A 20 mg core-loaded or core-shell biphasic release tablet containing merogabarine or a pharmaceutically acceptable salt thereof, and its preparation method thereof.

Abstract

This invention relates to a 20 mg core-type or core-shell type biphasic-release tablet containing merogabarine or a pharmaceutically acceptable salt thereof, and a method for preparing the same. The tablet is a core-type, compressed-coated tablet, or core-shell type film-coated tablet, comprising an immediate-release portion located in the outer layer or outer coating and a sustained-release portion located in the core, wherein the core is continuously surrounded by the outer layer in the radial direction; the immediate-release portion of the outer layer carries 20%–30% of the total drug content, and the sustained-release portion of the core carries 70%–80% of the total drug content; the core contains hydroxypropyl methylcellulose K15M, polyethylene oxide, and ethylcellulose, suitable for development into an oral sustained-release formulation for once-daily administration.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a 20mg core-type or core-shell type biphasic release tablet containing merogabarine or a pharmaceutically acceptable salt thereof, and a method for preparing the same. Background Technology

[0002] This invention pertains to the field of pharmaceutical formulations, specifically relating to a 20mg core-type or core-shell type biphasic-release tablet containing merogabarine or a pharmaceutically acceptable salt thereof, and its preparation method. This formulation achieves spatial and temporal separation and regulation of the initial release and subsequent maintenance release by arranging the immediate-release portion in the outer layer and the maintenance-release portion in the core.

[0003] Compared to the planar structure of bilayer tablets where both layers are exposed to the medium simultaneously, core-type or core-shell tablets have a spatial encapsulation structure in which the core is continuously surrounded by the outer layer. This can further enhance the "fast outside and slow inside" drug release pathway in the formulation structure, which is beneficial for reducing peak concentration and smoothing out peak and valley fluctuations.

[0004] While existing publications already contain concepts of monolayer sustained-release matrix and general biphasic release, further development is still needed for merogabalin, focusing on 20mg core-type or core-shell monolayer structures, spatial isolation between immediate release from the outer layer and sustained release from the inner core, and the resulting peak concentration suppression and fluctuation control. Summary of the Invention

[0005] This invention provides a biphasic release tablet limited to 20mg dosage and limited to core-type or core-shell type. The outer immediate-release portion of the tablet carries 20% to 30% of the total drug dose, while the core sustained-release portion carries 70% to 80% of the total drug dose; wherein the core is continuously surrounded by the outer layer in the radial direction to improve the time lag and fluctuation control capability of the drug release structure.

[0006] Preferably, the total dosage of the tablet is 20 mg, and the core sustained-release portion comprises hydroxypropyl methylcellulose K15M, polyethylene oxide, and ethyl cellulose; the formulation satisfies a predetermined release window in three media and maintains a small media difference at 8 hours and 12 hours. Detailed Implementation

[0007] Components Outer layer (mg / tablet) Kernel (mg / tablet) Function Merogabalin besylate (calculated as merogabalin) 5.0 15.0 Active ingredients Mannitol 32.0 42.0 diluent microcrystalline cellulose 15.0 18.0 diluent Cross-linked polyvinylpyrrolidone 8.0 — Disintegrant Hydroxypropyl methylcellulose K15M — 22.0 Hydrophilic sustained-release polymer Polyethylene — 8.0 Hydrophilic sustained-release polymer Ethyl cellulose — 6.0 Hydrophobic drug release regulator Povidone K30 2.0 3.0 Adhesive Colloidal silica 1.0 1.0 Flow aid magnesium stearate 1.0 1.2 lubricant Film coating premix — 6.0 (Total) Coating material Implementation method: First, a sustained-release tablet core is prepared. Then, a core-pressing process is used to press the outer layer of instant-release material onto the core to obtain a pressed tablet core. Optionally, a thin film coating is applied to obtain the finished product. Preferably, the outer layer material is prepared using direct tableting or dry granulation, and the core material is prepared using dry granulation or low-moisture granulation. The relative humidity of the environment is controlled to be no higher than 40% throughout the entire preparation process.

[0008] I. Method for determining release rate Unless otherwise stated, the release rate in this application is determined according to Method II of the current edition of the Chinese Pharmacopoeia. A paddle apparatus is preferred, with a rotation speed of 50 rpm, a temperature of 37 ± 0.5 °C, and a release medium volume of 900 mL. Parallel determination media are prepared using hydrochloric acid (pH 1.2), acetate buffer (pH 4.5), and phosphate buffer (pH 6.8), respectively.

[0009] II. Experimental Examples The following experimental examples are experimental data applicable to 20mg core-type or core-shell schemes, highlighting the fluctuation control and structural necessity brought about by the outer / inner core space isolation.

[0010] Example 1: Evaluation of in vitro release rate (verification of pH independence)

[0011] Time (h) pH 1.2 hydrochloric acid pH 4.5 acetate pH 6.8 phosphate Coefficient of variation (RSD) Rights Window Requirements 1 24.8 23.9 25.1 3.8% 15%～35% 4 46.9 46.1 48.0 2.9% 35%～60% 8 67.2 66.4 68.9 2.3% 55%～80% 12 80.5 79.8 81.7 1.9% 70%～90% 24 95.1 94.6 95.8 0.9% ≥85% f2 similarity factor — 80.8 (1.2 vs 4.5) 82.7 (1.2 vs 6.8) 81.9 (4.5 vs 6.8) All > 80 Results and conclusions: The release curves of the core-type / core-shell type tablets of the present invention highly overlapped in the pH range of 1.2 to 6.8, and the f2 similarity factor was greater than 80, indicating that their release behavior is independent of the gastrointestinal pH environment.

[0012] Experimental Example 2: Structural Comparison with Bilayer Tablet Control Formulation B

[0013] Evaluation indicators This invention relates to a core-shell / core-type tablet (20mg). Control formulation B (30mg bilayer tablets) Structural Differences Argument 1-hour release rate (%) 24.8% 25.2% Both can quickly establish early exposure Cmax (ng / mL) 176.4 184.2 Core / core-shell structure has lower peak values Volatility Index FI 0.78 0.84 Core / shell structure has less fluctuation Results and conclusions: Compared with bilayer sheets, the core-type / core-shell type sheets of the present invention can further reduce Cmax and reduce the volatility index while maintaining similar early release, indicating that the spatial structure of the outer layer covering the core helps to smooth out peak and valley fluctuations.

[0014] Experiment 3 Stability Study

[0015] Testing items 0 months 3 months 6 months evaluate Properties White or off-white film No significant changes No significant changes Stablize Total impurities 0.04% 0.08% 0.11% Well below the 0.5% limit Moisture (%) 1.8% 1.9% 2.1% excellent control Release behavior Meets the predetermined release window Meets the predetermined release window Meets the predetermined release window Release remains good Results and conclusions: Under accelerated conditions, the appearance, total impurities, moisture content and release behavior of the core-type / core-shell type wafers of the present invention remained good, indicating that the low-moisture core-pressing process has a good stability basis.

[0016] Experimental Example 4: Demonstration of Outer Layer Proportion

[0017] Sample group Outer layer instant release ratio 1-hour release rate (%) Cmax (ng / mL) Volatility Index FI evaluate Proportion Group A 10% 10.9% 138.7 0.96 Insufficient outer layer ratio results in slower onset of action. Proportion Group B 25% 24.8% 176.4 0.78 Optimal ratio: Balancing effectiveness and low volatility Proportion group C 50% 49.7% 231.2 1.21 The outer layer releases too quickly, resulting in a high peak value. Results and conclusions: When the immediate release ratio of the outer layer is about 25%, it can balance early exposure establishment and a low volatility index, reflecting the sensitivity and criticality of the core / shell structure to the ratio window.

[0018] Experimental Example 5: Tableting Process Adaptability

[0019] Batch / Condition Content uniformity (A+1.8S) Outer layer integrity Sticking / Defect Rate Tableting adaptability Remark Small batch 4.1±1.3% Compliant with control standards <0.08% good Prepared under 35% humidity conditions pilot batch 5.0±1.4% Compliant with control standards <0.1% good Core amplification quality under control Results and conclusions: Under conditions of relative humidity below 40%, the small and pilot batches of the core-shell type / core-shell type wafer of the present invention showed good coating integrity, process adaptability and scale-up stability.

[0020] Experimental Example 6: Evaluation of Wave Control in a Continuously Enclosed Outer Layer Structure

[0021] parameter This invention relates to a core-shell / core-type tablet (20mg). Control formulation B (double-layer tablets) Technological advantages Cmax (ng / mL) 176.4 184.2 Further reduction in peak value is beneficial for reducing peak-related adverse reactions. Volatility Index FI 0.78 0.84 Smaller fluctuations, more stable blood drug concentrations 1-hour release rate (%) 24.8% 25.2% Maintain the ability to establish early exposure 12-hour release rate (%) 80.5% 82.1% Maintain comparable release levels during the maintenance release phase. Results and conclusions: Under the premise of the same total drug amount and both satisfying the biphasic release window, the representative core-type / core-shell type formulation can further reduce the peak value and reduce the fluctuation, indicating that the spatial structure of continuously surrounding the core is more conducive to the smoothing of peak and valley.

[0022] Experimental Example 7: Evaluation of Core Encapsulation Integrity and Process Consistency

[0023] Batch / Condition Core eccentricity Outer layer continuous coating integrity Cross-sectional consistency in conclusion Small batch ≤10% Compliant with control standards good It can form a stable kernel-encapsulated structure pilot batch ≤10% Compliant with control standards good It can still maintain the integrity of the coating after magnification.

Claims

1. A 20mg core-loaded or core-shell biphasic release tablet, characterized in that, The tablet contains melogabalin or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients; the tablet is only a chip, a compressed coated tablet or a core-shell film coated tablet, and does not include bilayer tablets; the tablet includes an immediate-release portion located in an outer layer or outer coating and a sustained-release portion located in a core, wherein the core is continuously surrounded by the outer layer in the radial direction; Based on the free base of melogabalin, the total content of melogabalin in a single dosage unit is 20 mg; the outer immediate-release portion contains 20%–30% of the total content, and the core sustained-release portion contains 70%–80% of the total content; the core sustained-release portion comprises hydroxypropyl methylcellulose K15M, polyethylene oxide, and ethyl cellulose; and under the conditions of the second method for release determination in the current edition of the Chinese Pharmacopoeia, measured with 900 mL of release medium, 50 rpm, and 37±0.5℃, in any of the following media: pH 1.2 hydrochloric acid medium, pH 4.5 acetate buffer medium, and pH 6.8 phosphate buffer medium, the cumulative release of the tablet meets the following requirements: 15%–35% at 1 hour, 35%–60% at 4 hours, 55%–80% at 8 hours, 70%–90% at 12 hours, and not less than 85% at 24 hours, and the maximum difference in cumulative release among the three media at 8 hours and 12 hours is not higher than 15 percentage points respectively.

2. The 20mg core-loaded or core-shell biphasic release tablet according to claim 1, characterized in that, The weight ratio of melogabalin in the outer immediate release portion to the core sustained release portion is 20:80 to 30:70, preferably 25:

75.

3. The 20mg core-loaded or core-shell biphasic release tablet according to claim 1 or 2, characterized in that, The pharmaceutically acceptable salt of melogabalin is benzenesulfonate.

4. The 20mg core-loaded or core-shell biphasic release tablet according to any one of claims 1 to 3, characterized in that, The disintegrant in the outer instant-release portion is selected from crospovidone, low-substituted hydroxypropyl cellulose, or a combination thereof.

5. The 20mg core-loaded or core-shell biphasic release tablet according to any one of claims 1 to 4, characterized in that, The amount of hydroxypropyl methylcellulose K15M used is 12% to 30% of the total weight of the core, the amount of polyethylene oxide used is 4% to 15% of the total weight of the core, and the amount of ethyl cellulose used is 3% to 15% of the total weight of the core.

6. A method for preparing the 20mg core-type or core-shell type biphasic release tablet according to any one of claims 1 to 5, characterized in that, The process includes the following steps: (1) First, the sustaining release portion is prepared as a core chip, wherein the sustaining release portion is prepared by dry granulation or low moisture granulation process; (2) Then, the instant release portion is placed on the periphery of the core, and a core chip is formed by pressing and coating process to form a core chip with an outer layer continuously surrounding the core, or further forming a core-shell type core chip; (3) Selectively perform film coating; wherein, the relative humidity of the environment is controlled not to exceed 35% throughout the entire preparation process, and the residual moisture of the final core chip is controlled at 0.5% to 3.0%.

7. The method according to claim 6, characterized in that, The weight gain of the film coating is 2% to 6% of the core weight.

8. The method according to claim 6 or 7, characterized in that, The core is located in the central region of the chip cross-section, and the outer layer continuously surrounds the core to control the peak concentration and fluctuation index.