolution and long-term storage stability of ursodeoxycholic acid (UDCA) through the synergistic effect of pentaerythritol and HPMCAS, its release characteristic is a single immediate-release mode, and the effective concentration of UDCA in bile is maintained for a limited time. However, litholytic therapy in patients after biliary stent placement requires a longer effective concentration of UDCA in bile to continuously act on the stone surface and promote its gradual dissolution. To solve the above technical problems, this example prepares pentaerythritol in two groups with different crystallinities separately and mixes them in a specific ratio. Utilizing the slower dissolution rate of highly crystalline pentaerythritol in the biliary environment, a sustained-release micro-storage is constructed to achieve a dual-phase release of UDCA, combining immediate and sustained release, thus prolonging the effective concentration maintenance time.

[0057] Based on Embodiment 1, the following technical solutions are further included: The pentaerythritol comprises low-crystallinity pentaerythritol and high-crystallinity pentaerythritol, wherein the residual crystallinity of low-crystallinity pentaerythritol is ≤2%, the residual crystallinity of high-crystallinity pentaerythritol is 5%-10%, and the weight ratio of low-crystallinity pentaerythritol to high-crystallinity pentaerythritol is 3:1.

[0058] In step 2, the preparation of the pentaerythritol-HPMCAS-ursodeoxycholic acid ternary solid dispersion further includes the separate preparation of a low-crystallinity pentaerythritol solid dispersion and a high-crystallinity pentaerythritol solid dispersion: The preparation method of low-crystallinity pentaerythritol solid dispersion is as follows: 250 parts of ursodeoxycholic acid, 30 parts of low-crystallinity pentaerythritol, and 30 parts of HPMCAS are added to anhydrous ethanol, with a weight ratio of ursodeoxycholic acid to anhydrous ethanol of 1:15. The mixture is stirred until completely dissolved and placed in a rotary evaporator. The evaporation is carried out under the conditions of a water bath temperature of 45℃ and a vacuum degree of -0.09MPa. At the same time, the outer wall temperature of the evaporation flask is rapidly reduced to 0-5℃ using an ice bath rapid cooling method, with a cooling rate ≥20℃ / min. After the ethanol is completely evaporated, the mixture is placed in a vacuum drying oven and dried for 9 hours under the conditions of a temperature of 43℃ and a vacuum degree of -0.09MPa. The powder is then pulverized and passed through an 80-mesh sieve to obtain low-crystallinity pentaerythritol solid dispersion powder.

[0059] The preparation method of highly crystalline pentaerythritol solid dispersion is as follows: 250 parts of ursodeoxycholic acid, 10 parts of highly crystalline pentaerythritol, and 30 parts of HPMCAS are added to anhydrous ethanol, with a weight ratio of ursodeoxycholic acid to anhydrous ethanol of 1:15. The mixture is stirred until completely dissolved and placed in a rotary evaporator. The evaporation is carried out under the conditions of a water bath temperature of 55℃ and a vacuum degree of -0.09MPa. At the same time, the evaporation flask is naturally cooled to room temperature by natural cooling method, with a cooling rate ≤1℃ / min. After the ethanol is completely evaporated, the mixture is placed in a vacuum drying oven and dried for 5 hours under the conditions of a temperature of 47℃ and a vacuum degree of -0.09MPa. The powder is then pulverized and passed through an 80-mesh sieve to obtain highly crystalline pentaerythritol solid dispersion powder.

[0060] The residual crystallinity of low-crystallinity pentaerythritol was controlled to be ≤2% by rapid cooling in an ice bath at a rate ≥20℃ / min and drying time ≤9h; the residual crystallinity of high-crystallinity pentaerythritol was controlled to be 5%-10% by natural slow cooling at a rate ≤1℃ / min and drying time ≤5h.

[0061] In step 3, the premixing involves adding 30 parts of the low-crystallinity pentaerythritol solid dispersion powder, 10 parts of the high-crystallinity pentaerythritol solid dispersion powder, 15 parts of microcrystalline cellulose, and 28 parts of starch obtained in step 2 into a mixer and mixing for 15 minutes at a mixing speed of 10 rpm to ensure that the two groups of solid dispersion powders are fully and evenly mixed before mixing with the excipients.

[0062] Steps 4 to 8 are the same as in Example 1.

[0063] Experiments were conducted to verify the effect of the combination of low-crystallinity pentaerythritol and high-crystallinity pentaerythritol in Example 2 on the release behavior of ursodeoxycholic acid capsules. In each experimental group, ursodeoxycholic acid was 250 parts, HPMCAS 30 parts, microcrystalline cellulose 15 parts, starch 35 parts, colloidal silica 5 parts, magnesium stearate 2 parts, and purified water 120 parts. The total amount of pentaerythritol was 40 parts in each group. Five experimental groups were set up according to Table 4, with only the ratio of low-crystallinity pentaerythritol to high-crystallinity pentaerythritol differing.

[0064] Table 4 Experimental Grouping in Example 2

[0065] Experiment 8 served as the control group (i.e., Experiment 5 of Example 1), with only 40 parts of low-crystallinity pentaerythritol added, without the addition of high-crystallinity pentaerythritol, and the preparation method was the same as in Example 1.

[0066] In Experiments 9-12, the preparation methods for the low-crystallinity pentaerythritol solid dispersions were the same as in Example 2: water bath temperature 45℃, ice bath quenching, and drying for 9 hours. The preparation methods for the high-crystallinity pentaerythritol solid dispersions were the same as in Example 2: water bath temperature 55℃, natural cooling, and drying for 5 hours. After mixing the two groups of solid dispersion powders in the corresponding proportions, they were premixed with microcrystalline cellulose and starch, and the remaining steps were the same as in Example 1.

[0067] Performance testing methods: 1. Dissolution test (dynamic dilution method). Referring to the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 0931, Method II (paddle method), the dissolution medium was 900 ml of phosphate buffer (pH 7.5), the rotation speed was 75 rpm, and the temperature was 37.5℃ ± 0.5℃. At 60 min and 120 min of the dissolution experiment, 500 ml of the dissolution solution (filtered through a 0.22 μm filter for concentration determination) was taken from the dissolution vessel, and an equal volume of fresh dissolution medium at 37.5℃ was immediately added to simulate the flow of bile in the biliary system and the continuous clearance of UDCA. Samples were taken at 5 min, 15 min, 30 min, 60 min, 90 min (30 min after the first addition), 150 min (30 min after the second addition), 210 min, and 270 min to determine the cumulative release of UDCA in the dissolution solution (after correction calculation to deduct the dilution effect caused by sampling and addition). The preparation of the test solution and reference solution, and the high-performance liquid chromatography detection methods are the same as those in Example 1. Six samples were measured in each group, and the average value was taken.

[0068] 2. Determination of residual pentaerythritol in the dissolution residue. After the dissolution experiment (270 min), the remaining undissolved particulate residue in each group's dissolution vessel was collected, vacuum dried at 40℃ to constant weight, and ground into a fine powder. An appropriate amount of the residue powder was accurately weighed, and anhydrous ethanol was added for ultrasonic extraction for 30 min. After filtration, the content of pentaerythritol in the extract was determined by high-performance liquid chromatography (HPLC). The residual amount of pentaerythritol in the residue and its percentage of the initial total pentaerythritol were calculated. Three samples were measured for each group, and the average value was taken.

[0069] 3. Accelerated stability testing, electrostatic assessment, and particle flowability determination were performed using the same methods as in Example 1. The test results are shown in Tables 5, 6, and 7: Table 5. Results of Dissolution Test in Example 2

[0070] Table 6 Results of Pentaerythritol Residue Determination in Leaching Residue of Example 2

[0071] Table 7 Results of Accelerated Stability Test, Electrostatic Assessment and Particle Flowability Measurement in Example 2

[0072] Experimental results showed that, under simulated in vivo dynamic clearance conditions, Experiment 9 (low-crystallinity pentaerythritol: high-crystallinity pentaerythritol = 3:1) maintained early rapid release performance comparable to Example 1 (84.8% release at 15 min, essentially equivalent to 86.4% in Experiment 8), while also continuously replenishing UDCA into the system through the slow dissolution of high-crystallinity pentaerythritol, effectively resisting the dynamic dilution effect. At 270 min, its cumulative release remained at 53.4%, while Experiment 8 (Example 1) only had 25.6%, showing a significant increase in release. Further confirmation from the determination of residual pentaerythritol in the residue showed that 42.8 mg of pentaerythritol (10.7% of the initial total) was detected in the residue of Experiment 9, significantly higher than the 1.2 mg (3.0%) in Experiment 8, demonstrating that high-crystallinity pentaerythritol continued to exist and be slowly released in the later stages of dissolution. Based on the combined dissolution curves and residue verification results, Example 2 extended the effective concentration maintenance time of UDCA from approximately 2 hours in the single rapid release mode to 4-6 hours.

[0073] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages: In this embodiment, low-crystallinity pentaerythritol dissolves rapidly in the biliary environment, instantly releasing anchored UDCA molecules, achieving a rapid release effect, allowing UDCA to reach an effective litholytic concentration within 15-30 minutes. High-crystallinity pentaerythritol contains some pentaerythritol microcrystals, whose crystalline regions have ordered molecular arrangement and higher lattice energy. Dissolution requires overcoming additional lattice energy barriers, therefore its dissolution rate is significantly lower than that of low-crystallinity pentaerythritol. After the release of low-crystallinity pentaerythritol, it continues to dissolve slowly, continuously replenishing UDCA into the bile. The chemical compositions of the two groups of pentaerythritol are identical, and their hydrogen bond anchoring mechanisms with UDCA and HPMCAS are consistent. Therefore, the pentaerythritol microcrystals in high-crystallinity pentaerythritol are anchored by the HPMCAS protective cage during storage, preventing phase separation and precipitation. When low-crystallinity pentaerythritol and high-crystallinity pentaerythritol are combined in a certain proportion, the release of UDCA exhibits a dual-phase characteristic of immediate and sustained release: rapid release in the early stage establishes an effective therapeutic concentration, while continuous and slow supplementation in the later stage prolongs the duration of the effective concentration, thus extending the duration of the effective concentration of UDCA in bile from about 2 hours in the single immediate release mode to 4-6 hours.

[0074] In this embodiment, residual crystals, which are considered process defects in the preparation of solid dispersions, are used as a combination for long-term utilization. By actively controlling the cooling rate and drying time, the residual crystallinity of pentaerythritol is quantitatively controlled within a specific range. The high lattice energy barrier of the crystallization region itself is used as a slow-release regulation mechanism, and the highly crystalline pentaerythritol is used as a slow-release micro-reservoir to achieve time-sequential regulation of the release behavior.

[0075] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. An ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement, characterized in that, By weight, it contains the following raw and auxiliary materials: 230-270 parts of ursodeoxycholic acid, 20-60 parts of pentaerythritol, 10-50 parts of hydroxypropyl methylcellulose acetosuccinate, 10-20 parts of microcrystalline cellulose, 25-45 parts of starch, 4-6 parts of colloidal silica, 1-3 parts of magnesium stearate, and 100-140 parts of purified water.

2. The ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement according to claim 1, characterized in that, The pentaerythritol has a particle size D90 ≤ 50 μm; the hydroxypropyl methylcellulose acetosuccinate is a micronized grade AS-MF type with an average particle size D50 ≤ 3 μm.

3. The ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement according to claim 1, characterized in that, By weight, it contains the following raw and auxiliary materials: 250 parts ursodeoxycholic acid, 40 parts pentaerythritol, 30 parts hydroxypropyl methylcellulose acetosuccinate, 15 parts microcrystalline cellulose, 35 parts starch, 5 parts colloidal silica, 2 parts magnesium stearate, and 120 parts purified water.

4. The ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement according to claim 3, characterized in that, The pentaerythritol includes low-crystallinity pentaerythritol and high-crystallinity pentaerythritol. The residual crystallinity of low-crystallinity pentaerythritol is ≤2%, and the residual crystallinity of high-crystallinity pentaerythritol is 5%-10%. The weight ratio of low-crystallinity pentaerythritol to high-crystallinity pentaerythritol is 3:

1.

5. A method for preparing an ursodeoxycholic acid capsule formulation for dissolving stones after biliary stent placement according to any one of claims 1-4, characterized in that, Includes the following steps: Step 1: Pass pentaerythritol through a 100-mesh sieve and collect the sieve residue for later use; Hydroxypropyl methylcellulose acetosuccinate can be used directly; Step 2: Ursodeoxycholic acid, pentaerythritol and hydroxypropyl methylcellulose acetosuccinate were added to anhydrous ethanol at a weight ratio of 1:

15. The mixture was stirred until completely dissolved and then rotary evaporated at 50°C and -0.09 MPa vacuum until the ethanol was completely evaporated. The mixture was then dried for 10 hours at 45°C and -0.09 MPa vacuum. The powder was then pulverized through an 80-mesh sieve to obtain a ternary solid dispersion powder. Step 3: Add the ternary solid dispersion powder obtained in Step 2, microcrystalline cellulose and 28 parts of starch into a mixer and mix for 10 minutes at a mixing speed of 10 rpm; Step 4: Take 108 parts of purified water and heat it to 85℃. Keep it warm for 10 minutes. Slowly add the remaining 7 parts of starch to the insulated container and stir to gelatinize the starch. Cool down to 68℃ to obtain starch slurry. Step 5: Add the premixed material from Step 3 to a wet granulator, premix for 60 seconds at a stirring speed of 80 rpm and a cutter speed of 2000 rpm; spray 9.6 parts of purified water onto the surface of the material, granulate for 180 seconds at a stirring speed of 120 rpm and a cutter speed of 2000 rpm for the first granulation; add the starch slurry obtained in Step 4 to the material while it is still hot, granulate for 180 seconds at a stirring speed of 180 rpm and a cutter speed of 2000 rpm for the second granulation; add 3.2 parts of purified water, granulate for 180 seconds at a stirring speed of 120 rpm and a cutter speed of 2000 rpm for the third granulation; discharge the material and granulate it through a 20-mesh sieve to obtain wet granules; Step 6: Place the wet granules in a fluidized bed for drying, with an inlet air temperature of 60℃ and the material temperature controlled below 45℃, until the moisture content is ≤2%; Step 7: Sieve the dried granules through a 2.0mm sieve to form larger granules, add colloidal silica and magnesium stearate, and mix for 10 minutes at a mixing speed of 10 rpm; Step 8: Fill the shell with the mixed granules to obtain ursodeoxycholic acid capsule formulation.

6. The method for preparing ursodeoxycholic acid capsules for dissolving stones after biliary stent placement according to claim 5, characterized in that, The pentaerythritol mentioned in step 2 includes low-crystallinity pentaerythritol and high-crystallinity pentaerythritol. The residual crystallinity of low-crystallinity pentaerythritol is ≤2%, and the residual crystallinity of high-crystallinity pentaerythritol is 5%-10%. The weight ratio of low-crystallinity pentaerythritol to high-crystallinity pentaerythritol is 3:

1.

7. The method for preparing ursodeoxycholic acid capsules for dissolving stones after biliary stent placement according to claim 5, characterized in that, Step 2 further includes preparing a low-crystallinity pentaerythritol solid dispersion and a high-crystallinity pentaerythritol solid dispersion, respectively: The preparation method of the low crystallinity pentaerythritol solid dispersion is as follows: 250 parts of ursodeoxycholic acid, 30 parts of low crystallinity pentaerythritol and 30 parts of hydroxypropyl methylcellulose acetosuccinate are added to anhydrous ethanol, with the weight ratio of ursodeoxycholic acid to anhydrous ethanol being 1:

15. The mixture is stirred until completely dissolved, and then rotary evaporated under a water bath temperature of 45℃ and a vacuum degree of -0.09MPa. At the same time, a rapid cooling method using an ice bath is adopted to ensure a cooling rate of ≥20℃ / min. After the ethanol is completely evaporated, the mixture is dried for 9 hours under a temperature of 43℃ and a vacuum degree of -0.09MPa, and then pulverized through an 80-mesh sieve. The preparation method of the highly crystalline pentaerythritol solid dispersion is as follows: 250 parts of ursodeoxycholic acid, 10 parts of highly crystalline pentaerythritol, and 30 parts of hydroxypropyl methylcellulose acetosuccinate are added to anhydrous ethanol, with the weight ratio of ursodeoxycholic acid to anhydrous ethanol being 1:

15. The mixture is stirred until completely dissolved, and then rotary evaporated at a water bath temperature of 55℃ and a vacuum degree of -0.09MPa, while using natural cooling to keep the cooling rate ≤1℃ / min. After the ethanol is completely evaporated, the mixture is dried for another 5 hours at a temperature of 47℃ and a vacuum degree of -0.09MPa, and then pulverized through an 80-mesh sieve.

8. The method for preparing ursodeoxycholic acid capsules for dissolving stones after biliary stent placement according to claim 5, characterized in that, The premixing in step 3 is as follows: 30 parts of low-crystallinity pentaerythritol solid dispersion powder, 10 parts of high-crystallinity pentaerythritol solid dispersion powder, 15 parts of microcrystalline cellulose and 28 parts of starch are added to a mixer and mixed for 15 minutes at a mixing speed of 10 rpm.

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