Pharmaceutical composition containing melogabalin besylate serving as active ingredient

Abstract

The invention provides a pharmaceutical composition containing melogabalin besylate as an active ingredient. The pharmaceutical composition comprises the following components: melogabalin besylate, polyoxyethylene, polyvinylpolypyrrolidone, sodium alginate and mannitol, the mass ratio of the melogabalin benzene sulfonate to the polyoxyethylene to the polyvinylpolypyrrolidone to the sodium alginate to the mannitol is (0.5-8): (20-40): (5-15): (20-40): (3-20). The pharmaceutical composition is a sustained release preparation, and can ensure that melogabalin besylate is continuously released and absorbed in vivo, so that the drug effect is improved, the adverse reaction is reduced, and the treatment effect is enhanced while the administration frequency is reduced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a pharmaceutical composition containing the active ingredient melogabalin besylate. Background Technology

[0002] Merogabalin besylate is a medication used to treat diabetic peripheral neuropathy-related neuralgia and postherpetic neuralgia. It belongs to the calcium channel modulator class and relieves pain by regulating nerve signal transmission. Its mechanism of action involves inhibiting the α2δ subunit of voltage-dependent calcium channels in the central nervous system, reducing calcium ion influx, inhibiting excessive neurotransmitter release, thereby reducing abnormal nerve excitability and improving neuralgia symptoms.

[0003] Merogabalin besylate (trade name: Delijin®) is currently available in China in the form of regular tablets. It was approved in China in June 2024 for the treatment of diabetic peripheral neuropathic pain (DPNP) in adults, becoming the first imported original drug for this indication in China. No extended-release formulation has yet been approved. Regular tablets need to be taken twice daily (e.g., 15mg), meaning the drug release is relatively rapid, which may lead to excessively high drug concentrations in the body within a short period, thus increasing the risk of adverse reactions. For example, central nervous system adverse reactions such as dizziness and drowsiness may be more pronounced.

[0004] In order to prolong the release time of the active ingredient melogabalin besylate, the pharmaceutical industry has developed its sustained-release formulations. However, the development of sustained-release melogabalin besylate formulations still faces some common challenges and shortcomings: (1) The performance of sustained-release formulations is very sensitive to the source of excipients and process parameters. For example, changing the manufacturer or batch number of a certain excipient, such as hydroxypropyl methylcellulose (HPMC), may cause large fluctuations in the release curve. (2) The active ingredient of melogabalin besylate is sensitive to damp heat, and the product stability is poor. During long-term release, the levels of related substances are significantly increased, posing a significant threat to human safety. (3) Some sustained-release formulations are sensitive to the gastrointestinal environment and are prone to burst release, or the drug release rate of some sustained-release formulations is too slow, and they cannot well balance the release time and release efficiency, resulting in poor analgesic effect.

[0005] Therefore, a novel sustained-release formulation of melogabalin besylate has been developed to address the problems existing in current sustained-release formulations, which is of great significance for the development of medical and health care and the improvement of human medical quality. Summary of the Invention

[0006] To address the problems and shortcomings of existing technologies, this invention provides a pharmaceutical composition containing the active ingredient melogabalin besylate. This pharmaceutical composition is a sustained-release formulation, which ensures the continuous release and absorption of melogabalin besylate in the body, reducing the frequency of administration while improving efficacy, reducing adverse reactions, and enhancing therapeutic effects.

[0007] This invention provides a pharmaceutical composition comprising the following components: merogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol; the mass ratio of merogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol is 0.5~8:20~40:5~15:20~40:3~20. In the mass ratio of the above substances, the mass fraction of merogabalin besylate can be, for example, 0.5 parts, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, etc.; the mass fraction of polyoxyethylene can be, for example, 20 parts, 22 parts, 25 parts, 27 parts, 30 parts, 32 parts, 35 parts, 38 parts, 40 parts, etc.; the mass fraction of crospovidone can be, for example, 5 parts, 7 parts, 10 parts, 12 parts, 15 parts; and the mass fraction of sodium alginate can be, for example, 5 parts, 7 parts, 10 parts, 12 parts, 15 parts. The number of parts can be, for example, 20, 22, 25, 27, 30, 32, 35, 38, 40, etc., and the number of mannitol by weight can be, for example, 3, 4, 5, 6, 10, 12, 15, 18, 20, etc.; however, the number of melogabalin benzenesulfonic acid, polyoxyethylene, crospovidone, sodium alginate, and mannitol by weight is not limited to the values ​​listed, and other unlisted values ​​within the range are also applicable.

[0008] The pharmaceutical composition provided by this invention is a sustained-release formulation. By adjusting the proportions of the excipients in the formulation, a stable, sustained, and highly controllable release of the active ingredient, melogabalin besylate, can be achieved. Specifically, it ensures a relatively gradual and sufficient release of melogabalin besylate within 24 hours, effectively avoiding the "peak-trough" phenomenon in blood drug concentration commonly seen in conventional formulations, thereby improving efficacy and reducing side effects and dosing frequency. Simultaneously, the sufficient release of the drug component within 24 hours effectively enhances the drug's effect. In other words, the pharmaceutical composition provided by this invention achieves a balance between release rate and release amount, maximizing the optimization of the drug's effect.

[0009] In particular, the pharmaceutical composition of this invention incorporates mannitol in a specific mass ratio. Mannitol is not merely a simple filler, but also a highly efficient pore-forming agent. When the tablet comes into contact with water, the mannitol particles dissolve rapidly, leaving numerous perforated micropores in situ. These micropores synergistically enhance the pores created by the swelling and expansion of cross-linked povidone, forming a dense network of drug release channels. This ensures that the drug can be effectively "guided" out from the inside of the tablet. Thus, the specific amount of mannitol can effectively regulate the release rate of drug molecules, avoiding excessively fast or slow release and improving the controllability of sustained-release. Simultaneously, mannitol's strong hydrophilicity helps water penetrate the tablet interior more quickly and evenly, facilitating the comprehensive and rapid hydration of polyoxyethylene and sodium alginate. This results in the simultaneous formation of a complete and uniformly thick gel layer on the tablet surface and inside, achieving a stable and controllable sustained-release effect. Moreover, mannitol, as a water-soluble filler, can uniformly dilute and disperse trace amounts of the active ingredient throughout the entire matrix network. This uniform dispersion ensures the consistency of drug distribution within the gel matrix, which helps to ensure that the release rates of each part of the gel are similar, thus improving the reproducibility of intra-batch and inter-batch release behavior.

[0010] In addition to the specific role of mannitol, the sustained-release controllability of the pharmaceutical composition provided by this invention also lies in the synergistic effect of the components in the formulation, which together establish a dynamic and controllable release system. For example, polyoxyethylene and sodium alginate constitute the main barrier for release, preventing rapid drug release. Cross-linked povidone and mannitol can form a release regulation channel. Cross-linked povidone "expands" the channel through swelling, while mannitol "leaves" pores through dissolution. The two work together to precisely control the release rate of drug molecules. In particular, at the mass ratio of the above components, the mechanical properties of the pharmaceutical composition can be enhanced when it enters the human body or gastrointestinal tract, that is, the mechanical properties of the gel can be improved. Furthermore, the pharmaceutical composition can have a suitable number and size of pores after absorbing water, thereby enabling the drug molecule melogabalin besylate to be released at a slower and more controllable rate. This achieves a high degree of controllability of sustained-release behavior, thereby improving the efficacy of the drug and patient medication compliance.

[0011] It should also be noted that the melogabalin besylate sustained-release formulation prepared from the above-mentioned substances contains expanding materials such as polyoxyethylene and cross-linked povidone, which rapidly expand upon contact with water or gastrointestinal fluid, making the formulation larger than the pylorus (under a specific mass ratio of substances, the sustained-release formulation expands upon contact with water, making the formulation larger than the pylorus), thereby achieving gastric retention and prolonging the release time. Since the pylorus is in a better closed state at night and the gastric emptying rate is slower, the improved gastric retention sustained-release tablet (i.e., the sustained-release formulation of this invention) has prolonged gastric retention and release, which can achieve a sustained-release effect and promote drug absorption. It only needs to be taken once a day, reducing the frequency of administration, which can increase patient compliance, and can also effectively reduce adverse reactions such as dizziness and drowsiness.

[0012] In addition, it should be emphasized here that the structural formula of melogabalin benzyl sulfonate is It contains a variety of specific groups, including benzenesulfonic acid group (-SO3H), bicyclic structure, aminomethyl (-CH2NH2), and carboxyl group (-COOH). The above excipients are designed based on the specific structure of melogabalin benzenesulfonic acid. That is, the above excipients will also interact with melogabalin benzenesulfonic acid to a certain extent (such as specific hydrogen bonds, electrostatic interactions, and other intermolecular interactions), which further improves the sustained-release performance of the drug molecule melogabalin benzenesulfonic acid. For example, (1) PEO and PVPP retain the drug in the formed pore network or gel to different degrees through hydrogen bonds, increasing the diffusion resistance. For example, the benzenesulfonic acid group and carboxyl group of melogabalin benzenesulfonic acid can form hydrogen bonds with the hydroxyl group (-OH) of polyoxyethylene, increasing the uniformity of drug dispersion in the polymer matrix, thereby prolonging the drug release time. The bicyclic structure and aminomethyl group of melogabalin benzenesulfonic acid can interact with the hydroxyl group (-OH) in polyoxyethylene through van der Waals forces and hydrogen bonds. This interaction can slow down the diffusion rate of the drug from the matrix and achieve a sustained-release effect. (2) The carboxyl and benzenesulfonic acid groups of melogabalin benzenesulfonic acid can form ionic and hydrogen bonds with the carboxyl group (-COOH) of sodium alginate. Simultaneously, the carboxylate ion (-COO) in sodium alginate... - ) and protonated amino group (-NH3) + (3) Mannitol is highly hydrophilic. As a water-soluble filler, it contains a large number of hydrogen bonds. Hydrogen bonds are more conducive to close contact with melogabalin besylate containing carboxyl groups, so that it can uniformly dilute and disperse trace amounts of the active ingredient (melogabalin besylate, the smallest proportion) in the entire skeleton network, laying the foundation for the formation of a uniform sustained-release system, ensuring the uniformity and reproducibility of drug release, and avoiding excessively high local drug concentrations. Moreover, under a specific mass ratio, the above excipients and melogabalin besylate have a better interaction effect. In particular, after the entire sustained-release preparation is swollen with water or gastric juice, these substances show a stronger interaction force, which allows the melogabalin drug in the sustained-release preparation to be released at a slower and more stable rate, improving the drug's efficacy and reducing adverse reactions.

[0013] Preferably, the above-mentioned melogabalin besylate sustained-release formulation comprises, by mass fraction, the following components: 0.5-8% melogabalin besylate, 20-40% polyoxyethylene, 5-15% crospovidone, 20-40% sodium alginate, and 3-20% mannitol. Among the mass fractions of the above substances, the mass fraction of melogabalin benzyl sulfonate can be, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, etc.; the mass fraction of polyoxyethylene can be, for example, 20%, 25%, 30%, 32%, 35%, 38%, 40%, etc.; the mass fraction of crospovidone can be, for example, 5%, 7%, 10%, 12%, 15%, etc.; the mass fraction of sodium alginate can be, for example, 20%, 25%, 30%, 32%, 35%, 38%, 40%, etc.; and the mass fraction of mannitol can be, for example, 3%, 4%, 5%, 6%, 10%, 12%, 15%, 18%, 20%, etc.; however, the mass fractions of melogabalin benzyl sulfonate, polyoxyethylene, crospovidone, sodium alginate, and mannitol are not limited to the listed values, and other unlisted values ​​within the range are also applicable.

[0014] Preferably, in the above-mentioned melogabalin besylate sustained-release formulation, the mass ratio of melogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol is 0.5~8:20~40:5~15:20~40:3~12.

[0015] Preferably, the above-mentioned melogabalin besylate sustained-release formulation comprises, by mass fraction, the following components: 0.5-8% melogabalin besylate, 20-40% polyoxyethylene, 5-15% crospovidone, 20-40% sodium alginate, and 3-12% mannitol.

[0016] Preferably, the average molecular weight of polyoxyethylene is between 1 million and 5 million. For example, the average molecular weight of polyoxyethylene can be 1 million, 2 million, 2.5 million, 3 million, 3.2 million, 3.5 million, 3.8 million, 4 million, 4.3 million, 4.5 million, 4.7 million, or 5 million, but is not limited to the listed values; other unlisted values ​​within this range are also applicable. Generally, low molecular weight PEO swells more quickly after absorbing water, forming a hydrophilic gel layer. This rapid swelling helps the formulation remain in the stomach, improving drug utilization. However, excessively low molecular weight polyoxyethylene has a lower swelling rate and the resulting gel layer has lower mechanical strength, which may lead to premature expulsion of the formulation or premature rupture of the gel layer, affecting the degree and uniformity of drug release and potentially impacting the efficacy of the product. Conversely, if the molecular weight of PEO is too high, the hydration rate is slower, and the gel may become too tough after gelation, resulting in excessive resistance to drug diffusion and incomplete release in later stages. Therefore, controlling the average molecular weight of polyoxyethylene within the above range is beneficial to balancing its expansion properties, mechanical strength, and sustained drug release properties.

[0017] Preferably, the average molecular weight of the polyoxyethylene is 2 million to 5 million.

[0018] Preferably, the average particle size of crospovidone is 30–150 μm. The average particle size of crospovidone can be, for example, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, or 150 μm, but is not limited to the listed values; other unlisted values ​​within the range are also applicable. As an expanding material, the particle size of crospovidone affects its expanding performance. Controlling the average particle size of crospovidone within the above range can balance the expanding performance and mechanical strength of crospovidone as a expanding agent, which is more conducive to controlling the slow and stable release of drugs.

[0019] Preferably, the average molecular weight of sodium alginate is 4*10. 6 ~10 7 Daltons. The average molecular weight of sodium alginate can be, for example, 4*10^6. 6 5*10 6 6*10 6 7*10 6 8*10 6 9*10 6 10 7 The value is in Daltons, but not limited to the listed values; other unlisted values ​​within the range also apply. A relatively high average molecular weight of sodium alginate provides stronger gel strength and a slower drug release rate. However, excessively high molecular weight sodium alginate can also lead to slow drug release, failing to achieve a timely and effective therapeutic effect and affecting the uniform release of the drug, thus impacting efficacy.

[0020] Preferably, the above-mentioned pharmaceutical composition further includes microcrystalline cellulose. Preferably, the mass ratio of mannitol to microcrystalline cellulose is 3-20:6-35. In the above-mentioned mass ratio of mannitol to microcrystalline cellulose, the mass parts of mannitol can be, for example, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 14 parts, 16 parts, 18 parts, 20 parts, etc., and the mass parts of microcrystalline cellulose can be, for example, 6 parts, 8 parts, 10 parts, 13 parts, 15 parts, 17 parts, 20 parts, 23 parts, 25 parts, 30 parts, 32 parts, 35 parts, etc., but the mass parts of mannitol and microcrystalline cellulose are not limited to the listed values; other unlisted values ​​within the range are also applicable. Microcrystalline cellulose can further interact with mannitol and other excipients mentioned above, enhancing the gel mechanical strength of the drug composition while better controlling the dissolution rate of the gel layer and adjusting the tortuosity of the diffusion path of the drug through the gel layer, so that the active ingredient of the sustained-release formulation is released more slowly and more steadily.

[0021] Preferably, the pharmaceutical composition further comprises 6-35% microcrystalline cellulose by mass fraction. The mass fraction of microcrystalline cellulose may be, for example, 6%, 8%, 10%, 13%, 15%, 17%, 20%, 23%, 25%, 30%, 32%, 35%, etc., but is not limited to the listed values, and other unlisted values ​​within the range are also applicable.

[0022] Preferably, the degree of polymerization of microcrystalline cellulose is 100-350, and the D90 is 50-200 μm. The degree of polymerization of microcrystalline cellulose can be, for example, 100, 150, 200, 250, 300, or 350; the D50 can be, for example, 50 μm, 100 μm, 150 μm, or 200 μm; however, the degree of polymerization and D50 of microcrystalline cellulose are not limited to the listed values, and other unlisted values ​​within the range are also applicable. Controlling the molecular weight and D50 of microcrystalline cellulose within the above range is more conducive to ensuring a more stable structure of the sustained-release formulation during expansion and release, while ensuring uniform drug distribution, avoiding excessively high local concentrations, and thus more conducive to regulating drug release at an appropriate rate, ensuring full efficacy.

[0023] Preferably, the moisture content of microcrystalline cellulose is no higher than 4%. Controlling the moisture content of microcrystalline cellulose can improve the problem of the active pharmaceutical ingredient melogabalin besylate being easily degraded or inactivated due to water absorption.

[0024] Preferably, the moisture content of the microcrystalline cellulose is not higher than 3%. More preferably, the moisture content of the microcrystalline cellulose is not higher than 1.5%.

[0025] Preferably, the above-mentioned pharmaceutical composition further includes anhydrous calcium hydrogen phosphate. Preferably, the mass ratio of mannitol to anhydrous calcium hydrogen phosphate is 3~20:3~20. In the above-mentioned mass ratio of mannitol to anhydrous calcium hydrogen phosphate, the mass parts of mannitol can be, for example, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 14 parts, 16 parts, 18 parts, 20 parts, etc., and the mass parts of anhydrous calcium hydrogen phosphate can be, for example, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 14 parts, 16 parts, 18 parts, 20 parts, etc., but the mass parts of mannitol and anhydrous calcium hydrogen phosphate are not limited to the listed values, and other unlisted values ​​within the range are also applicable.

[0026] Preferably, the above-mentioned pharmaceutical composition further includes anhydrous calcium bicarbonate. Preferably, the mass ratio of mannitol to anhydrous calcium bicarbonate is 3~20:3~20.

[0027] Preferably, the pharmaceutical composition further comprises 3-20% anhydrous calcium bicarbonate by mass fraction.

[0028] Preferably, the above-mentioned pharmaceutical composition further includes a stabilizer, a flow aid, and a lubricant. Preferably, the mass ratio of merogabarine besylate, the stabilizer, the flow aid, and the lubricant is 0.5~8:0.2~2:0.2~1:0.2~1. In the mass ratio of merogalaline benzyl sulfonate, stabilizer, gliding agent, and lubricant, the mass fraction of merogalaline benzyl sulfonate can be, for example, 0.5 parts, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, etc.; the mass fraction of stabilizer can be, for example, 0.2 parts, 0.4 parts, 0.6 parts, 0.8 parts, 1 part, 1.2 parts, 1.6 parts, 2.0 parts, etc.; the mass fraction of gliding agent can be, for example, 0.2 parts, 0.4 parts, 0.6 parts, 0.8 parts, 1.0 parts, etc.; and the mass fraction of lubricant can be, for example, 0.2 parts, 0.4 parts, 0.6 parts, 0.8 parts, 1.0 parts, etc. However, the mass fractions of merogalaline benzyl sulfonate, stabilizer, gliding agent, and lubricant are not limited to the listed values, and other unlisted values ​​within the range are also applicable.

[0029] Preferably, the pharmaceutical composition further comprises, by mass fraction, 0.2-2% stabilizer, 0.2-1% gliding agent, and 0.2-1% lubricant. The mass fraction of the stabilizer can be, for example, 0.2%, 0.4%, 0.6%, 0.8%, 1%, 1.2%, 1.6%, 2.0%, etc.; the mass fraction of the gliding agent can be, for example, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, etc.; and the mass fraction of the lubricant can be, for example, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, etc. However, the mass fractions of merogabarine besylate, stabilizer, gliding agent, and lubricant are not limited to the listed values, and other unlisted values ​​within the range are also applicable.

[0030] Preferably, the stabilizer includes at least one of fumaric acid, citric acid, and malic acid; the flow aid includes at least one of magnesium aluminum metasilicate, silicon dioxide, and the lubricant includes at least one of magnesium stearate, sodium stearate fumarate, calcium stearate, and sodium stearate.

[0031] Preferably, the above-mentioned pharmaceutical composition is taken once daily after dinner; the mass of the pharmaceutical composition taken each time is 5-40 mg (calculated as free base). For example, it can be 5 mg, 10 mg, 20 mg, 30 mg, or 40 mg, and the dosage can be determined according to specific needs. Peripheral neuropathic pain is more pronounced at night. The short half-life of immediate-release formulations may lead to the risk of nighttime pain in patients, and the most common adverse reactions of immediate-release formulations are dizziness and drowsiness. The sustained-release formulation provided by this invention is intended to be taken after dinner every day. Since the drug concentration reaches its peak when administered at night, patients have less daily activity or are already asleep, which can increase drug tolerance and patient compliance.

[0032] Preferably, the above-mentioned pharmaceutical composition is in the form of a tablet.

[0033] Preferably, the pharmaceutical composition provided by the present invention can be obtained by direct compression of powder mixtures or by dry granulation and compression.

[0034] Preferably, the hardness of the tablets of the above-mentioned pharmaceutical composition is 100-300N.

[0035] In summary, the pharmaceutical composition (a sustained-release formulation) provided by this invention, through ingenious material formulation design, exhibits excellent synergistic effects between merogabarine besylate and several specifically selected excipients at a specific mass ratio. This significantly improves the sustained-release performance of the drug, increases its stability, and significantly reduces the frequency of drug use, while effectively reducing adverse drug reactions. In other words, the sustained-release formulation of this invention has a more suitable drug release rate, achieving not only a rapid and sustained analgesic effect of merogabarine besylate, but also reducing the frequency of administration, increasing patient compliance, and minimizing adverse drug reactions, thus maximizing the drug's efficacy. Attached Figure Description

[0036] Figure 1 The release curve of the drug composition (sustained-release formulation) in Example 1 in a medium of pH 1.2 (hydrochloric acid) (paddle method / 50 rpm).

[0037] Figure 2 Release curves of the pharmaceutical compositions (sustained-release formulations) in Formulations 1 and 2 of Example 2 in a medium of pH 1.2 (hydrochloric acid) (paddle method / 50 rpm). Detailed Implementation

[0038] To enable those skilled in the art to better understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0039] Example 1 The formulation (mass fraction) of the pharmaceutical composition (sustained-release preparation) in this embodiment is shown in Table 1: Table 1 Formulation of the pharmaceutical composition (sustained-release formulation) in Example 1

[0040] In this embodiment, the average molecular weight of polyoxyethylene is 4 million; the average particle size of crosslinked polyvinyl ketone is 100 μm; and the average molecular weight of sodium alginate is 8*10. 6The degree of polymerization of microcrystalline cellulose is 325, the D50 is 100 μm, and the water content is no more than 1.5%.

[0041] The sustained-release formulation of melogabalin besylate of this embodiment was prepared according to the following steps: Disperse the active pharmaceutical ingredient through a 40-mesh sieve; Add the prescribed amount of raw materials, sodium alginate, microcrystalline cellulose, polyoxyethylene, crospovidone, mannitol, anhydrous calcium hydrogen phosphate, and fumaric acid to a mixer and mix at 10 rpm for 10 minutes. Then add magnesium stearate and magnesium aluminum metasilicate to the mixer and mix at 10 rpm for 5 minutes to obtain a mixed powder. The total powder mixture is compressed into tablets with a hardness of 100-300N, and then coated to obtain the final product.

[0042] The release curve of the drug composition (sustained-release formulation) prepared in this embodiment was tested in a medium of pH=1.2 (hydrochloric acid) (paddle method / 50 rpm).

[0043] The test results are as follows Figure 1 And as shown in Table 2, by Figure 1 It can be seen that the formulation has sustained-release characteristics in pH 1.2 medium, with a release of 5% to 25% in 1 hour and no burst release; a release of 50% to 70% in 6 hours; a release of 75% to 95% in 12 hours; and a release of more than 80% in 16 hours, indicating complete release.

[0044] Table 2. Results of release curve tests for the formulation in Example 1 at pH 1.2.

[0045] Example 2 This embodiment sets up two prescriptions, referred to as Prescription 1 and Prescription 2, and the formulations of the drug composition (sustained-release preparation) in Prescription 1 and Prescription 2 are shown in Table 3: Table 3. Formulations of the pharmaceutical compositions (sustained-release formulations) in Formula 1 and Formula 2 in Example 2.

[0046] Kollidon SR was supplied by BASF.

[0047] The pharmaceutical compositions (sustained-release formulations) in Formulation 1 and Formulation 2 of this embodiment were prepared according to the preparation method in Example 1.

[0048] The release profiles of the pharmaceutical compositions (sustained-release formulations) prepared from Formulations 1 and 2 in this embodiment were tested in a pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The test results are as follows. Figure 2 And as shown in Table 4, by Figure 2It can be seen that when microcrystalline cellulose is replaced with Kollidon SR, the prepared melogabalin besylate pharmaceutical composition (Formula 2 of Example 2) exhibits significantly slower release, with less than 75% release after 12 hours of dissolution and incomplete release after 24 hours. This indicates that, compared to Kollidon SR, microcrystalline cellulose is more conducive to the full release of the active drug melogabalin besylate within 24 hours, thereby improving the drug's efficacy. In other words, microcrystalline cellulose can achieve both effective sustained-release and full drug release within 24 hours, thus balancing the sustained-release effect and release efficiency.

[0049] Table 4. Test results (data points) of the drug compositions (sustained-release formulations) in Formulation 1 and Formulation 2 of Example 2 in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm) for release curves.

[0050] Example 3 The formulation of the pharmaceutical composition (sustained-release preparation) in this embodiment differs from that in Formulation 1 of Example 2 in that the mass fractions of melogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol are 5.3%, 25%, 15%, 20%, and 12%, respectively, while the rest are the same as in Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this embodiment is in accordance with Example 1.

[0051] The drug composition (sustained-release formulation) prepared according to the formulation in this embodiment was tested for release curves in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 5 below.

[0052] Table 5. Test results (data points) of the release curve of the formulation in Example 3 in pH 1.2 medium.

[0053] Experimental results show that the drug composition prepared according to the formulation ratio of this embodiment meets the release control requirements in pH 1.2 medium. However, compared with Formulation 1 of Example 2, the drug composition releases too quickly, which may result in a shorter drug duration.

[0054] Example 4 The formulation of the pharmaceutical composition (sustained-release preparation) in this embodiment differs from that in Formulation 1 of Example 2 in that the mass fractions of melogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol are 5.3%, 40%, 5%, 24%, and 3%, respectively, while the rest are the same as in Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this embodiment is based on Example 1.

[0055] The drug composition (sustained-release formulation) prepared according to the formulation in this embodiment was tested for release profile in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 6 below.

[0056] Table 6. Test results (data points) of the release curve of the formulation in Example 4 in pH 1.2 medium.

[0057] Experimental results show that the drug composition prepared according to the material ratio of this embodiment meets the release control requirements in pH 1.2 medium. However, compared with Formulation 1 of Example 2, the drug composition releases more slowly, which may lead to a lower in vivo exposure.

[0058] Example 5 The formulation of the pharmaceutical composition (sustained-release preparation) in this embodiment differs from that in Formulation 1 of Example 2 in that the mass fractions of melogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol are 5.3%, 20%, 5%, 23%, and 20%, respectively, while the rest are the same as in Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this embodiment is based on Example 1.

[0059] The drug composition (sustained-release formulation) prepared according to the formulation in this embodiment was tested for release profile in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 7 below.

[0060] Table 7. Test results (data points) of the release curve of the formulation in Example 5 in pH 1.2 medium.

[0061] Experimental results show that the drug composition in this embodiment meets the product release requirements in a pH 1.2 medium. However, compared with Formulation 1 in Example 2, the drug composition release is faster.

[0062] Example 6 The formulation of the pharmaceutical composition (sustained-release preparation) in this embodiment differs from that in Formulation 1 of Example 2 in that the mass fractions of melogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol are 5.3%, 20%, 5%, 40%, and 7%, respectively, while the rest are the same as in Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this embodiment is in accordance with Example 1.

[0063] The drug composition (sustained-release formulation) prepared according to the formulation in this embodiment was tested for release curves in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 8 below.

[0064] Table 8. Test results (data points) of the release curve of the formulation in Example 6 in pH 1.2 medium.

[0065] Experimental results show that the drug composition in this embodiment meets the release control requirements in pH 1.2 medium. However, compared with Formulation 1 in Example 2, the drug composition releases more slowly and is not fully released, which is detrimental to the drug's efficacy.

[0066] Examples 7-8 The formulation of the pharmaceutical composition (sustained-release preparation) in Example 7 differs from that in Formulation 1 of Example 2 in that the mass fractions of melogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol are 0.5%, 30%, 8%, 27%, and 11.8%, respectively, while the rest are the same as in Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this example is in accordance with Example 1.

[0067] The formulation of the pharmaceutical composition (sustained-release preparation) in Example 8 differs from that in Formulation 1 of Example 2 in that the mass fractions of melogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol are 8%, 24%, 8%, 27%, and 10.3%, respectively, while the rest are the same as in Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this example is based on Example 1.

[0068] The drug compositions (sustained-release formulations) prepared according to the formulations in Examples 7 and 8 were tested for release profiles in a pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 9 below.

[0069] Table 9. Test results (data points) of the release curves of the formulations in Examples 7 and 8 in pH 1.2 medium.

[0070] Experimental results show that when the active pharmaceutical ingredient accounts for 0.5% to 8% of the formulation, the release of the drug composition in a pH 1.2 medium meets the release control requirements.

[0071] Example 9 The formulation of the pharmaceutical composition (sustained-release preparation) in this embodiment differs from Formulation 1 of Example 2 in that the average molecular weight of the polyoxyethylene used is 600,000. The rest is the same as Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this embodiment is based on Example 1.

[0072] The drug composition (sustained-release formulation) prepared according to the formulation in this embodiment was tested for release curves in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 10 below.

[0073] Table 10. Test results (data points) of the release curve of the formulation in Example 10 in pH 1.2 medium.

[0074] Experimental results show that the drug composition of this embodiment meets the release control requirements in pH 1.2 medium. However, compared with Formulation 1 of Example 2, the use of lower molecular weight polyoxyethylene results in less expansion of the sustained-release tablets, which may pose a risk of premature expulsion in vivo. Furthermore, the tablets are prone to disintegration and detachment in the later stages, leading to a faster release.

[0075] Example 10 The formulation of the pharmaceutical composition (sustained-release preparation) in this embodiment differs from Formulation 1 of Example 2 in that the average molecular weight of the polyoxyethylene used is 7 million. The rest is the same as Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this embodiment is based on Example 1.

[0076] The drug composition (sustained-release formulation) prepared according to the formulation in this embodiment was tested for release curves in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 11 below.

[0077] Table 11 Test results (data points) of the release curve of the formulation in Example 10 in pH 1.2 medium.

[0078] Experimental results show that the drug composition of this embodiment meets the release control requirements in pH 1.2 medium. However, compared with Formulation 1 of Example 2, the drug composition in this embodiment expands rapidly and has a larger volume in pH 1.2 medium due to the higher molecular weight of polyoxyethylene, and the dissolution rate is slower than that of the tablets in Formulation 1 of Example 2. Example 11 The formulation of the pharmaceutical composition (sustained-release preparation) in this embodiment differs from Formulation 1 of Example 2 in that the average particle size of the cross-linked povidone used is 170 μm. The rest is the same as Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this embodiment is based on Example 1.

[0079] The drug composition (sustained-release formulation) prepared according to the formulation in this embodiment was tested for release curves in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 12 below.

[0080] Table 12 Test results (data points) of the release curve of the formulation in Example 11 in pH 1.2 medium.

[0081] Experimental results show that the drug composition of this embodiment meets the release control requirements in pH 1.2 medium. However, compared with Formulation 1 of Example 2, the cross-linked povidone particle size is larger in this embodiment, the formulation expands rapidly in pH 1.2 medium, and more large particles are shed, resulting in lower continuity of the sustained-release layer and faster release. At the same time, the strength of the formulation is reduced due to the shedding of insoluble particles.

[0082] Example 12 The formulation of the pharmaceutical composition (sustained-release preparation) in this embodiment differs from that in Formulation 1 of Example 2 in that the sodium alginate used has an average molecular weight of 3*10. 6 10,000. The rest is consistent with Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release formulation) in this example is in accordance with Example 1.

[0083] The drug composition (sustained-release formulation) prepared according to the formulation in this embodiment was tested for release curves in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 13 below.

[0084] Table 13 Test results (data points) of the release curve of the formulation in Example 12 in pH 1.2 medium.

[0085] Experimental results show that the drug composition of this embodiment meets the release control requirements in pH 1.2 medium. However, compared with Formulation 1 of Example 2, the sample prepared using low molecular weight sodium alginate has lower gel strength and slightly faster release in pH 1.2 medium. This may lead to the risk of premature excretion due to excessively rapid dissolution in vivo, thus affecting the bioavailability of the product.

[0086] Comparative Examples 1-2 Referring to the formulation ratio of Example 4 in Daiichi Sankyo Co., Ltd. Patent CN114786653, a 15mg immediate-release formulation was prepared based on the 5mg formulation, with the same formulation ratio, serving as Comparative Example 1; Comparative Example 2 was also an immediate-release formulation, but without the addition of tocopherol compared to the formulation of Comparative Example 1. The formulations of Comparative Example 1 and Comparative Example 2 are shown in Table 14.

[0087] Table 14 Formulations of Comparative Example 1 and Comparative Example 2

[0088] The preparation process of the formulation of Comparative Example 1 is as follows: Tocopherol and microcrystalline cellulose are dispersed by high-speed mixing to obtain a tocopherol / microcrystalline cellulose mixture; the mixture and all materials except magnesium stearate are added to a three-dimensional mixer and mixed at 10 rpm for 10 min; then magnesium stearate is added and the mixture is further mixed (10 rpm for 5 min) to obtain a total powder; the total powder is compressed into tablets and then coated to obtain the final product.

[0089] The preparation process of the formulation of Comparative Example 2 is as follows: all materials except magnesium stearate are added to a three-dimensional mixer and mixed at 10 rpm for 10 min. Then magnesium stearate is added and the mixture is further mixed at 10 rpm for 5 min to obtain a total powder. The total powder is then compressed into tablets and coated to obtain the final product.

[0090] Dissolution profiles of the formulations in Comparative Examples 1 and 2 were tested in a pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The tablets were completely dissolved within 6-10 min, and more than 85% were dissolved within 15 min, which is a very rapid dissolution.

[0091] Comparative Example 3 The formulation of the pharmaceutical composition (sustained-release preparation) in this comparative example differs from that in Formulation 1 of Example 2 in that it does not contain mannitol, and the amounts of the remaining substances are in the same mass ratio as in Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this comparative example is as described in Example 1.

[0092] The drug composition (sustained-release formulation) prepared according to the formulation in this comparative example was tested for release profile in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 15 below.

[0093] Table 15. Test results (data points) of the release curve of Comparative Example 3 formulation in pH 1.2 medium.

[0094] Experimental results show that after removing mannitol, the prepared sample releases significantly slower in pH 1.2 medium, and the dissolution endpoint is lower.

[0095] Comparative Example 4 The formulation of the pharmaceutical composition (sustained-release preparation) in this comparative example differs from that in Formulation 1 of Example 2 in that the mass fractions of melogabalin besylate, polyoxyethylene, crospovidone, sodium alginate, and mannitol are 5.3%, 18%, 4%, 44%, and 6%, respectively, while the rest are the same as in Formulation 1 of Example 2. The preparation of the pharmaceutical composition (sustained-release preparation) in this comparative example is in accordance with Example 1.

[0096] The drug composition (sustained-release formulation) prepared according to the formulation in this comparative example was tested for release profile in pH 1.2 (hydrochloric acid) medium (paddle method / 50 rpm). The results are shown in Table 16 below.

[0097] Table 16. Test results (data points) of the release curve of formulation 4 in pH 1.2 medium.

[0098] Experimental results show that the comparative pharmaceutical composition contains a high proportion of sodium alginate and a low proportion of polyoxyethylene and cross-linked povidone, resulting in a slower overall release of the formulation. This is because the formulation in this comparative example forms a strong gel in pH 1.2 medium, while exhibiting minimal expansion and a slower release, exceeding the quality standard limits and posing a risk of incomplete release in vivo.

[0099] Test Analysis (1) The pharmacokinetic parameters of the drug composition (sustained-release formulation) in Formulation 1 of Example 2 and the immediate-release formulation in Comparative Example 1 were tested in beagle dogs. The specific test method is as follows: the chromatographic peak areas of the analyte and the internal standard were collected, and the concentration of the analyte in the calibration standard was linearly regressed using the weighted (W=1 / x²) least squares method with the concentration of the analyte in plasma (x) and the peak area ratio (y). The resulting regression equation (y=ax+b) is the standard curve. The pharmacokinetic parameters were calculated using the WinNonlin software non-compartment model, including but not limited to: t 1 / 2 (Half-life), ke (elimination rate constant), Vz (apparent volume of distribution), MRT (mean residence time), AUC 0-t (Area under the curve during drug administration), AUC 0-∞、 Cmax (peak concentration) and Tmax (time to peak), etc.

[0100] The test results are shown in Table 17.

[0101] Table 17. Pharmacokinetic parameters of formulation 1 in beagle dogs for Example 2 and Comparative Example 1.

[0102] As shown in Table 17, the AUC of the sustained-release merogabalin besylate formulation in Example 2, Formulation 1, and the immediate-release merogabalin formulation in Comparative Example 1 are... 0-t The geometric means were 14.0 ng / mL and 13.5 ng / mL, respectively, with a geometric mean ratio of 96.4%; AUC 0-∞The geometric means were 14.1 h*ng / mL and 13.6 h*ng / mL, respectively, with a geometric mean ratio of 96.5%. After two-cycle crossover oral administration of the sustained-release merogalaline besylate formulation from Example 2, Formula 1, and the immediate-release formulation from Comparative Example 1, the merogalaline exposure results in beagle dogs showed bioequivalence between the two formulations. Furthermore, the sustained-release merogalaline besylate formulation from Example 2, Formula 1, exhibited a clear sustained-release characteristic with no burst release, consistent with the pharmacokinetic characteristics of sustained-release formulations.

[0103] (2) Stability test: Open-air stability at 40℃ and 75%RH (a) Examination conditions The tablets of Formulation 1 from Example 2 and Comparative Examples 1-2 were placed in open bottles at 40°C and 75% RH for 10 days and 30 days, respectively. The content of related substances in the samples was determined by HPLC.

[0104] (b) Related substances determination methods and test results Instrumentation: High-performance liquid chromatograph; Column: C18 (250 mm × 4.6 mm, 5 μm) or equivalent column; Mobile phase: Mobile phase A: 0.01 mol / L K₂HPO₄ (pH adjusted to 2.5 with phosphoric acid), Mobile phase B: Acetonitrile. Gradient elution was performed according to Table 18, with a flow rate of 1.0 mL / min; column temperature: 30 °C; detection wavelength: 210 nm; injection volume: 10 μL.

[0105] Table 18 Gradient elution program

[0106] The detection results of related substances are shown in Table 19. Among them, impurity 5-I and the maximum unknown single impurity in Table 19 correspond to different peaks. The mass fraction of impurity 5-I and the maximum unknown single impurity can be calculated based on the peak area. Meanwhile, the total impurity is the mass fraction calculated by summing the peak areas of all peaks except the excipient peak.

[0107] Table 19. Detection of related substances in Formulation 1 of Example 2 and Comparative Examples 1-2

[0108] In Table 19 above, “RRT 1.79” indicates that the retention time of this component is 1.79 times that of melogabalin benzyl sulfonate.

[0109] The stability study results in Table 19 show that the melogabalin besylate sustained-release formulation provided by this invention has similar stability to the original formulation under open conditions of 40°C and 75% RH, ensuring product stability during shelf life.

[0110] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention, but such modifications or substitutions are all within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, It includes the following components: melogabalin benzenesulfonic acid, polyoxyethylene, crospovidone, sodium alginate, and mannitol; The mass ratio of melogabalin benzenesulfonic acid, polyoxyethylene, crosslinked polyvinylpyrrolidone, sodium alginate, and mannitol is 0.5~8:20~40:5~15:20~40:3~20.

2. The pharmaceutical composition according to claim 1, characterized in that: The mass ratio of melogabalin benzenesulfonic acid, polyoxyethylene, crosslinked polyvinylpyrrolidone, sodium alginate, and mannitol is 0.5~8:20~40:5~15:20~40:3~12.

3. The pharmaceutical composition according to claim 1, characterized in that: The average molecular weight of the polyoxyethylene is 1 million to 5 million.

4. The pharmaceutical composition according to claim 1, characterized in that: The average particle size of the cross-linked polyvinylpyrrolidone is 30–150 μm.

5. The pharmaceutical composition according to claim 1, characterized in that: The average molecular weight of the sodium alginate is 4*10. 6 ~10 7 Dalton.

6. The pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition also includes microcrystalline cellulose.

7. The pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition also includes anhydrous calcium hydrogen phosphate.

8. The pharmaceutical composition according to claim 1, characterized in that: It also includes stabilizers, flow aids, and lubricants.

9. The melogabalin besylate sustained-release formulation as described in claim 8, characterized in that: The stabilizer includes at least one of fumaric acid, citric acid, and malic acid; The flow aid includes at least one of magnesium aluminum metasilicate and silicon dioxide; The lubricant includes at least one of magnesium stearate, sodium stearate fumarate, and calcium stearate.

10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that: Take once daily after dinner; the mass of the pharmaceutical composition taken each time is 5 to 40 mg (calculated as free base).

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