A solid dispersion of tisopurine and a method of preparing the same

Abstract

This invention relates to solid dispersion preparation technology in the field of biopharmaceutical manufacturing, and discloses a tenapano solid dispersion and its preparation method. The tenapano solid dispersion is composed of tenapano, a povidone polymer, and an enteric-coated acrylic resin. Tenapano is dispersed in an amorphous form within a biphase blended polymer matrix, forming an interpenetrating continuous phase network structure, with an open-pore microporous network within the powder. During preparation, the components are mixed and then subjected to step-by-step heating and melting. A supercritical fluid is injected into the molten zone, followed by extrusion, rapid cooling and solidification, and then pulverization and sieving. This method, through the combination of a biphase blended matrix and an open-pore microporous network, inhibits macroscopic phase separation and recrystallization between the drug and the carrier, maintains the stability of the amorphous form, and achieves rapid drug release.

Description

Technical Field

[0001] This invention relates to solid dispersion preparation technology in the field of biopharmaceutical manufacturing, and discloses a tenapano solid dispersion and its preparation method. Background Technology

[0002] Tenapano is a poorly soluble drug, and preparing it into a solid dispersion is a conventional technique to improve its in vitro dissolution rate. The closest existing conventional approach is to use a single hydrophilic carrier, such as conventional povidone or copovidone, to prepare the tenapano solid dispersion via hot-melt extrusion or solvent evaporation. The specific implementation of this conventional approach involves physically mixing tenapano with a single hydrophilic carrier in a specific ratio, then removing the solvent by heating and melting or dissolving. This allows tenapano to be dispersed amorphously within the hydrophilic carrier, utilizing the steric hindrance of the carrier molecules and single hydrogen bonding to inhibit drug crystallization, thereby improving dissolution rate.

[0003] Based on the conventional technical solution using a single hydrophilic carrier, during long-term storage, because the carrier system contains only a homogeneous hydrophilic phase and lacks microscopic physical structures to hinder drug molecule migration, tenapano molecules are prone to macroscopic phase separation from the carrier. This phase separation leads to the spontaneous recrystallization of tenapano, which originally existed in an amorphous form, causing irreversible decrease in the in vitro dissolution rate of the solid dispersion formulation, resulting in insufficient physical stability. Summary of the Invention

[0004] To address the shortcomings of existing technologies that use a single hydrophilic carrier to prepare tenapanol solid dispersions, which are prone to macroscopic phase separation during long-term storage, leading to spontaneous recrystallization of amorphous tenapanol, irreversible decrease in formulation dissolution, and insufficient physical stability, this invention provides a tenapanol solid dispersion and its preparation method.

[0005] To address the aforementioned technical problems, this invention provides a tenapano solid dispersion, comprising the following technical features: the tenapano solid dispersion is composed of tenapano, a povidone polymer, and an enteric-coated acrylic resin; based on the total mass of the tenapano solid dispersion, the mass percentage of tenapano is 5% to 30%, the mass percentage of the povidone polymer is 40% to 70%, and the mass percentage of the enteric-coated acrylic resin is 10% to 50%; the tenapano is amorphously dispersed in a biphase blend polymer matrix formed by the povidone polymer and the enteric-coated acrylic resin, the biphase blend polymer matrix forming an interpenetrating continuous phase network structure within the tenapano solid dispersion, and the powder of the tenapano solid dispersion possesses an open-pore microporous network formed by supercritical fluid physical foaming, the open-pore microporous network penetrating the interior and surface of the powder particles.

[0006] In practice, the biphase blended polyvinyl ketone polymer and enteric-coated acrylic resin form an interpenetrating continuous phase network. The hydrophilic continuous phase composed of the polyvinyl ketone polymer anchors the amorphous tenapano through hydrogen bonding. The phase interface formed by the enteric-coated acrylic resin constructs a microscopic physical barrier structure, restricting the migration and aggregation of tenapano molecules. The through-hole open-pore microporous network formed by supercritical fluid physical foaming allows the dissolution medium to quickly enter the interior of the powder particles, expanding the contact interface between the drug and the dissolution medium, while not compromising the stabilizing effect of the polymer matrix on the drug.

[0007] Furthermore, in the above technical solution, the polyvinylpyrrolidone polymer is a copolyvinylpyrrolidone, which is a copolymer of N-vinylpyrrolidone and vinyl acetate. The weight-average molecular weight of the copolyvinylpyrrolidone is 40,000 to 70,000. The copolyvinylpyrrolidone exists in an amorphous form in the biphase blend polymer matrix, and the mass of the copolyvinylpyrrolidone accounts for 100% of the total mass of the polyvinylpyrrolidone polymer.

[0008] In practice, copovidones in this molecular weight range have both matching glass transition temperatures and hydrogen bonding capabilities. Amorphous copovidones can form a uniform molecular-level mixture with tenapano molecules. The carbonyl groups on their molecular chains can form stable hydrogen bonds with the active hydrogen sites of tenapano, preventing the aggregation and recrystallization of tenapano molecules.

[0009] Furthermore, in the above technical solution, the enteric acrylic resin is a methacrylic acid-ethyl acrylate copolymer, wherein the mass ratio of methacrylic acid monomer units to ethyl acrylate monomer units in the methacrylic acid-ethyl acrylate copolymer is 1:4, the weight-average molecular weight of the methacrylic acid-ethyl acrylate copolymer is 100,000 to 150,000, and the enteric acrylic resin constitutes discontinuous hydrophobic island-like structural regions in the biphase blend polymer matrix.

[0010] In practice, the methacrylic acid-ethyl acrylate copolymer with the monomer ratio and molecular weight range can form a stable phase separation structure when blended with copovidone. Its hydrophobic island structure region can form a multi-dimensional phase interface in the hydrophilic continuous phase, which hinders the long-range migration of tenapano molecules through steric hindrance effect. At the same time, the carboxyl groups on its molecular chain can provide additional hydrogen bonding sites.

[0011] Furthermore, in the above technical solution, based on the total mass of the tenapano solid dispersion, the mass percentage of tenapano is 10% to 20%, the mass percentage of copovidone is 50% to 60%, the mass percentage of the methacrylate-ethyl acrylate copolymer is 25% to 35%, and the molecular-level dispersion of tenapano is characterized by the formation of a solid-phase intermolecular hydrogen bond network structure between the carbonyl groups of tenapano and copovidone, and the carboxyl groups of the methacrylate-ethyl acrylate copolymer.

[0012] In practice, at this mass ratio, copovidone and methacrylate-ethyl acrylate copolymer can form a structurally uniform biphase blend matrix. Tenapano can simultaneously form multi-site hydrogen bonds with the polar groups of the two polymers, thereby achieving drug fixation at the molecular scale and reducing the molecular migration rate and recrystallization tendency of tenapano.

[0013] Furthermore, in the above technical solution, the tenapano solid dispersion further comprises mesoporous silica, the mesoporous silica having a specific surface area of ​​500 to 1000 square meters per gram and an average pore size of 10 to 30 nanometers. Based on the total mass of the tenapano solid dispersion, the mass percentage of the mesoporous silica is 5% to 15%. The tenapano, the povidone polymer, and the enteric acrylic resin are loaded inside the pores and on the outer surface of the mesoporous silica.

[0014] In practice, the nanoscale pores of mesoporous silica can provide nanoscale confinement space, restricting the aggregation and crystal growth of tenapanol molecules within the pores. Its high specific surface area can increase the binding sites between the polymer matrix and the carrier, thereby improving the structural stability of the solid dispersion.

[0015] Furthermore, in the above technical solution, the pore size distribution of the open-pore microporous network is 0.5 micrometers to 5 micrometers, the internal volume ratio of the open-pore microporous network in the tenapano solid dispersion is 10% to 30%, the pore walls of the open-pore microporous network are formed by the phase interface between the polyvinyl ketone polymer and the enteric acrylic resin, and the open-pore microporous network is formed in situ after phase transformation expansion in the molten polymer matrix by supercritical carbon dioxide fluid and removal under reduced pressure.

[0016] In practice, the open-pore microporous network with the specified pore size and volume ratio can construct a dissolution medium channel that runs through the powder particles without damaging the overall structure of the polymer matrix. The pore walls formed by the two-phase interface can maintain the mechanical stability of the microporous structure. The in-situ molding method of supercritical carbon dioxide phase change expansion can achieve a uniform distribution of the microporous structure and avoid local structural collapse.

[0017] To address the aforementioned technical problems, the present invention also provides a method for preparing a tenapano solid dispersion, comprising the following steps: Step 1: Tenapano, povidone polymers, and enteric acrylic resin are added to a high-speed mixer in a set ratio for physical mixing to obtain a premixed material. Step 2: The premixed material is fed into the feed inlet of a twin-screw extruder, which is divided into a feeding zone, a melting zone, a mixing zone, and a die zone along the material conveying direction. A stepped heating program is applied to each zone of the twin-screw extruder. Step 3: Supercritical fluid is injected into the premixed material in the melting zone of the twin-screw extruder as a temporary plasticizer. Step 4: After passing through the mixing zone, the premixed material is extruded through the die in the die zone, and the extrudate is introduced into a quenching device for curing. Step 5: The cured extrudate is transferred to a pulverizer for pulverization and then sieved through a vibrating screen to collect powder within the target particle size range.

[0018] In practice, the stepped heating process allows the material to gradually melt and plasticize, avoiding drug degradation caused by local overheating; the supercritical fluid injected into the melting zone can reduce the melt viscosity of the polymer system, improve the mixing uniformity of tenapanol and the polymer matrix, and provide a foaming medium for the subsequent formation of microporous structures; rapid cooling and solidification can quickly lock the amorphous form of tenapanol, avoiding drug recrystallization and excessive evolution of polymer phase structure during the cooling process.

[0019] Furthermore, in the above technical solution, the stepped heating program is specifically as follows: the temperature of the feeding zone is set to 60 degrees Celsius to 80 degrees Celsius, the temperature of the melting zone is set to 120 degrees Celsius to 150 degrees Celsius, the temperature of the mixing zone is set to 140 degrees Celsius to 160 degrees Celsius, the temperature of the die head zone is set to 130 degrees Celsius to 150 degrees Celsius, and the screw speed of the twin-screw extruder is set to 100 rpm to 300 rpm.

[0020] In practice, this stepped temperature gradient matches the changes in the state of the material throughout the entire process from conveying, melting, mixing to extrusion. Combined with the corresponding screw speed, it can ensure that the material has sufficient mixing and plasticizing time in the extruder, avoiding material retention and degradation or uneven mixing.

[0021] Furthermore, in the above technical solution, the supercritical fluid in step three is supercritical carbon dioxide. The supercritical carbon dioxide is injected into the melting zone through a high-pressure metering pump. The injection pressure of the supercritical carbon dioxide is set to 8 MPa to 15 MPa. The flow rate of the supercritical carbon dioxide is set to 0.5 liters to 2 liters per kilogram of premixed material per hour. The residence time of the supercritical carbon dioxide with the premixed material in the melting zone is set to 30 seconds to 90 seconds.

[0022] In practice, the injection pressure and flow rate allow supercritical carbon dioxide to be uniformly dispersed in the molten polymer system, achieving a plasticizing effect on the polymer system. The corresponding residence time ensures that the supercritical carbon dioxide and the molten material are fully mixed, providing a foundation for the uniform molding of the subsequent microporous structure.

[0023] Furthermore, in the above technical solution, the quenching device in step four is a tracked cooling tank with a circulating cold air system. The temperature of the conveyor belt of the tracked cooling tank is set to -10 degrees Celsius to 5 degrees Celsius, and the wind speed of the circulating cold air system is set to 5 meters per second to 10 meters per second. In step five, the screen aperture of the vibrating screen is set to 80 mesh to 150 mesh. After the powder within the target particle size range is sieved, it is sealed and packaged by a vacuum degassing packaging machine. The absolute vacuum pressure of the vacuum degassing packaging machine is set to 100 Pa to 500 Pa.

[0024] In practice, the rapid cooling device under these temperature and wind speed conditions can quickly cool and solidify the extrudate, lock in the amorphous drug and biphase polymer structure, and eliminate internal thermal stress in the extrudate; vacuum degassing packaging can remove residual gas inside the powder particles, prevent the microporous structure from collapsing during storage, and maintain the structural stability of the solid dispersion.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention constructs a biphase blended polymer matrix by combining polyvinyl ketone polymers and enteric-coated acrylic resin. The matrix forms an interconnected continuous phase network structure, with the enteric-coated acrylic resin constituting discontinuous hydrophobic island-like structural regions. This phase interface between the hydrophilic and hydrophobic phases increases the spatial confinement and migration hindrance of tenapanol molecules at the microscopic level, preventing macroscopic phase separation between the drug and the carrier and inhibiting spontaneous recrystallization of amorphous tenapanol during long-term storage. By injecting supercritical carbon dioxide into the molten zone during the preparation process and forming an open-pore microporous network in situ after extrusion, this open-pore microporous network penetrates the interior and surface of the powder particles, increasing the contact area between the drug and the dissolution medium, enabling the release of tenapanol while maintaining its amorphous form and physical stability.

[0026] 2. This invention limits the povidone polymer to copovidone with a specific weight-average molecular weight, and combines it with a specific monomer mass ratio and a methacrylate-ethyl acrylate copolymer with a specific weight-average molecular weight. Under a specific mass ratio, this promotes the formation of a solid-phase intermolecular hydrogen bond network between the carbonyl groups of tenapano and copovidone, and the carboxyl groups of the copolymer, further locking the amorphous form of the drug at the molecular scale. The introduction of mesoporous silica with a specific specific surface area and average pore size loads the above polymer matrix and tenapano onto its pores and outer surface, providing additional physical confinement effects. The stepped heating program set in the preparation method, combined with the specific injection pressure and flow rate of supercritical carbon dioxide, ensures sufficient plasticization and uniform mixing of the material in the twin-screw extruder. Subsequent rapid cooling curing and vacuum degassing packaging steps eliminate internal thermal stress and residual gas in the extrudate, ensuring the consistency of the final powder morphology. Detailed Implementation

[0027] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0028] The raw materials and instruments used in the following embodiments and comparative examples of the present invention are all commercially available materials and instruments in the art; the detection methods used are all conventional detection methods in the art.

[0029] The core specifications of the raw materials used are as follows: Tenapano: Purity ≥ 99.5%, particle size D90 ≤ 50 μm; Copolyvinylpyrrolidone: N-vinylpyrrolidone to vinyl acetate in a mass ratio of 6:4, with a weight-average molecular weight of 50,000 and an amorphous form; Povidone PVPK30: weight average molecular weight 50,000; Methacrylic acid-ethyl acrylate copolymer: methacrylic acid to ethyl acrylate monomer units in a mass ratio of 1:4, with a weight average molecular weight of 120,000; Mesoporous silica: specific surface area 800 m² / g, average pore size 20 nm; Supercritical carbon dioxide: purity ≥ 99.99%.

[0030] Example 1: This example provides a tenapano solid dispersion, the formulation of which is as follows (by mass): Tenapano 150g (15% by weight); 500g of copovidone (50% by weight); 250g of methacrylic acid-ethyl acrylate copolymer (25% by mass); 100g of mesoporous silica (10% by mass); Total weight 1000g; The method for preparing the tenapano solid dispersion in this embodiment includes the following steps: Step 1, Premix material preparation: According to the above formula ratio, add tenapano, copovidone, methacrylate-ethyl acrylate copolymer, and mesoporous silica into a high-speed mixer, set the mixing speed to 1500 rpm, and the mixing time to 10 min to obtain a uniform premix material. Step 2, setting the parameters of the twin-screw extruder: The premixed material is fed into the feed inlet of the twin-screw extruder. The twin-screw extruder is divided into a feeding zone, a melting zone, a mixing zone, and a die zone along the material conveying direction. A stepped heating program is set: feeding zone temperature 70℃, melting zone temperature 135℃, mixing zone temperature 150℃, and die zone temperature 140℃; the screw speed of the twin-screw extruder is set to 200 rpm. Step 3, supercritical fluid injection: In the melting zone of the twin-screw extruder, supercritical carbon dioxide is injected into the molten premixed material through a high-pressure metering pump. The injection pressure is set to 12 MPa, the flow rate is set to 1.2 L / (kg premixed material·h), and the residence time of supercritical carbon dioxide and molten premixed material in the melting zone is 60 s. Step 4, Extrusion and Rapid Cooling Curing: After the premixed material is fully mixed and plasticized in the mixing zone, it is extruded through the slit die in the die head area. The extrudate is immediately introduced into a tracked cooling tank with a circulating cold air system for curing. The conveyor belt temperature of the tracked cooling tank is set to 0℃, the wind speed of the circulating cold air system is set to 8m / s, and the residence time of the extrudate in the cooling tank is 2 minutes to complete the curing. Step 5, crushing, sieving and packaging: Transfer the solidified extrudate to a hammer mill for crushing at a speed of 3000 rpm for 3 minutes. The crushed material is then sieved through a 100-mesh vibrating screen. The sieved powder is collected and sealed using a vacuum degassing packaging machine with an absolute vacuum pressure of 300 Pa to obtain the tenapanol solid dispersion.

[0031] Example 2: This example provides a tenapano solid dispersion, the formulation of which is as follows (by mass): Tenapano 50g (5% by weight); Copovidone 600g (60% by weight); 250g of methacrylic acid-ethyl acrylate copolymer (25% by mass); 100g of mesoporous silica (10% by mass); Total weight 1000g; The preparation method of the tenapano solid dispersion in this embodiment is completely consistent with the other conditions in Example 1.

[0032] Example 3: This example provides a tenapano solid dispersion, the formulation of which is as follows (by mass): Tenapano 300g (30% by weight); Copovidone 400g (40% by weight); 200g of methacrylate-ethyl acrylate copolymer (20% by mass); 100g of mesoporous silica (10% by mass); Total weight 1000g; The preparation method of the tenapano solid dispersion in this embodiment is completely consistent with the other conditions in Example 1.

[0033] Example 4: This example provides a tenapano solid dispersion, the formulation of which is as follows (by mass): Tenapano 150g (15% by weight); Copovidone 550g (55% by weight); 300g of methacrylate-ethyl acrylate copolymer (30% by mass); Total weight 1000g; The preparation method of the tenapano solid dispersion in this embodiment is completely consistent with the other conditions in Example 1.

[0034] Example 5: This example provides a tenapano solid dispersion, the formulation of which is as follows (by mass): Tenapano 150g (15% by weight); Povidone PVPK30 500g (50% by weight); 250g of methacrylic acid-ethyl acrylate copolymer (25% by mass); 100g of mesoporous silica (10% by mass); Total weight 1000g; The preparation method of the tenapano solid dispersion in this embodiment is completely consistent with the other conditions in Example 1.

[0035] Example 6: This example provides a tenapano solid dispersion, the formulation of which is as follows (by mass): Tenapano 150g (15% by weight); Copovidone 400g (40% by weight); 350g of methacrylate-ethyl acrylate copolymer (35% by mass); 100g of mesoporous silica (10% by mass); Total weight 1000g; The preparation method of the tenapano solid dispersion in this embodiment is completely consistent with the other conditions in Example 1.

[0036] Example 7: This example provides a tenapano solid dispersion with a formulation that is completely consistent with that of Example 1.

[0037] The preparation method of tenapano solid dispersion in this embodiment only adjusts the stepped heating program and screw speed of the twin-screw extruder. Specifically, the feed zone temperature is 60°C, the melting zone temperature is 120°C, the mixing zone temperature is 140°C, the die zone temperature is 130°C, and the screw speed is set to 100 rpm. The remaining process conditions are completely consistent with those in Example 1.

[0038] Example 8: This example provides a tenapano solid dispersion with a formulation that is completely consistent with that of Example 1.

[0039] The preparation method of tenapano solid dispersion in this embodiment only adjusts the injection parameters of supercritical carbon dioxide. Specifically, the injection pressure is set to 8 MPa, the flow rate is set to 0.5 L / (kg premixed material·h), and the residence time of supercritical carbon dioxide and molten premixed material in the molten zone is 30 s; the remaining process conditions are completely consistent with those in Example 1.

[0040] Comparative Example 1: This comparative example provides a tenapano solid dispersion, the formulation of which, by mass, is as follows: Tenapano 150g (15% by weight); Copovidone 750g (75% by weight); 100g of mesoporous silica (10% by mass); Total weight 1000g; The preparation method of the tenapano solid dispersion in this comparative example is completely consistent with that in Example 1, except for the other conditions.

[0041] Comparative Example 2: This comparative example provides a prior art tenapano solid dispersion, the formulation of which, by mass, is as follows: Tenapano 150g (15% by weight); Copovidone 850g (85% by weight); Total weight 1000g; The preparation method of the tenapano solid dispersion in this comparative example adopts the conventional hot melt extrusion method described in the background art, and includes the following steps: Step 1, Premix preparation: According to the above formula ratio, add tenapano and copovidone to a high-speed mixer and mix at 1500 rpm for 10 min to obtain the premix. Step 2, twin-screw extrusion: The premixed material is fed into the twin-screw extruder. The temperature of each zone of the extruder is set as follows: feed zone 70℃, melt zone 135℃, mixing zone 150℃, die zone 140℃, screw speed 200rpm, and no supercritical carbon dioxide is injected. Step 3, Cooling and Crushing: The extrudate is placed at room temperature to cool and solidify naturally. After solidification, it is crushed by a hammer mill at 3000 rpm for 3 minutes, sieved through a 100-mesh vibrating screen, and the powder is collected and packaged in a conventional sealed package.

[0042] Comparative Example 3: This comparative example provides a tenapano solid dispersion with a formulation that is completely consistent with that of Example 1.

[0043] The preparation method of the tenapano solid dispersion in this comparative example is exactly the same as that in Example 1, except that the supercritical carbon dioxide injection pressure is set to 5 MPa.

[0044] Comparative Example 4: This comparative example provides a tenapano solid dispersion with a formulation that is completely consistent with that of Example 1.

[0045] The preparation method of the tenapano solid dispersion in this comparative example omits the supercritical carbon dioxide injection operation in step three, and the remaining process conditions are completely consistent with those in Example 1.

[0046] Test method: (1) In vitro dissolution test According to the 2025 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 0931, Method II (Paddle Method), the dissolution medium was 900 mL of pH 6.8 phosphate buffer, the rotation speed was 50 rpm, the temperature was 37℃±0.5℃, and samples were taken at 45 min. The dissolution amount of tenapano was determined by high performance liquid chromatography (HPLC), and the cumulative dissolution rate over 45 min was calculated.

[0047] (2) Accelerated stability test The samples of each embodiment and comparative example were placed in a constant temperature and humidity chamber with conditions set at 40℃±2℃ and relative humidity of 75%±5%. They were sealed and stored for 6 months. Samples were taken at 0 months (initial) and 6 months to determine the cumulative dissolution rate, drug crystallinity and content of related substances over 45 minutes.

[0048] (3) Crystallinity test X-ray powder diffraction (XRD) was used, and the test conditions were as follows: Radiation, tube voltage 40kV, tube current 40mA, scanning range The scanning speed was 2° / min, and the crystallinity of tenapano was calculated based on the integrated area of ​​the characteristic diffraction peaks.

[0049] (4) Related substance testing The total content of related substances of tenapano in the sample was determined by HPLC and calculated by peak area normalization.

[0050] Test results: Table 1. Performance test results of each embodiment and comparative example. Sample number Initial cumulative dissolution rate (%) at 45 min Accelerated cumulative dissolution rate (%) over 6 months and 45 minutes Accelerate crystallization by 6 months (%) Accelerated total content of related substances (%) over 6 months Example 1 98.7 96.2 0.8 0.23 Example 2 97.5 94.8 1.2 0.21 Example 3 95.3 91.5 2.7 0.25 Example 4 96.8 92.3 3.1 0.22 Example 5 97.2 93.6 2.4 0.24 Example 6 96.5 93.1 2.2 0.23 Example 7 98.1 95.4 1.1 0.22 Example 8 97.8 94.9 1.3 0.23 Comparative Example 1 92.4 61.3 26.8 0.35 Comparative Example 2 85.7 48.2 37.5 0.42 Comparative Example 3 82.6 65.7 21.4 0.31 Comparative Example 4 74.3 71.8 3.5 0.24 Results analysis: The tenapanol solid dispersions prepared in Examples 1-8 of this invention all exhibited an initial 45-minute cumulative dissolution rate of ≥95%, significantly higher than the 85.7% of Comparative Example 2 in the prior art. After 6 months of accelerated dissolution at 40℃ / 75%RH, the 45-minute cumulative dissolution rate remained above 90%, with a dissolution rate decline rate of less than 5%, while the dissolution rate decline rate of Comparative Examples 1-3 all exceeded 30%. Furthermore, after 6 months of accelerated dissolution, the drug crystallinity of all examples was less than 3.5%, and the total content of related substances was less than 0.3%, indicating that the solid dispersions of this invention possess excellent in vitro dissolution performance and long-term physical stability, effectively inhibiting the recrystallization of amorphous tenapanol, avoiding irreversible dissolution rate decline, and fully realizing the beneficial effects claimed by this invention.

[0051] Among them, the best embodiment 1 exhibited the best performance, with an initial dissolution rate of 98.7%. After 6 months of accelerated dissolution, the dissolution rate only decreased by 2.5 percentage points, and the crystallinity was only 0.8%, indicating that the preferred formulation ratio and process parameters of the present invention can achieve the optimal synergistic effect. Embodiment 4, without the addition of mesoporous silica, still maintained excellent stability, with only a slight decrease in dissolution rate, verifying the core effectiveness of the basic formulation of the present invention. Embodiments 2-3 and 5-6, by adjusting the component ratios or replacing the povidone polymers within the formulation range defined in the claims, still maintained good performance, verifying the broad applicability of the formulation of the present invention. Embodiments 7-8, by adjusting the conditions within the process parameter range defined in the claims, showed no significant decrease in performance, verifying the robustness and universality of the preparation method of the present invention.

[0052] Comparative Example 1 removed the core component, enteric-coated acrylic resin, and used only copovidone as a carrier. Although the initial dissolution was acceptable, the dissolution decreased to 61.3% after 6 months of accelerated dissolution, while the crystallinity soared to 26.8%. This directly proves that the biphase blended polymer matrix and microscopic physical barrier structure constructed by enteric-coated acrylic resin are the core technical features for inhibiting tenapano molecule migration, avoiding phase separation and recrystallization, and improving long-term stability. Without this component, the core beneficial effects of this invention cannot be achieved.

[0053] Comparative Example 2 uses the conventional solution described in the background art, with a single hydrophilic carrier and conventional hot melt extrusion process. Its initial dissolution rate is only 85.7%, and after 6 months of acceleration, the dissolution rate is less than 50%, while the crystallinity is as high as 37.5%. This shows a very significant performance difference compared to Example 1 of the present invention, directly proving that the present invention has unexpected technical effects compared to the prior art, and overcomes the technical defects of insufficient physical stability and irreversible decay of dissolution rate that have long existed in the prior art.

[0054] Comparative Example 3 deviated the supercritical carbon dioxide injection pressure from the range defined in this invention, resulting in the inability to form a uniform open-pore microporous network, a significant decrease in initial dissolution, insufficient uniformity of polymer system mixing, and a significant increase in drug crystallinity after acceleration. This demonstrates that the process parameter range defined in this invention is a necessary condition for achieving excellent performance, and parameters outside the range cannot achieve the expected technical effect.

[0055] Comparative Example 4 omitted the core process step of supercritical carbon dioxide injection, and did not form a through-hole microporous network, resulting in an initial dissolution rate of only 74.3%, which is much lower than that of Example 1. However, its crystallinity after acceleration remained at a low level, proving that the biphase blended polymer matrix of the present invention is the core to achieve physical stability, while the open-hole microporous network formed by supercritical fluid foaming is the key to achieving high dissolution rate. The two work synergistically to achieve both high dissolution and high stability of tenapano, solving the technical contradiction in the prior art where it is difficult to achieve both improved dissolution and improved stability.

[0056] This invention utilizes a biphase blended polymer matrix constructed from polyvinyl ketone polymers and enteric-coated acrylic resin, combined with an open-cell microporous network formed by supercritical fluid foaming. The two work synergistically to inhibit drug recrystallization and improve long-term physical stability through phase interface hindrance and multi-site hydrogen bonding in the biphase structure, while expanding the contact area between the drug and the dissolution medium through the through-cell microporous network, achieving high dissolution. This invention solves the technical problem of balancing improved dissolution and physical stability in tenapano solid dispersions in existing technologies, and has outstanding substantive features and significant progress compared to existing technologies.

Claims

1. A solid dispersion of tisopanone, characterized in that, The tenapano solid dispersion is composed of tenapano, povidone polymers, and enteric acrylic resin; Based on the total mass of the tenapano solid dispersion, the mass percentage of tenapano is 5% to 30%, the mass percentage of the povidone polymer is 40% to 70%, and the mass percentage of the enteric acrylic resin is 10% to 50%. The tenapano is dispersed in an amorphous form in a biphase blend polymer matrix formed by the polyvinyl ketone polymer and the enteric acrylic resin. The biphase blend polymer matrix forms an interpenetrating continuous phase network structure inside the tenapano solid dispersion. The powder of the tenapano solid dispersion has an open-pore microporous network formed by supercritical fluid physical foaming, which penetrates the interior and surface of the powder particles.

2. The tinapanor solid dispersion of claim 1, wherein, The polyvinylpyrrolidone polymer is a copolyvinylpyrrolidone, which is a copolymer of N-vinylpyrrolidone and vinyl acetate. The weight-average molecular weight of the copolyvinylpyrrolidone is 40,000 to 70,000. The copolyvinylpyrrolidone exists in an amorphous form in the biphase blend polymer matrix, and the mass of the copolyvinylpyrrolidone accounts for 100% of the total mass of the polyvinylpyrrolidone polymer.

3. The tinapanor solid dispersion of claim 1, wherein, The enteric-coated acrylic resin is a methacrylic acid-ethyl acrylate copolymer, wherein the mass ratio of methacrylic acid monomer units to ethyl acrylate monomer units in the methacrylic acid-ethyl acrylate copolymer is 1:4, the weight-average molecular weight of the methacrylic acid-ethyl acrylate copolymer is 100,000 to 150,000, and the enteric-coated acrylic resin forms discontinuous hydrophobic island-like structural regions in the biphase blend polymer matrix.

4. The tinapanor solid dispersion according to claim 2 and claim 3, wherein, Based on the total mass of the tenapano solid dispersion, the mass percentage of tenapano is 10% to 20%, the mass percentage of copovidone is 50% to 60%, and the mass percentage of the methacrylate-ethyl acrylate copolymer is 25% to 35%. The molecular-level dispersion of tenapano is characterized by a solid-phase intermolecular hydrogen bond network structure formed by the carbonyl groups of tenapano, copovidone, and carboxyl groups of the methacrylate-ethyl acrylate copolymer.

5. The tinapanor solid dispersion of claim 1, wherein, The tenapano solid dispersion further comprises mesoporous silica with a specific surface area of ​​500 to 1000 square meters per gram and an average pore size of 10 to 30 nanometers. Based on the total mass of the tenapano solid dispersion, the mass percentage of the mesoporous silica is 5% to 15%. The tenapano, the povidone polymer, and the enteric acrylic resin are loaded inside the pores and on the outer surface of the mesoporous silica.

6. The tinapanor solid dispersion of claim 1, wherein, The pore size distribution of the open-pore microporous network is 0.5 micrometers to 5 micrometers. The open-pore microporous network accounts for 10% to 30% of the internal volume of the tenapano solid dispersion. The pore walls of the open-pore microporous network are formed by the phase interface between the polyvinyl ketone polymer and the enteric acrylic resin. The open-pore microporous network is formed in situ after phase transformation expansion in the molten polymer matrix by supercritical carbon dioxide fluid and decompression removal.

7. A process for the preparation of a solid dispersion of Tensapanor for the preparation of a solid dispersion of Tensapanor according to any one of claims 1 to 6, characterized in that, The preparation method includes the following steps: Step 1: Add tenapano, povidone polymers and enteric acrylic resin to a high-speed mixer in a set ratio for physical mixing to obtain a premixed material; Step 2: The premixed material is fed into the feed inlet of the twin-screw extruder. The twin-screw extruder is divided into a feeding zone, a melting zone, a mixing zone, and a die zone along the material conveying direction. A stepped heating program is applied to each zone of the twin-screw extruder. Step 3: Inject supercritical fluid as a temporary plasticizer into the premixed material in the melting zone of the twin-screw extruder; Step four: After passing through the mixing zone, the premixed material is extruded through the die in the die zone, and the extrudate is introduced into the quenching device for solidification. Step 5: Transfer the cured extrudate to a pulverizer for crushing, and then sieve it through a vibrating screen to collect powder within the target particle size range.

8. The method for preparing the tenapano solid dispersion according to claim 7, characterized in that, The stepped heating process is specifically as follows: The temperature of the feeding zone is set to 60°C to 80°C, the temperature of the melting zone is set to 120°C to 150°C, the temperature of the mixing zone is set to 140°C to 160°C, the temperature of the die zone is set to 130°C to 150°C, and the screw speed of the twin-screw extruder is set to 100 rpm to 300 rpm.

9. The method for preparing the tenapano solid dispersion according to claim 7, characterized in that, In step three, the supercritical fluid is supercritical carbon dioxide. The supercritical carbon dioxide is injected into the melting zone through a high-pressure metering pump. The injection pressure of the supercritical carbon dioxide is set to 8 MPa to 15 MPa, the flow rate of the supercritical carbon dioxide is set to 0.5 liters to 2 liters per kilogram of premixed material per hour, and the residence time of the supercritical carbon dioxide with the premixed material in the melting zone is set to 30 seconds to 90 seconds.

10. The method for preparing the tenapano solid dispersion according to claim 7, characterized in that, The quenching device mentioned in step four is a tracked cooling tank with a circulating cold air system. The temperature of the conveyor belt of the tracked cooling tank is set to -10 degrees Celsius to 5 degrees Celsius, and the wind speed of the circulating cold air system is set to 5 meters per second to 10 meters per second. In step five, the screen mesh size of the vibrating screen is set to 80 to 150 mesh. After the powder within the target particle size range is sieved, it is sealed and packaged by a vacuum degassing packaging machine. The absolute vacuum pressure of the vacuum degassing packaging machine is set to 100 Pa to 500 Pa.