A solid pharmaceutical composition of meloxicam benzene sulfonic acid, preparation and method thereof

Abstract

The application discloses a solid pharmaceutical composition of meloxicam benzene sulfonic acid, a preparation and a preparation method thereof. The solid pharmaceutical composition comprises meloxicam benzene sulfonic acid, and further comprises L-tartaric acid, ascorbic acid palmitate and a non-ionic ester compound selected from at least one of hydrogenated castor oil and glycerol behenate. The solid pharmaceutical composition of meloxicam benzene sulfonic acid has the stability obviously superior to that of the prior art, and the dissolution performance of the solid preparation is excellent, due to the combination of L-tartaric acid, ascorbic acid palmitate and the non-ionic ester compound selected from at least one of hydrogenated castor oil and glycerol behenate, and the synergistic effect of the three.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a merogabarine besylate solid pharmaceutical composition, formulation, and preparation method thereof. Background Technology

[0002] Mirogabalin besilate is a neuropathic pain medication. It is a ligand for the α2δ subunit of a potential-dependent calcium channel. α2δ ligands are believed to relieve pain by reducing the influx of calcium ions into the presynaptic terminal and inhibiting the release of excitatory neurotransmitters. This drug exerts its analgesic effect by specifically binding to the α2δ subunit. Mirogabalin besilate is a white to pale yellow powder, and its chemical name is [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate.

[0003] Merogabalin besylate solid pharmaceutical compositions and tablets have been reported in the prior art. For example, patent CN104334169B by Daiichi Sankyo Co., Ltd. of Japan discloses a solid composition containing merogabalin besylate, specifically disclosing mannitol as the filler with an average particle size of 100 μm or smaller, calcium carboxymethyl cellulose as the disintegrant, and magnesium stearate or sodium stearate as the lubricant. Another patent from the same company, CN107405322B, discloses a solid dosage form containing an antioxidant, specifically disclosing that the filler is selected from one or more of mannitol, lactose, corn starch, and microcrystalline cellulose; the disintegrant is calcium carboxymethyl cellulose; and the antioxidant is selected from one or more of sodium edetate, citrate hydrate, butylated hydroxytoluene, propyl gallate, magnesium citrate (anhydrous), soybean lecithin, tocopherol, tocopheryl acetate, and β-cyclodextrin. However, the stability of this solid dosage form still needs improvement. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide an improved merogabarine besylate solid pharmaceutical composition and its formulation, which addresses the shortcomings and deficiencies of the prior art. The formulation has improved stability and excellent dissolution properties.

[0005] To solve the above technical problems, the present invention adopts the following technical solution:

[0006] A solid pharmaceutical composition of melogabalin besylate, the solid pharmaceutical composition comprising melogabalin besylate, and further comprising L-tartaric acid, ascorbyl palmitate, and a nonionic ester compound selected from at least one of hydrogenated castor oil and behenic acid glycerides.

[0007] In this invention, the chemical structural formula of melogabalin benzylsulfonic acid is as follows: .

[0008] In the prior art, the stabilizers for merogabarine besylate solid dosage forms, such as tablets, typically employ a combination of citric acid and tocopherol. However, the stability of these solid dosage forms needs improvement, as they tend to contain higher levels of impurities under high-temperature conditions. The inventors of this application have discovered that by employing a combination of L-tartaric acid, ascorbate palmitate, and at least one nonionic ester compound selected from hydrogenated castor oil and behenicol, a stable synergistic effect can be achieved. This improves the micro-pH environment of the pharmaceutical composition, effectively scavenging oxygen and metal ions, thereby significantly enhancing the stability of the solid dosage form.

[0009] In some embodiments, the solid pharmaceutical composition comprises, by weight percentage, 0.5%-3.0% tartaric acid and 0.1%-0.6% ascorbate palmitate.

[0010] In some embodiments, the solid pharmaceutical composition comprises 1%-5% nonionic ester compounds by weight percentage.

[0011] In some embodiments, the solid pharmaceutical composition further includes magnesium stearate, wherein the mass ratio of magnesium stearate to the nonionic ester compound is 1-2:1-2.

[0012] In some embodiments, the solid pharmaceutical composition further includes magnesium stearate, wherein the mass ratio of magnesium stearate to the nonionic ester compound is 1:1.

[0013] In some embodiments, the solid pharmaceutical composition further includes an adjuvant selected from at least one of excipients, disintegrants, and anti-caking agents.

[0014] In some embodiments, the solid pharmaceutical composition comprises 0.5%-7% merogalaline besylate by weight percentage. Preferably, the solid pharmaceutical composition comprises 3%-5% merogalaline besylate by weight percentage.

[0015] In some embodiments, the solid pharmaceutical composition further includes excipients, disintegrants, and anti-caking agents.

[0016] In some embodiments, the solid pharmaceutical composition comprises 76%-95% excipients by weight. Preferably, the solid pharmaceutical composition comprises 80%-90% excipients by weight.

[0017] In some embodiments, the solid pharmaceutical composition comprises 2%-10% disintegrant by weight percentage. Preferably, the solid pharmaceutical composition comprises 4%-10% disintegrant by weight percentage.

[0018] In some embodiments, the solid pharmaceutical composition comprises 0.1%-1% anti-caking agent by weight percentage. Preferably, the solid pharmaceutical composition comprises 0.1%-0.5% anti-caking agent by weight percentage.

[0019] In some embodiments, the excipient is selected from one or more combinations of mannitol, microcrystalline cellulose, sorbitol, lactose, and corn starch.

[0020] In some embodiments, the solid pharmaceutical composition comprises 75%-85% mannitol and 1%-10% microcrystalline cellulose by weight percentage.

[0021] In some embodiments, the disintegrant is selected from one or more combinations of calcium carboxymethyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium carboxymethyl cellulose.

[0022] In some embodiments, the anti-caking agent is selected from one or more combinations of magnesium aluminum metasilicate and colloidal silica.

[0023] The present invention also provides a merogabarine besylate solid dosage form, wherein the solid dosage form is prepared from the aforementioned merogabarine besylate solid pharmaceutical composition.

[0024] In some embodiments, the solid dosage form is a tablet.

[0025] The present invention also provides a method for preparing the aforementioned melogabalin benzyl sulfonate solid dosage form, the preparation method comprising the following steps: 1) mixing the raw materials to obtain a mixture; 2) shaping the mixture into the solid dosage form.

[0026] In some implementations, step 2) involves forming a tablet.

[0027] In some embodiments, the preparation method further includes a film coating step after molding.

[0028] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0029] 1) The melogabalin besylate solid pharmaceutical composition of the present invention, by employing a combination of L-tartaric acid, ascorbate palmitate and at least one nonionic ester compound selected from hydrogenated castor oil and behenic acid glyceride, achieves significantly better stability than the prior art through the synergistic effect of the three compounds, and the solid dosage form has excellent dissolution performance.

[0030] 2) The melogabalin besylate tablets of the present invention exhibit very low levels of both single and total impurities when left exposed at 60°C for 10 days, demonstrating excellent stability.

[0031] 3) The melogabalin besylate tablets of the present invention exhibit very low levels of both single and total impurities and excellent stability when stored at 40°C and 75% RH for 30 days.

[0032] 4) The melogabalin benzyl sulfonate tablets of the present invention exhibit excellent dissolution properties in various media, such as 0.1M hydrochloric acid solution, pH 4.5 acetate medium, and pH 6.8 phosphate medium. Detailed Implementation

[0033] In this invention, the mechanism by which the combination of L-tartaric acid, ascorbyl palmitate, and at least one nonionic ester compound selected from hydrogenated castor oil and behenicol glycerides improves the stability of solid dosage forms is as follows:

[0034] First, behenate glyceryl and hydrogenated castor oil, being non-ionic structures, reduce chemical interactions with the active pharmaceutical ingredient of melogabalin besylate. In contrast, traditional magnesium stearate is a typical ionic compound composed of stearate anions and magnesium cations, exhibiting strong polarity and easy dissociation. Its cations or anions (stearate) may react with the active pharmaceutical ingredient of melogabalin besylate, leading to drug degradation. Behenate glyceryl and hydrogenated castor oil, being non-ionic, have no free ionic groups in their molecules. They bind to the drug particle surface through van der Waals forces via hydrophobic long carbon chains, participating almost entirely without chemical reaction, thus avoiding degradation of the active pharmaceutical ingredient due to ionic interactions.

[0035] Secondly, behenate glyceryl and hydrogenated castor oil have a neutral pH, which can prevent changes in the acidity or alkalinity of the formulation's microenvironment. In contrast, the aqueous suspension of traditional magnesium stearate is weakly alkaline, which may alter the pH of the tablet's internal microenvironment. In this invention, the active pharmaceutical ingredient melogabalin besylate has both amino (NH2) and carboxyl (-COOH) groups in its structure, both of which are sensitive to pH. Such pH fluctuations can accelerate the degradation of the active pharmaceutical ingredient. However, behenate glyceryl and hydrogenated castor oil are neutral substances, insoluble in water, and have almost no impact on the pH of the tablet's microenvironment, thus contributing to improved tablet stability.

[0036] Furthermore, the low hygroscopicity and chemical inertness of the stabilizing components can improve the physical stability of solid dosage forms. Studies have shown that the melogabalin besylate active pharmaceutical ingredient of this invention exhibits significant degradation under humid conditions in stability studies. While conventional magnesium stearate has low hygroscopicity (equilibrium moisture absorption rate of approximately 0.2%), significantly better than calcium stearate and zinc stearate, it can still slowly absorb water in high humidity environments, leading to tablet softening or deliquescence, thus negatively impacting the stability of the formulation of this invention. In contrast, glyceryl behenate and hydrogenated castor oil have extremely strong overall hydrophobicity (large contact angle with water) and even lower hygroscopicity (equilibrium moisture absorption rate <0.1%). Simultaneously, the ester bonds in their chemical structures are chemically stable under dry conditions at room temperature and are not easily hydrolyzed, allowing them to maintain the physical form of the tablets for a long period, thus improving the stability of the formulation of this invention.

[0037] Fourth, when the stabilizing component provides steric hindrance protection, it can reduce the influence of external factors, which is beneficial to improving the stability of the formulation. The behenicol glyceride and the long-chain alkyl group (C) of hydrogenated castor oil in this invention... 17 H 35 -) A dense hydrophobic film can be formed on the surface of drug particles, which isolates external factors such as moisture and oxygen through steric hindrance, reducing the oxidation or hydrolysis of the active drug melogabalin besylate, thereby further improving stability. In contrast, the traditional magnesium stearate lubricating film is thin and highly ionic, with weak oxygen barrier ability, and may fail due to film aging, especially in the later stages of storage.

[0038] In summary, this invention employs a combination of L-tartaric acid, ascorbyl palmitate, and at least one nonionic ester compound selected from hydrogenated castor oil and behenic acid glycerides as stabilizing components in the pharmaceutical composition. The nonionic ester compounds, such as behenic acid glycerides and hydrogenated castor oil, due to their nonionic nature, neutral pH, and low reactivity, protect the active pharmaceutical components through physical isolation rather than chemical interaction. This avoids acid-base reactions, complexation, or pH fluctuations that may be caused by traditional components such as magnesium stearate, thereby significantly improving the chemical and physical stability of the tablet formulation.

[0039] Of course, since the solid pharmaceutical composition of the present invention already contains a combination of L-tartaric acid, ascorbate palmitate and at least one nonionic ester compound selected from hydrogenated castor oil and behenic acid glyceride as stabilizing components, the stability is high. The pharmaceutical composition may also further include conventional magnesium stearate to improve processing performance, etc.

[0040] The technical solutions of the present invention will be described in detail below with reference to specific embodiments, so that those skilled in the art can better understand and implement the technical solutions of the present invention, but the present invention is not limited to the scope of the examples described.

[0041] Example 1: This example provides a melogabalin besylate tablet, the raw material components and their weight percentages are shown in Table 1, and its preparation method is as follows:

[0042] Merogabalin besylate was passed through an 80-mesh sieve and set aside. Stabilizer component one was ground and passed through an 80-mesh sieve and set aside. Excipients and disintegrants were passed through a 60-mesh sieve and set aside. The above-mentioned merogabalin besylate, stabilizer, excipients, disintegrants and anti-caking agents were weighed and mixed evenly. Stabilizer component two was then added and mixed together. The mixture was then directly compressed into tablets using a 10.7*5.7 punch, with a tablet weight of 200 mg and a hardness of 7~10 kg. After coating, film-coated tablets were obtained.

[0043] Examples 2-9: Examples 2-9 also provide a melogabalin besylate tablet, the preparation method of which is basically the same as that of Example 1, the only difference being that the types and weight percentages of each component may be different, as shown in Table 1-2, where “ / ” represents the absence of the component.

[0044]

[0045]

[0046] Comparative Examples 1-12: Comparative Examples 1-12 also provide merogabarine besylate tablets, the preparation method of which is basically the same as that of Example 1, the only difference being that the types and weight percentages of each component may be different, as shown in Tables 3-4. Among them, no stabilizing component one is added in Comparative Example 1, while the types of stabilizing component one are changed in Comparative Examples 2-6, and the stabilizing component one in Comparative Example 2 is a stabilizer of the original drug.

[0047]

[0048] In Comparative Example 7, one of the stabilizing components was L-tartaric acid; in Comparative Example 8, one of the stabilizing components was ascorbyl palmitate; and in Comparative Examples 9-12, the second stabilizing component was magnesium stearate.

[0049]

[0050] Performance testing:

[0051] I. High Temperature Stability

[0052] The tablets from each example and comparative example were placed in an open container at 60°C for 10 days. Experiments were conducted according to the key quality indicator methods of the Chinese Pharmacopoeia. The experimental results are shown in Table 6 below, where day 0 represents the initial storage period. Changes in related substances were detected by HPLC for each sample, and the content of related substances was calculated using the area normalization method.

[0053] Related substances detection method: Chromatographic column: Welch Xtimate C18, 4.6×250mm, 5.0μm or equivalent column; Mobile phase: phosphate buffer solution [10mmol / L potassium dihydrogen phosphate solution (adjusted to pH 7.0 with potassium hydroxide solution)] as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the conditions in Table 5. Column temperature 35℃, flow rate 1.0ml / min, wavelength 210nm, injection volume 10μl.

[0054]

[0055]

[0056] The comparison between Comparative Example 9 and Comparative Examples 7-8 shows that by simultaneously using L-tartaric acid and ascorbyl palmitate as one of the stabilizing components, this application achieves a synergistic effect of stabilizers compared to using L-tartaric acid or ascorbyl palmitate alone, significantly improving tablet stability. The comparison between Comparative Example 10 and Comparative Example 2 (original stabilizer formulation) shows that the tablet stabilization effect of this application, using L-tartaric acid and ascorbyl palmitate as one of the stabilizing components, is superior to the combination of tocopherol and citric acid in Comparative Example 2. The comparison between Comparative Example 6 and Comparative Examples 3-5 shows that in the formulation system of this application, the stabilizing effect of L-tartaric acid is superior to other conventional stabilizers such as L-malic acid, fumaric acid, and maleic acid. The comparison between Comparative Example 6 and Comparative Example 2 shows that in the formulation system of this application, the stabilizing effect of L-tartaric acid is also superior to the original stabilizer.

[0057] A comparison of Examples 1-2 and Comparative Example 9 (the only difference between the two is the type of stabilizing component two; Examples 1-2 use hydrogenated castor oil or glyceryl behenate, while Comparative Example 9 uses conventional magnesium stearate) shows that the present application uses hydrogenated castor oil or glyceryl behenate as stabilizing component two, which, compared with conventional magnesium stearate, produces a more synergistic stabilizing effect with stabilizing component one, further improving the stability of the tablet, and the stabilizing effect of glyceryl behenate is superior.

[0058] A comparison of Examples 8 and 9 and Comparative Example 12 (the only difference between the two is the type of stabilizing component two; Example 8 uses a 1:1 mass ratio mixture of magnesium stearate and hydrogenated castor oil, Example 9 uses a 1:1 mass ratio mixture of magnesium stearate and glyceryl behenate, while Comparative Example 12 uses conventional magnesium stearate) shows that the present application uses a mixture of magnesium stearate and hydrogenated castor oil in a specific mass ratio as stabilizing component two. Compared with the use of conventional magnesium stearate, this mixture can produce a more synergistic stabilizing effect with stabilizing component one, further improving the stability of the tablet.

[0059] The comparison between Comparative Example 11 and Comparative Example 9 (the only difference between the two is the type of disintegrant; Comparative Example 11 uses crospovidone, while Comparative Example 9 uses calcium carboxymethyl cellulose. Although the amount of disintegrant used in the two examples seems different, the disintegration effect of the two examples is different. Although the amount of calcium carboxymethyl cellulose used in Comparative Example 9 is more, the final disintegration effect of the two examples is basically the same) shows that when crospovidone is used as the disintegrant, the tablets can achieve a better stability effect compared with traditional calcium carboxymethyl cellulose.

[0060] In this application, under the premise of using L-tartaric acid, ascorbyl palmitate and at least one nonionic ester compound selected from hydrogenated castor oil and behenic acid glyceride as stabilizing components, the disintegrant can be calcium carboxymethyl cellulose or crospovidone, etc. When both are used in tablets, the tablets have excellent stability, and the stabilizing effect is better when crospovidone is used.

[0061] II. Stability under Acceleration Conditions

[0062] Based on this, Example 8 (with the best overall stability effect) and the reference tablet (merogabalin besylate tablets marketed in Japan, trade name Tarlige, specification 5mg) were placed in a double-layer "polyester / aluminum / polyethylene pharmaceutical composite bag", with a desiccant placed in the outer bag, and placed at 40°C and 75%RH for 30 days (accelerated conditions). The changes in the content of related substances were tested using the same method described above. The results are shown in Table 7 below.

[0063]

[0064] It is evident that the tablets of Example 8 of this application exhibit better stability under accelerated conditions than the commercially available reference formulation.

[0065] III. Dissolution Performance

[0066] According to the Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0931, Method II (Paddle Method), the cumulative dissolution of Example 8 in 0.1M hydrochloric acid solution, pH 4.5 acetate medium, and pH 6.8 phosphate medium was determined. The results are shown in Table 8 below, where RSD is the relative standard deviation. It can be seen that the tablets of Example 8 of this application dissolve extremely rapidly in different media.

[0067]

[0068] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A solid pharmaceutical composition of merogalaline besylate, said solid pharmaceutical composition comprising merogalaline besylate, characterized in that: The solid pharmaceutical composition further includes L-tartaric acid, ascorbyl palmitate, and a nonionic ester compound selected from at least one of hydrogenated castor oil and behenate glycerides; The solid pharmaceutical composition comprises, by weight percentage, 0.5%-3.0% L-tartaric acid and 0.1%-0.6% ascorbate palmitate; The solid pharmaceutical composition comprises 1%-5% nonionic ester compounds by weight percentage.

2. The merogabarine besylate solid pharmaceutical composition according to claim 1, characterized in that: The solid pharmaceutical composition further includes magnesium stearate, wherein the mass ratio of magnesium stearate to the nonionic ester compound is 1-2:1-2.

3. The merogabarine besylate solid pharmaceutical composition according to claim 1, characterized in that: The solid pharmaceutical composition further includes magnesium stearate, wherein the mass ratio of magnesium stearate to the nonionic ester compound is 1:

1.

4. The merogabarine besylate solid pharmaceutical composition according to claim 1, characterized in that: The solid pharmaceutical composition comprises 0.5%-7% melogabalin besylate by weight percentage.

5. The merogabarine besylate solid pharmaceutical composition according to claim 1, characterized in that: The solid pharmaceutical composition further includes an adjuvant selected from at least one of excipients, disintegrants, and anti-caking agents; the excipients are selected from one or more combinations of mannitol, microcrystalline cellulose, sorbitol, lactose, and corn starch; the disintegrants are selected from one or more combinations of calcium carboxymethyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium carboxymethyl cellulose; and the anti-caking agents are selected from one or more combinations of magnesium aluminum metasilicate and colloidal silica.

6. The merogabarine besylate solid pharmaceutical composition according to claim 5, characterized in that: The solid pharmaceutical composition further includes the excipient, the disintegrant, and the anti-caking agent; the excipient is selected from one or more combinations of mannitol, microcrystalline cellulose, sorbitol, lactose, and corn starch; the disintegrant is selected from one or more combinations of calcium carboxymethyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium carboxymethyl cellulose; and the anti-caking agent is selected from one or more combinations of magnesium aluminum metasilicate and colloidal silica.

7. The merogabarine besylate solid pharmaceutical composition according to claim 6, characterized in that: The solid pharmaceutical composition comprises 76%-95% of the excipients by weight; and / or, the solid pharmaceutical composition comprises 2%-10% of the disintegrants by weight.

8. The merogabarine besylate solid pharmaceutical composition according to claim 6, characterized in that: The solid pharmaceutical composition comprises 0.1%-1% of the anti-caking agent by weight percentage.

9. The merogabarine besylate solid pharmaceutical composition according to claim 6, characterized in that: The solid pharmaceutical composition comprises 75%-85% mannitol and 1%-10% microcrystalline cellulose by weight percentage.

10. A merogabarine benzyl sulfonate solid dosage form, characterized in that: The solid dosage form is prepared from the merogabalin benzyl sulfonate solid pharmaceutical composition according to any one of claims 1-9.

11. The merogabarine benzyl sulfonate solid dosage form according to claim 10, characterized in that: The solid dosage form is a tablet.

Images