Melogabalin besylate pharmaceutical composition and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a melogabalin besylate pharmaceutical composition and a preparation method thereof. The melogabalin besylate gel comprises melogabalin besylate based on melogabalin, a hydrophilic polymer carrier (HPMCP or HPMCAS), a surfactant and colloidal silicon dioxide. The medicine, the carrier and other components are prepared into a solid dispersion by adopting a hot melt extrusion technology. By optimizing a carrier and a process, the technical problems of low dissolution rate and high hygroscopicity of raw material medicines are solved, the dissolution rate of the obtained product exceeds 95% within 15 minutes, and the stability of the product in a high-humidity environment is remarkably improved. The composition is preferably an oral granule, is convenient for patients with dysphagia to take, has excellent bioavailability and patient compliance, is green and efficient in production process, and is easy for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and more specifically, to a melogabalin benzyl sulfonate pharmaceutical composition and its preparation method. Background Technology

[0002] Merogabalin besylate is an effective drug for treating peripheral neuropathic pain. However, the inherent physicochemical properties of this active pharmaceutical ingredient present significant challenges for its formulation development. Currently, traditional formulation technology has the following key defects: (1) Dissolution-limited absorption: Merogabalin besylate has limited solubility in water and belongs to Class II or IV drugs in the Biopharmaceutics Classification System (BCS). Its oral absorption is limited by the dissolution rate. Conventional tablets or capsules dissolve slowly in the body, resulting in delayed onset of action and unsatisfactory bioavailability. Studies have shown that the original formulation has a dissolution rate of less than 70% in simulated intestinal fluid within 30 minutes. (2) Strong hygroscopicity: This compound is extremely hygroscopic, and the weight gain due to moisture absorption can reach more than 5%. During production, packaging and storage, moisture absorption will lead to poor powder flowability, clumping, and decreased content uniformity. More seriously, it will cause drug degradation, increase related substances, and seriously affect the chemical stability and shelf life of the product. It is difficult to effectively overcome this problem by using conventional excipients and processes (such as direct compression of powder or wet granulation), which often requires harsh production environments (such as extremely low relative humidity) and expensive packaging materials. (3) Patient compliance issues: Most patients with neuropathic pain are elderly and may have difficulty swallowing tablets or capsules, and existing dosage forms have not adequately addressed this need.

[0003] While solid dispersion technology can theoretically be used to improve the dissolution of poorly soluble drugs, conventional hydrophilic polymer carriers (such as PVP, PEG, etc.) cannot solve the problem of strong hygroscopicity for merogabaline besylate, and may even exacerbate the drug's hygroscopic degradation. In addition, such carrier systems have poor physical stability, and the drug is prone to crystallization during storage, leading to a decrease in dissolution. Summary of the Invention

[0004] The purpose of this invention is to provide a melogabalin besylate pharmaceutical composition with high dissolution, good stability, and good patient compliance, and a method for preparing the same, so as to solve the problems mentioned in the background art.

[0005] To achieve the above objectives, firstly, the present invention provides a melogabalin besylate pharmaceutical composition comprising the following raw materials: Merogabalin besylate: 10-50 parts (calculated as merogabalin), as the active pharmaceutical ingredient; Hydrophilic polymeric carrier: 30-70 parts, selected from one or a combination of two of hydroxypropyl methylcellulose phthalate (HPMCP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS), used to form a solid dispersion, improve dissolution and inhibit drug moisture absorption; Surfactant: 2-10 parts, selected from one of polyoxyethylene (40) hydrogenated castor oil, sucrose fatty acid ester or sodium dodecyl sulfate, to further improve the wettability and apparent solubility of the drug; Anti-sticking agent / stabilizer: 5-20 parts, colloidal silica, to prevent adhesion during preparation and as a moisture-absorbing stabilizer in the final product; Flavoring agent: 1-5 parts, used to improve oral taste; Excipients, balances, such as fillers (mannitol, sorbitol, etc.).

[0006] In this invention, HPMCP or HPMCAS serves as a carrier. The hydrophobic groups (phthaloyl or acetyl / succinyl) in their molecular structure can form a microscopic barrier in the solid dispersion, effectively isolating water molecules from contact with the drug, thereby fundamentally solving the hygroscopicity problem. At the same time, these carriers dissolve rapidly at intestinal pH, allowing highly dispersed drug molecules to be released quickly, achieving a leap in dissolution rate. The surfactant works synergistically with the carrier to further reduce interfacial tension and ensure sufficient wetting of the drug. Colloidal silica acts as a physical hygroscopic agent and flow aid, providing dual stability.

[0007] Secondly, this invention provides a method for preparing the above-mentioned melogabalin benzyl sulfonate pharmaceutical composition, the key of which lies in using hot melt extrusion technology to prepare a solid dispersion, including the following steps: S1. Pretreatment: The melogabalin besylate raw material is pulverized and passed through a 100-mesh sieve. The hydrophilic polymer carrier, surfactant and other excipients are dried and passed through an 80-mesh sieve for later use.

[0008] S2. Mixing: Place the prescribed amount of melogabalin benzyl sulfonate, hydrophilic polymer carrier, surfactant, and part of the anti-adhesion agent (such as half the amount of colloidal silica) into a three-dimensional motion mixer and mix for 30-45 minutes until homogeneous.

[0009] S3. Hot-melt extrusion: The homogeneous mixture described above is fed into a twin-screw hot-melt extruder. Key process parameters: Set the processing temperature to 80-110℃ (this temperature is lower than the decomposition temperature of melogabalin, but higher than the glass transition temperature of the carrier material, sufficient to melt the carrier), and the screw speed to 50-150 rpm. Under the shearing and mixing action of the screw, the drug is highly dispersed in the molten carrier in a molecular or amorphous form, forming a homogeneous solid dispersion.

[0010] S4. Cooling and Crushing: The extruded strips are immediately cooled to room temperature using a cooling device (such as a cooling steel belt) to vitrify and set their shape. The brittle solid strips are then coarsely crushed and further pulverized using a multi-functional pulverizer, passing through a 20-40 mesh sieve to obtain preliminary granules.

[0011] S5. Final Mixing and Packaging: Add the remaining colloidal silica (anti-sticking agent) and flavoring agent to the initial granules, and mix in a V-type mixer for 15-20 minutes to ensure uniformity. Finally, dispense the finished granules according to dosage into aluminum-plastic composite bags or moisture-proof packaging with desiccant.

[0012] Thirdly, the present invention provides a dosage form for the pharmaceutical composition, preferably oral granules or fine granules. This dosage form can be swallowed directly or dissolved in water or liquid food, greatly facilitating elderly patients with swallowing difficulties and significantly improving medication compliance.

[0013] Compared with the prior art, the beneficial effects of the present invention are as follows: In this merogabarine besylate pharmaceutical composition and its preparation method, a stable solid dispersion system was successfully constructed by selecting HPMCP / HPMCAS as an enteric-coating material and employing hot-melt extrusion, a solvent-free and green process. This system encapsulates the drug at the molecular level through a hydrophobic enteric-coating material carrier, significantly improving the drug's dissolution rate and extent (dissolution rate >85% within 15 minutes), potentially enhancing its in vivo absorption. More importantly, the hydrophobic groups in the carrier molecules form an effective moisture barrier, solving the problem of the active pharmaceutical ingredient's strong hygroscopicity and significantly enhancing the product's stability under high humidity conditions. Secondly, the granule dosage form design directly targets the physiological characteristics of the target patient group, improving adaptability. Furthermore, the hot-melt extrusion process is a continuous production process with good reproducibility and ease of industrialization, overcoming the low production efficiency and organic solvent residue risks of traditional methods. Attached Figure Description

[0014] Figure 1 This is an overall flowchart of Embodiment 1 of the present invention. Detailed Implementation

[0015] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0016] Example 1: This embodiment of the invention provides a melogabalin besylate pharmaceutical composition, which is prepared into granules using HPMCP HP-55 as a carrier.

[0017] (1) Includes the following raw materials: Merogabalin benzenesulfonic acid (calculated as melogabalin) 20g, HPMCP HP-55 50g, polyoxyethylene (40) hydrogenated castor oil 5g, colloidal silica (internal) 5g, colloidal silica (external) 3g, mannitol 15.67g, aspartame 1g, strawberry flavor 0.33g.

[0018] (2) Preparation method (see) Figure 1 ): Weigh each component according to the prescription amount, and sieve and mix the melogabalin benzenesulfonic acid, HPMCP HP-55, polyoxyethylene (40) hydrogenated castor oil and the colloidal silica added to the internal part.

[0019] The mixture is fed into a twin-screw hot melt extruder (temperature settings: zone I 85℃, zone II 95℃, zone III 105℃, die head 100℃; screw speed 100 rpm) for extrusion.

[0020] The extruded strips were cooled and solidified by a cooling steel belt (10°C) and then pulverized through a 30-mesh sieve. The resulting granules were mixed with added colloidal silica, mannitol, aspartame, and strawberry flavoring in a mixer for 15 minutes. The mixture was then packaged in aluminum-plastic composite bags, each containing 1.0g and 20mg of melogabalin.

[0021] (3) Performance testing: Dissolution: Following the paddle method in the Chinese Pharmacopoeia, 900 ml of pH 6.8 phosphate buffer was used as the dissolution medium, and the paddle speed was 50 rpm. Results: The dissolution rate was 98.5% at 10 minutes and 99.2% at 15 minutes.

[0022] Hygroscopicity: Referring to the general rules of the Chinese Pharmacopoeia, an appropriate amount of sample was placed in a constant temperature and humidity chamber (25℃, RH 75%±5%) for 10 days. Result: The weight gain due to moisture absorption was 1.5%.

[0023] Related substances: After one month of accelerated testing (40℃ / 75%RH), the total increase in related substances was determined by HPLC and was <0.3%.

[0024] Example 2: Granules were prepared using HPMCAS HG grade as a carrier.

[0025] (1) Includes the following raw materials: Merogabalin benzyl sulfonate (calculated as melogabalin) 30g, HPMCAS-HG 60g, sucrose fatty acid ester (SE-15) 8g, colloidal silica (internal) 7g, colloidal silica (external) 5g, sorbitol 88.5g, orange flavor 1.5g.

[0026] (2) Preparation method: The process is the same as in Example 1, with the hot melt extrusion temperatures set as follows: Zone I 90℃, Zone II 100℃, Zone III 110℃, and die head 105℃; screw speed 120 rpm. It is packaged into 2.0g packets containing 30mg of melogabalin.

[0027] (3) Performance testing: Dissolution rate: 96.8% at 15 minutes.

[0028] Moisture absorption: Under conditions of 25℃ and 75% RH for 10 days, the weight gain due to moisture absorption is 1.2%.

[0029] Related substances: After 1 month of accelerated testing, the total increase in related substances was <0.25%.

[0030] Example 3: High drug loading.

[0031] (1) Includes the following raw materials: Merogabalin benzyl sulfonate (calculated as melogabalin) 40g, HPMCP HP-55 and HPMCAS-MG (1:1 mixture) 40g, sodium dodecyl sulfate 4g, colloidal silica (internal addition) 6g, colloidal silica (external addition) 4g, microcrystalline cellulose 5g, sucralose 1g.

[0032] (2) Preparation method: The process is the same as in Example 1, with the hot melt extrusion temperatures set as follows: Zone I 80℃, Zone II 95℃, Zone III 100℃, and die head 95℃; screw speed 80 rpm to prolong mixing time. It is packaged into 1.0g packets containing 40mg of melogabalin.

[0033] (3) Performance testing: Dissolution rate: 95.2% at 15 minutes.

[0034] Moisture absorption: Under conditions of 25℃ and 75% RH for 10 days, the weight gain due to moisture absorption is 1.8%.

[0035] Related substances: After 1 month of accelerated testing, the total increase in related substances was <0.4%.

[0036] Example 4: Bioavailability Study (1) Experimental methods: Beagle dogs were used as model animals and randomly divided into two groups. The test group was given a single oral dose of the granules prepared in Example 1 (test preparation, T) and the reference preparation of commercially available melogabalin besylate tablets (reference preparation, R). The dose for both groups was 20 mg of melogabalin. Blood samples were collected at different time points, and the plasma concentration of melogabalin was determined by LC-MS / MS.

[0037] (2) Experimental results: The time to peak concentration (Tmax) of the test formulation (T) was 1.2 hours, and the Tmax of the reference formulation (R) was 2.5 hours. The relative bioavailability (AUC0-∞) of the test formulation was 125.6% of that of the reference formulation. The results indicate that the granules of the present invention have a faster onset of action and a higher degree of absorption.

[0038] The above results demonstrate that the granules prepared by the present invention through specific carriers and processes can not only significantly improve the in vitro dissolution of drugs, but also effectively translate into substantial improvements in in vivo pharmacokinetic behavior, achieving faster onset of action and more complete absorption, and solving the problems of delayed onset of action and unsatisfactory bioavailability of existing formulations.

[0039] Comparative Example 1: Ordinary tablets (powder directly compressed into tablets).

[0040] (1) Includes the following raw materials: Merogabalin benzyl sulfonate (calculated as melogabalin) 20g, microcrystalline cellulose 70g, croscarmellose sodium 8g, magnesium stearate 2g.

[0041] (2) Preparation method: Mix all raw materials and compress directly into tablets.

[0042] (3) Performance testing: Dissolution rate: The dissolution rate was only 70.5% after 45 minutes.

[0043] Moisture absorption: After being placed at 25℃ and RH75% for 24 hours, obvious clumping occurs, and the weight gain from moisture absorption reaches 8.5% after 10 days.

[0044] Related substances: After 1 month of accelerated testing, the total increase in related substances was >1.2%.

[0045] Comparative Example 2: Wet Granulation Tablets.

[0046] (1) Raw materials: Same as comparative example 1.

[0047] (2) Preparation method: Wet granulation is performed using purified water as a binder, followed by drying and tableting.

[0048] (3) Performance test: Since the drug has come into contact with moisture during the granulation process, its initial related substances are higher than those of Comparative Example 1, and its stability is worse.

[0049] Comparative Example 3: Physical mixture particles without polymer carriers (1) Raw materials: 20g melogabalin benzenesulfonic acid, 75g mannitol, 5g polyoxyethylene (40) hydrogenated castor oil.

[0050] (2) Preparation method: simple mixing and packaging.

[0051] (3) Performance test: Its hygroscopicity is similar to that of ordinary tablets, and the improvement in dissolution is limited, indicating that the solid dispersion structure formed by the polymer carrier is the key to solving the hygroscopicity and improving the dissolution.

[0052] Related substances: Before the accelerated test, the total amount of related substances was 0.5% (due to contact with moisture during granulation). After 1 month of accelerated testing, the total increase in related substances was >1.5%, which was significantly higher than that of Comparative Example 1.

[0053] Dissolution rate: The dissolution rate at 45 minutes was 68.2%, which was worse than that of Comparative Example 1.

[0054] Table 1

[0055] As can be seen from the above embodiments and comparative examples, the solid dispersion granules prepared by the present invention using specific carrier materials (HPMCP / HPMCAS) and hot melt extrusion process achieve a breakthrough improvement in dissolution and stability compared to traditional formulations. This improvement stems from the effective encapsulation of the drug in molecular or amorphous form by a hydrophobic polymer carrier, which promotes dissolution and isolates it from moisture. The granule dosage form directly enhances the convenience of medication administration for patients.

[0056] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely preferred examples and are not intended to limit the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A merogabarine besylate pharmaceutical composition, characterized in that, The components include the following parts by weight: Merogabalin besylate, calculated as 10-50 parts; 30-70 parts of a hydrophilic polymeric carrier, wherein the hydrophilic polymeric carrier is selected from one or a combination of two of hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate. 2-10 parts of surfactant, wherein the surfactant is selected from one of polyoxyethylene (40) hydrogenated castor oil, sucrose fatty acid ester or sodium dodecyl sulfate; 5-20 parts of anti-adhesion agent, wherein the anti-adhesion agent is colloidal silica.

2. The melogabalin besylate pharmaceutical composition according to claim 1, characterized in that: The hydrophilic polymer carrier is HPMCP HP-55 or HPMCAS-HG.

3. The melogabalin besylate pharmaceutical composition according to claim 1, characterized in that: The weight ratio of melogabalin benzyl sulfonic acid to the hydrophilic polymer carrier is 1:0.8 to 1:

3.

4. The merogabarine besylate pharmaceutical composition according to claim 1, characterized in that: The composition is a solid dispersion, wherein the melogabalin benzyl sulfonate is dispersed in the hydrophilic polymer carrier in a molecular or amorphous form.

5. The melogabalin besylate pharmaceutical composition according to any one of claims 1-4, characterized in that: The composition is in the form of oral granules or fine granules.

6. A method for preparing the merogabarine besylate pharmaceutical composition according to any one of claims 1-5, characterized in that, The method employs hot melt extrusion technology and includes the following steps: S1. Merogabalin benzenesulfonic acid, hydrophilic polymer carrier, surfactant and part of anti-adhesion agent are mixed to obtain a homogeneous mixture; S2. The homogeneous mixture is hot-melted and extruded to obtain solid dispersion strips; S3. Cool and pulverize the solid dispersion strip to obtain a particulate intermediate; S4. The granular intermediate is mixed with the remaining excipients to obtain the pharmaceutical composition.

7. The method for preparing the melogabalin benzyl sulfonate pharmaceutical composition according to claim 6, characterized in that: In S2, the processing temperature of the hot melt extrusion is 80-110℃.

8. The method for preparing the melogabalin benzyl sulfonate pharmaceutical composition according to claim 6, characterized in that: In S2, the hot melt extrusion is performed using a twin-screw hot melt extruder with a screw speed of 50-150 rpm.

9. The method for preparing the melogabalin benzyl sulfonate pharmaceutical composition according to claim 6, characterized in that: In step S3, the cooling is achieved by using a cooling steel belt to cool the strip to room temperature, and the pulverized material is then passed through a 20-40 mesh sieve.

10. The method for preparing the melogabalin besylate pharmaceutical composition according to claim 6, characterized in that: The anti-adhesion agent is colloidal silica, and the portion added in S1 is an internal addition, while the portion added in S4 is an external addition.

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