An opicapone capsule and a method for its preparation

Abstract

The application discloses an opicapone capsule, which comprises a capsule content, wherein the capsule content is prepared by mixing opicapone solid dispersion powder with pharmaceutical excipients; the opicapone solid dispersion powder is obtained by low-temperature crushing of a solid dispersion prepared by hot melt extrusion of opicapone raw material, a hydrophilic polymer carrier and a plasticizer; and the pharmaceutical excipients comprise a filler, a disintegrant, a glidant and a lubricant. In the application, the poorly soluble opicapone is highly dispersed in the hydrophilic polymer carrier in a molecular or amorphous state, the dissolution rate and degree of the drug are improved, and the bioavailability of the drug is increased.

Description

Technical Field

[0001] This invention relates to the technical field of drug synthesis, specifically to an opipocorpon capsule and its preparation method. Background Technology

[0002] Opipapone, a third-generation catechol-O-methyltransferase (COMT) inhibitor, has significant clinical value in the adjunctive treatment of Parkinson's disease. However, its practical application faces multiple technical challenges. Among these challenges, opipapone, belonging to the BCS class II drugs, is characterized by low solubility and high permeability. Its inherent physicochemical properties limit its oral bioavailability due to the dissolution rate.

[0003] Existing research indicates that opipracene has extremely low solubility in water and exhibits unstable dissolution behavior within the gastrointestinal pH range, directly impacting its therapeutic efficacy and dosage accuracy. Furthermore, current research primarily focuses on improving the crystal form of opipracene. For example, CN102015696A discloses various opipracene crystal forms (A, B, C, D, E, F, etc.), but these forms have significant drawbacks: while crystal form A is thermodynamically stable, its low dissolution rate leads to insufficient bioavailability. Other crystal forms (C, D, E, F) are prone to crystal transformation during storage or formulation, affecting product quality stability. Crystal form B can further transform into crystal form A, causing fluctuations in dissolution performance. In addition, current micronization processes increase production costs and process complexity, and crystal form control requires stringent temperature and humidity conditions, making batch-to-batch quality stability difficult to guarantee. Moreover, the poor mixing uniformity of opipracene with excipients affects formulation homogeneity. Currently, attempts to improve solubility often come at the expense of stability, making it difficult to achieve a balance between the two. Existing crystal form control technologies have high equipment requirements, are sensitive to process parameters, and are difficult to scale up for production. Differences in crystal form between batches of active pharmaceutical ingredients lead to unstable formulation performance. Although patents such as CN102015696A attempt to solve the problem through crystal form improvement, there is an urgent need in this field for a new technical solution that can significantly improve dissolution without sacrificing stability, and can simplify the production process and reduce reliance on complex processes such as micronization. Summary of the Invention

[0004] This application provides an opipocorp capsule and its preparation method, which highly disperses poorly soluble opipocorp in a molecular or amorphous form in a hydrophilic polymer carrier, thereby increasing the dissolution rate and extent of the drug and thus increasing its bioavailability.

[0005] On one hand, this application provides an opipacone capsule containing capsule contents, the capsule contents being a mixture of opipacone solid dispersion micropowder and pharmaceutical excipients; the opipacone solid dispersion micropowder is obtained by low-temperature pulverization of a solid dispersion prepared by hot melt extrusion of opipacone active pharmaceutical ingredient, hydrophilic polymer carrier, and plasticizer; the pharmaceutical excipients include fillers, disintegrants, glidants, and lubricants.

[0006] By adopting the above technical solution, the capsule contents of this application are composed of opiparpon solid dispersion micronized powder and conventional pharmaceutical excipients. The opiparpon solid dispersion micronized powder is prepared by hot-melt extrusion and then subjected to low-temperature pulverization. This solution differs from existing technologies in that it does not rely on a specific drug crystal form, but rather converts the drug into an amorphous dispersion, fundamentally avoiding inconsistent dissolution behavior and stability problems caused by crystal form transformation. Furthermore, the hot-melt extrusion method for preparing solid dispersions is a continuous, solvent-free or low-solvent-consumption green process, avoiding the solvent residue, environmental pollution, and high cost problems that may arise from traditional solvent methods.

[0007] Preferably, in the opipicolane solid dispersion, the mass ratio of opipicolane active pharmaceutical ingredient to the hydrophilic polymer carrier is 1-2:2-4.

[0008] Preferably, the hydrophilic polymer carrier is at least one of polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol-povidone copolymer, and polyethylene oxide.

[0009] By adopting the above technical solutions, this application discloses a specific range of hydrophilic polymer carriers. These polymers are commonly used, safe, and suitable carriers for hot melt extrusion processes in the pharmaceutical industry. Highly dispersing poorly soluble opiacarbon in molecular or amorphous form within the hydrophilic polymer carrier can significantly improve the drug's dissolution rate and extent.

[0010] Preferably, the plasticizer is at least one selected from polyethylene glycol, citrate, glyceryl ester, poloxamer, and propylene glycol.

[0011] By adopting the above technical solutions, plasticizers are key excipients in hot melt extrusion processes for reducing polymer processing temperature and preventing drug degradation.

[0012] Preferably, the amount of plasticizer added accounts for 5% of the total mass of opipicolane active pharmaceutical ingredient and hydrophilic polymer carrier.

[0013] Preferably, in the pharmaceutical excipients, the filler is microcrystalline cellulose, the disintegrant is croscarmellose sodium, the flow aid is colloidal silica, and the lubricant is magnesium stearate.

[0014] By adopting the above technical solution, this application specifies four pharmaceutical excipients: a filler, a disintegrant, a flow aid, and a lubricant. The filler provides the matrix, the disintegrant promotes rapid disintegration, the flow aid ensures powder flowability for filling, and the lubricant reduces friction. This combination collectively ensures the uniformity of the capsule contents, its fillability, and rapid disintegration and dissolution in vivo.

[0015] On the other hand, this application provides a method for preparing opipacone capsules, comprising the following steps: S1, preparation of solid dispersion: opipacone active pharmaceutical ingredient and hydrophilic polymer carrier are mixed in proportion, plasticizer is added, and the mixture is melt-blended, extruded and cooled in a twin-screw hot melt extruder under a set temperature gradient to obtain opipacone solid dispersion; S2, micronization and mixing: the solid dispersion obtained in step S1 is pulverized at low temperature to a particle size D50 ≤ 20 μm to obtain opipacone solid dispersion micronized powder; the micronized powder is mixed evenly with filler, disintegrant, glidant and lubricant to obtain capsule contents; S3, capsule filling: the capsule contents obtained in step S2 are filled into hard capsule shells to obtain opipacone capsules.

[0016] By adopting the above technical solution, the preparation of opipocone capsules in this application specifically includes three steps: hot melt extrusion preparation of solid dispersion, micronization and mixing, and capsule filling, and provides optimized and industrial-scale specific process parameters.

[0017] Preferably, in step S1, the temperature gradient of the twin-screw hot melt extruder is set as follows: 80°C in the feeding zone, 120°C in the mixing zone, and 100°C in the extrusion zone, with a screw speed of 200 rpm.

[0018] Preferably, in step S2, the temperature of the low-temperature pulverization is -20°C.

[0019] Preferably, in step S2, the mixing is carried out in a three-dimensional mixer at a mixing speed of 30 rpm for 30 minutes.

[0020] One or more technical solutions provided in this application have at least the following technical effects or advantages: 1. This application prepares opipicolane solid dispersion by using hot melt extrusion, which highly disperses poorly soluble drugs in a molecular or amorphous form in a hydrophilic polymer carrier, breaking the solubility limitation of drug crystal structure, thereby improving the dissolution rate and extent of drug dissolution, and solving the problem of low oral bioavailability of opipicolane as a BCS Class II drug.

[0021] 2. The technical solution of this application does not rely on specific, easily changeable drug crystal forms (such as crystal forms B, C, D, etc. mentioned in the background art), but forms a stable amorphous solid dispersion, avoiding inconsistent dissolution behavior and product quality fluctuations caused by crystal form changes. At the same time, it reduces stability and safety issues caused by residual organic solvents, ensuring the physicochemical stability of the intermediate.

[0022] 3. The proposed solution involves low-temperature pulverization of the solid dispersion before mixing it with excipients, avoiding the stringent micronization process required in traditional methods, thus reducing process complexity and equipment requirements. Furthermore, the optimized excipient combination ensures the uniformity and good flowability of the capsule contents, resulting in a smooth capsule filling process, accurate dosage, and minimal batch-to-batch variation. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 The image shows the X-ray powder diffraction (XRD) analysis pattern of opycarbon in this application. Figure 2 High-performance liquid chromatography for the determination and analysis of opiacarbone content in this application; Figure 3 High performance liquid chromatography was used to determine the content of octopaine 5 min after dissolution in this application. Detailed Implementation

[0025] This application provides an opipocorp capsule and its preparation method, which highly disperses poorly soluble opipocorp in a molecular or amorphous form in a hydrophilic polymer carrier, thereby increasing the dissolution rate and extent of the drug and thus increasing its bioavailability.

[0026] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this application without creative effort are within the scope of protection of this application.

[0027] It should be noted that the terms "first," "second," etc., in the specification, claims, and accompanying drawings of this application are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of this application described herein can be implemented in orders other than those illustrated or described herein. Furthermore, the terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion; for example, a process, method, system, product, or server that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or modules not explicitly listed or inherent to such processes, methods, products, or devices. Example 1

[0028] Example 1 of this application provides a method for preparing opipocorpine capsules. The preparation method in Example 1 is based on polyvinylpyrrolidone K30 (PVP K30) carrier. The specific preparation steps are as follows: S1. Preparation of solid dispersions: First, accurately weigh 100.0 g of opiparbon active pharmaceutical ingredient (HPLC purity ≥99.0%, moisture ≤0.5%), 400.0 g of hydrophilic polymer carrier polyvinylpyrrolidone K30 (PVP K30), and 25.0 g of plasticizer polyethylene glycol 4000 (PEG4000) (its mass is exactly 5% of the total mass of 500 g of opiparbon and PVP K30). Place all three into a 20L three-dimensional motion mixer (model: SHK-20). Set the mixer speed to 30 rpm and mix for 20 minutes to ensure the active pharmaceutical ingredient, polymer carrier, and plasticizer are initially and evenly mixed. Then, feed the premixed material into a co-rotating twin-screw hot melt extruder (screw diameter 20 mm, L / D=40). Set the temperature gradient for each zone as follows: feed zone 80°C, mixing zone 120°C, extrusion zone 100°C. Set the screw speed to 200 rpm. The extruder is started, and the material is melted and blended under the conveying, shearing, and mixing action of the screw, and then extruded through the die head. The extruded strips are immediately cooled and drawn by a cooling and traction device to obtain a continuous strip-shaped solid dispersion with a diameter of about 2 mm, which is transparent or semi-transparent and in a glassy state. The dispersion is then cut and collected.

[0029] S2, Micronization and Mixing: The above-mentioned strip-shaped solid dispersion was pre-cooled at -20°C for 2 hours, and then pulverized using an impact pulverizer equipped with a liquid nitrogen cooling system. The pulverized material was passed through an 80-mesh sieve and measured with a laser particle size analyzer; its particle size distribution D50 was 18 μm, yielding opipicaraben solid dispersion micron powder. 125.0 g of the above opipicaraben solid dispersion micron powder was weighed (equivalent to 25.0 g of opipicaraben based on a drug loading of 20%). Then, 200.0 g of the filler microcrystalline cellulose (PH-101) and 20.0 g of the disintegrant croscarmellose sodium were weighed. The above micron powder, microcrystalline cellulose, and added croscarmellose sodium were then added together to a clean 20L three-dimensional motion mixer.

[0030] Set the mixer speed to 30 rpm and perform the first mixing step for 20 minutes. After the first mixing step is complete, add 5.0 g of colloidal silica as a flow aid and 5.0 g of magnesium stearate as a lubricant. Continue with the second mixing step for 10 minutes. After mixing is complete, discharge the material to obtain a uniform powder of capsule contents weighing approximately 355.0 g.

[0031] S3, Capsule Filling: A fully automatic capsule filling machine was used, employing No. 2 hard gelatin capsule shells. The uniformly mixed capsule contents powder was fed into the hopper, with a target filling weight set at 284.0 mg / capsule. The machine automatically completed the capsule separation, filling, fitting, and locking processes. Then, 100 capsules were randomly selected and weighed, with an average filling weight of 284.5 mg. The calculated content of each capsule was approximately 20.0 mg of opipicaraben. This yielded the opipicaraben capsules of this embodiment. Example 2

[0032] The difference between Example 2 and Example 1 is that polyethylene glycol-polyvinyl ketone copolymer is used as the hydrophilic polymer carrier and triethyl citrate is used as the plasticizer. The specific key steps are as follows.

[0033] S1. Preparation of solid dispersions: Weigh 100.0 g of opiacarbone active pharmaceutical ingredient (same as in Example 1), 400.0 g of the hydrophilic polymer carrier polyethylene glycol-polyvinyl acetate copolymer, and 25.0 g of the plasticizer triethyl citrate (5% of the total mass of the drug and carrier). Premixing was performed as in Example 1. A twin-screw hot-melt extruder of the same model was used. Due to the low glass transition temperature of the polyethylene glycol-polyvinyl acetate copolymer, the temperature gradient was finely adjusted to: 70°C in the feed zone, 110°C in the mixing zone, and 90°C in the extrusion zone. The screw speed remained at 200 rpm. Extrusion and cooling were performed as in Example 1, yielding a solid dispersion in strips.

[0034] S2, Micronization and Mixing: The pulverization conditions were the same as in Example 1, with low-temperature pulverization at -20°C to control the particle size D50 of the pulverized powder to be 19 μm. The excipients and proportions were exactly the same as in Example 1 (125.0 g of micronized powder, 200.0 g of microcrystalline cellulose, 20.0 g of croscarmellose sodium, 5.0 g of colloidal silica, and 5.0 g of magnesium stearate) and the mixing process (three-dimensional mixer, 30 rpm, mixing for 20 minutes first, then adding the latter two excipients and mixing for another 10 minutes) to obtain the capsule contents.

[0035] S3, Capsule Filling: The filling process was the same as in Example 1, resulting in capsules containing 20.0 mg of opipocorpine per capsule. Example 3

[0036] The difference between Example 3 and Example 1 is that hydroxypropyl methylcellulose (HPMC) is used as the hydrophilic polymer carrier and poloxamer is used as the plasticizer. The specific key steps are as follows.

[0037] S1. Preparation of solid dispersions: Weigh out 100.0 g of opiacarbone active pharmaceutical ingredient, 300.0 g of hydrophilic polymer carrier hydroxypropyl methylcellulose (HPMC E5), and 20.0 g of plasticizer poloxamer 188. Premixing was performed as in Example 1. Due to the high melting point of HPMC, the temperature gradient was set as follows: 90°C in the feeding zone, 140°C in the mixing zone, and 120°C in the extrusion zone. The screw speed was 200 rpm. Extrusion and cooling were performed as in Example 1.

[0038] S2, Micronization and Mixing: The pulverization conditions were the same as in Example 1, with low-temperature pulverization at -20°C to control the particle size D50 of the pulverized powder to be 17 μm. The same excipients (microcrystalline cellulose, croscarmellose sodium, colloidal silica, magnesium stearate) and mixing process (three-dimensional mixer, 30 rpm, total time 30 minutes) as in Example 1 were used to mix the contents of each capsule containing 20.0 mg of opiacarbone.

[0039] S3, Capsule Filling: The filling process was the same as in Example 1, resulting in capsules containing 20.0 mg of opipocorpine per capsule. Example 4

[0040] The difference between Example 4 and Example 1 is that copovidone (PVP / VA) is used as the hydrophilic polymer carrier and propylene glycol is used as the plasticizer. The specific key steps are as follows.

[0041] S1. Preparation of solid dispersions: Weigh out 100.0 g of opiacarbone active pharmaceutical ingredient, 400.0 g of hydrophilic polymer carrier copovidone (PVP / VA), and 25.0 g of propylene glycol plasticizer. Premixing was performed as in Example 1. The temperature gradient was set as follows: 75°C in the feeding zone, 115°C in the mixing zone, and 95°C in the extrusion zone. The screw speed was 200 rpm. Extrusion and cooling were performed as in Example 1.

[0042] S2, Micronization and Mixing: The pulverization conditions were the same as in Example 1, with low-temperature pulverization at -20°C to control the particle size D50 of the pulverized powder to be 20 μm. The same excipients (microcrystalline cellulose, croscarmellose sodium, colloidal silica, magnesium stearate) and mixing process (three-dimensional mixer, 30 rpm, total time 30 minutes) as in Example 1 were used to mix the contents of each capsule containing 20.0 mg of opiacarbonate.

[0043] S3, Capsule Filling: The filling process was the same as in Example 1, resulting in capsules containing 20.0 mg of opipocorpine per capsule. Example 5

[0044] The difference between Example 5 and Example 1 is that hydroxypropyl cellulose (HPC-SSL) is used as the hydrophilic polymer carrier and triacetin (glyceryl triacetate) is used as the plasticizer. The specific key steps are as follows.

[0045] S1. Preparation of solid dispersions: Weigh out 100.0 g of opiacarbone active pharmaceutical ingredient, 300.0 g of hydrophilic polymer carrier hydroxypropyl cellulose (HPC-SSL), and 20.0 g of plasticizer propylene glycol. Premixing was performed as in Example 1. The temperature gradient was set as follows: feed zone 85°C, mixing zone 130°C, extrusion zone 110°C. Screw speed was 200 rpm. Extrusion and cooling were performed as in Example 1.

[0046] S2, Micronization and Mixing: The pulverization conditions were the same as in Example 1, with low-temperature pulverization at -20°C to control the particle size D50 of the pulverized powder to be 20 μm. The same excipients (microcrystalline cellulose, croscarmellose sodium, colloidal silica, magnesium stearate) and mixing process (three-dimensional mixer, 30 rpm, total time 30 minutes) as in Example 1 were used to mix the contents of each capsule containing 20.0 mg of opiacarbonate.

[0047] S3, Capsule Filling: The filling process was the same as in Example 1, resulting in capsules containing 20.0 mg of opipocorpine per capsule. Example 6

[0048] The difference between Example 5 and Example 1 is that polyethylene oxide is used as the hydrophilic polymer carrier and propylene glycol is used as the plasticizer. The specific key steps are as follows.

[0049] S1. Preparation of solid dispersions: Weigh out 100.0 g of opiacarbone active pharmaceutical ingredient, 300.0 g of hydrophilic polymer carrier polyethylene oxide, and 20.0 g of plasticizer propylene glycol. Premixing is performed as in Example 1. The temperature gradient is set as follows: feed zone 85°C, mixing zone 120°C, extrusion zone 100°C. Screw speed is 200 rpm. Extrusion and cooling are performed as in Example 1.

[0050] S2, Micronization and Mixing: The pulverization conditions were the same as in Example 1, with low-temperature pulverization at -20°C to control the particle size D50 of the pulverized powder to be 20 μm. The same excipients (microcrystalline cellulose, croscarmellose sodium, colloidal silica, magnesium stearate) and mixing process (three-dimensional mixer, 30 rpm, total time 30 minutes) as in Example 1 were used to mix the contents of each capsule containing 20.0 mg of opiacarbonate.

[0051] S3, Capsule Filling: The filling process was the same as in Example 1, resulting in capsules containing 20.0 mg of opipocorpine per capsule.

[0052] Comparative Example Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that Comparative Example 1 uses a method based on micronized opiacarbonate to prepare capsules, and the specific steps are as follows: The opiacarbone crystalline form A raw material (from the same source as in Example 1) was micronized using an air jet mill to obtain a micronized powder with a particle size D50 of 15 μm. Then, 25 g of the above opiacarbone crystalline form A micronized powder, 200 g of microcrystalline cellulose, 20 g of croscarmellose sodium (added internally and 20 g externally), 5 g of colloidal silica, and 5 g of magnesium stearate were weighed. The mixing process was the same as in Example 1, yielding capsule contents with a total weight of 275 g.

[0053] Finally, the filling process was the same as in Example 1, and opiacarpon capsules were obtained.

[0054] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that Comparative Example 2 is based on the preparation of solid dispersions using a solvent method, and the specific steps are as follows: 100 g of opipicapped raw material and 400 g of PVP K30 were weighed and dissolved in 2000 mL of anhydrous ethanol, and stirred until completely dissolved. The solvent was removed by rotary evaporation under reduced pressure at 50°C to obtain a solid material. The obtained solid was dried in a vacuum drying oven at 40°C for 12 hours, pulverized, and sieved. Subsequent micronization was not specifically controlled by low temperature. The mixing and filling steps were the same as in Example 1 to prepare comparative opipicapped capsules.

[0055] Detection and Analysis The opiacarpon capsules prepared in Examples 1-5 and Comparative Examples 1-2 were analyzed. These included X-ray powder diffraction (XRD) analysis, dissolution determination, and content determination.

[0056] 1. X-ray powder diffraction (XRD) analysis: Solid dispersion micropowders from Examples 1-5, opycarbonate A micropowder from Comparative Example 1, and solvent-based solid dispersion powder from Comparative Example 2 were gently pressed into the sample trough to avoid preferred orientation. An X-ray powder diffractometer was used; the conditions were Cu-Kα radiation (λ=1.5406 Å), voltage 40 kV, and current 40 mA. The scanning range was 5° to 40° (2θ), the scanning step size was 0.02°, and the scanning speed was 4° / min.

[0057] 2. Dissolution analysis was performed according to Method II (paddle method) of General Chapter 0931 of the Chinese Pharmacopoeia. The medium was 900 mL of pH 6.8 phosphate buffer (containing 1.0% sodium dodecyl sulfate SDS to maintain the funnel conditions) at a temperature of 37.0 ± 0.5°C and a paddle rotation speed of 50 rpm. At specified time points, 5 mL samples were taken (with 5 mL of the same temperature medium added simultaneously), filtered through a 0.45 μm microporous membrane, and the concentration of opiacarbonate in the filtrate was determined using a validated HPLC method. The cumulative dissolution percentage was calculated.

[0058] 3. Content determination: Weigh an appropriate amount of opipicaraben reference standard, dissolve and quantitatively dilute it with a diluent (such as a methanol-water mixture) to prepare a solution containing approximately 20 μg per mL. Then, accurately weigh 20 tablets of this product and calculate the average fill weight. Take the contents, mix well, grind finely, accurately weigh an appropriate amount (approximately equivalent to 20 mg of opipicaraben), place it in a 100 mL volumetric flask, add an appropriate amount of diluent, sonicate to dissolve the opipicaraben, cool, dilute to volume with diluent, shake well, filter, and use the filtrate as the test solution. High-performance liquid chromatography (HPLC) was used. Chromatographic column: C18 column (4.6 × 250 mm, 5 μm); mobile phase: acetonitrile-0.1% phosphoric acid aqueous solution (gradient elution or optimized isocratic elution, such as 45:55); flow rate: 1.0 mL / min; detection wavelength: 240 nm; column temperature: 30°C; injection volume: 10 μL.

[0059] Reference Figure 1 Analysis shows that the numbers 00P2508025-2, 00P2508025-1, 20P2506008-1A, 20P2506008, and 240431-1A in the figure correspond to embodiments 1-6 of this application, respectively; and 209-20240204BY and C-62-250103-tiandao correspond to comparative examples 1-2 of this application, respectively.

[0060] according to Figure 1 Analysis of the X-ray powder diffraction (XRD) spectra in Examples 1-6 revealed a broad range of diffuse peaks within the 5°-40° (2θ) range, without any sharp characteristic diffraction peaks of the opipicaraben crystal form. This demonstrates that through hot-melt extrusion, opipicaraben is dispersed at the molecular level in an amorphous form within the polymer carrier, forming a stable solid dispersion. This is the fundamental reason for the improved dissolution rate. The spectrum in Comparative Example 1 shows a series of sharp characteristic diffraction peaks, completely consistent with the standard spectrum of opipicaraben crystal form A. The sample is in a complete crystalline state, and its dissolution requires overcoming lattice energy, resulting in a limited dissolution rate. The spectrum in Comparative Example 2 is predominantly a diffuse dispersion. This indicates that the solid dispersion prepared by solvent evaporation has poor physical stability due to its amorphous form, and partial drug recrystallization has occurred during drying or storage.

[0061] Reference Figure 2 This is a high-performance liquid chromatography (HPLC) analysis of the dissolution determination in Example 1 of this application. Figure 3 High-performance liquid chromatography (HPLC) was used to determine the content of opiacarbon 5 minutes after dissolution. The data regarding dissolution and content determination from all Examples 1-6 and Comparative Examples 1-2 are summarized in the following table.

[0062] Table 1. Content and dissolution determination of Examples 1-6 and Comparative Examples 1-2

[0063] Analysis of the table shows that, based on the dissolution rate and extent, the dissolution rate of the example was significantly higher than that of Comparative Example 1 and Comparative Example 2 at 5 minutes. Furthermore, Example 2, using polyethylene glycol-povidone copolymer as a hydrophilic polymer carrier, achieved a dissolution rate of 65%, demonstrating the fastest initial dissolution rate. Additionally, during complete release, the dissolution rate of the example reached 86%-94% at 15 minutes, indicating rapid and substantial absorption of the drug in vivo. In contrast, the comparative examples only dissolved 40%-45% at the same time point. This demonstrates that the dissolution rate and extent of the drug can be improved, solving the problems of unstable dissolution behavior and low bioavailability of opiapicarbon.

[0064] Furthermore, a comparative analysis with the comparative examples showed that even when micronizing poorly soluble drugs, dissolution bottlenecks still exist; and by converting them into amorphous solid dispersions, dissolution limitations can be overcome.

[0065] Secondly, a comparison was made between Comparative Example 2 and Example 1. The dissolution rate of Example 1, especially the initial dissolution and content, was superior to that of Comparative Example 2. This demonstrates that the hot-melt extrusion method of the present invention is superior to the traditional solvent evaporation method in avoiding organic solvent residue, achieving more uniform drug-carrier mixing, and obtaining a more stable amorphous form.

[0066] It should be noted that the order of the embodiments described above is merely for descriptive purposes and does not represent the superiority or inferiority of the embodiments. Furthermore, specific embodiments have been described above. Other embodiments are within the scope of the appended claims. In some cases, the actions or steps described in the claims can be performed in a different order than that shown in the embodiments and still achieve the desired result. Additionally, the processes depicted in the drawings do not necessarily require a specific or sequential order to achieve the desired result. In some embodiments, multitasking and parallel processing are also possible or may be advantageous.

[0067] The above description is only a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

[0068] This specification and accompanying drawings are merely illustrative examples of this application and are intended to cover any and all modifications, variations, combinations, or equivalents within the scope of this application. Clearly, those skilled in the art can make various alterations and modifications to this application without departing from its scope. Therefore, if such modifications and modifications fall within the scope of this application and its equivalents, this application intends to include such modifications and modifications.

Claims

1. An opipocorpon capsule, characterized in that, The product contains capsule contents, which are a mixture of opiacarbone solid dispersion micronized powder and pharmaceutical excipients; The opipicolane solid dispersion micro powder is obtained by low-temperature pulverization of a solid dispersion prepared by hot melt extrusion of opipicolane active pharmaceutical ingredient, hydrophilic polymer carrier, and plasticizer. The pharmaceutical excipients include fillers, disintegrants, flow aids, and lubricants.

2. The opipocorpon capsule as described in claim 1, characterized in that, In the opipicolane solid dispersion, the mass ratio of opipicolane active pharmaceutical ingredient to hydrophilic polymer carrier is 1-2:2-4.

3. The opipocorpon capsule as described in claim 1, characterized in that, The hydrophilic polymer carrier is at least one of polyvinylpyrrolidone, copolyvinyl ketone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol-polyvinyl ketone copolymer, and polyethylene oxide.

4. The opipocorpon capsule as described in claim 1, characterized in that, The plasticizer is at least one of polyethylene glycol, citrate, glyceryl ester, poloxamer, and propylene glycol.

5. The opipocorpon capsule as described in claim 4, characterized in that, The amount of plasticizer added is 5% of the total mass of opipicolane active pharmaceutical ingredient and hydrophilic polymer carrier.

6. The opipocorpon capsule as described in claim 1, characterized in that, In the pharmaceutical excipients, the filler is microcrystalline cellulose, the disintegrant is croscarmellose sodium, the flow aid is colloidal silica, and the lubricant is magnesium stearate.

7. A method for preparing opiacarpon capsules according to any one of claims 1-6, characterized in that, Includes the following steps: S1. Preparation of solid dispersion: Opipicapone active pharmaceutical ingredient and hydrophilic polymer carrier are mixed in proportion, plasticizer is added, and the mixture is melt-blended, extruded and cooled in a twin-screw hot melt extruder under a set temperature gradient to obtain opipicapone solid dispersion; S2. Micronization and mixing: The solid dispersion obtained in step S1 is pulverized at low temperature to a particle size D50 ≤ 20 μm to obtain opipocaborpone solid dispersion micronized powder; the micronized powder is mixed evenly with filler, disintegrant, glidant and lubricant to obtain capsule contents; S3. Capsule filling: The capsule contents obtained in step S2 are filled into hard capsule shells to obtain opipocorpine capsules.

8. The opipocorpon capsule as described in claim 7, characterized in that, In step S1, the temperature gradient of the twin-screw hot melt extruder is set as follows: 80°C in the feeding zone, 120°C in the mixing zone, and 100°C in the extrusion zone, with a screw speed of 200 rpm.

9. The opipocorpon capsule as described in claim 7, characterized in that, In step S2, the temperature of the cryogenic pulverization is -20°C.

10. The opipocorpon capsule as described in claim 7, characterized in that, In step S2, the mixing is carried out in a three-dimensional mixer at a speed of 30 rpm for 30 minutes.

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