Powder-coated melogabalin besylate orally disintegrating tablet

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a melogabalin besylate orally disintegrating tablet coated with powder. The powder-coated melogabalin besylate orally disintegrating tablet provided by the invention has good wet stability, effectively masks the bitter taste of the raw material medicines, obviously improves the taste, has good dissolution behavior, shows extremely rapid dissolution in key media, is beneficial to the absorption of melogabalin besylate by the body, and can be used for preparing the oral disintegrating tablet for treating melogabalin besylate. The melogabalin besylate orally disintegrating tablet provided by the invention has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a powder-coated merogabarine besylate orally disintegrating tablet. Background Technology

[0002] Mirogabalin Besilate, also known as minobaline benzenesulfonate, has the chemical name [(1R,5S,6S)-6(-aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate, with a molecular weight of 367.46 (structural formula shown below). It is readily soluble in 1,3-dimethyl-2-imidazolium dione, methanol, and ethanol (99.5%), slightly soluble in water (solubility 1.53 mg / mL), sparingly soluble in acetone, extremely sparingly soluble in acetonitrile, and almost insoluble in anisole and methyl tert-butyl ether. Its melting point is 169℃.

[0003]

[0004] Merogabalin besylate, developed by Daiichi Sankyo Co., Ltd. of Japan, is a novel, highly selective, and highly active α2δ-1 ligand that exerts its analgesic effect by selectively binding to the α2δ-1 subunit of voltage-dependent calcium channels. Merogabalin besylate belongs to the oral gabapentin class of drugs and plays an important role in the treatment of postherpetic neuralgia, fibromyalgia, and diabetic peripheral neuropathy. It was approved for marketing in Japan by the Pharmaceuticals and Medical Devices Agency (PMDA) on April 1, 2019. The marketed product is in tablet form. Under normal circumstances, the initial dose for adult patients is 5 mg orally twice daily, followed by gradual increases of 5 mg at intervals of at least one week, up to a maximum of 15 mg. The dosage may be adjusted appropriately between 10 mg and 15 mg orally twice daily according to age and symptoms.

[0005] Gabapentin is a standard medication for treating neuropathic pain. Peripheral neuropathic pain (PNP) is caused by peripheral nerve damage or dysfunction due to various reasons. Typical PNPs include diabetic PNP (DPNP) and postherpetic neuralgia (PHN). Diabetic peripheral neuropathic pain is one of the most common long-term complications in diabetic patients. Symptoms include acute pain or hypersensitivity, numbness, loss of balance and coordination, tingling, and burning sensations, which worsen at night. Shingles is caused by a weakened immune system against the varicella-zoster virus, which forms a latent infection in the ganglia. In PHN, even after shingles has healed, burning pain or electric shock-like pain persists. This condition is considered intractable and can lead to muscle weakness and, in rare cases, paralysis.

[0006] Currently, gabapentin and pregabalin are the only medications available for treating neuropathic pain, but both have significant limitations in clinical application. Milobalin besylate, an α2δ ligand, administered orally, preferentially and selectively binds to the α2δ-1 subunit of voltage-dependent calcium channels (1 and 2). These calcium channels are widely distributed throughout the nervous system, mediating pain transmission and processing in various parts of the body. Milobalin besylate exhibits unique binding properties and a long-lasting effect with these calcium channels. Clinical studies have shown that its efficacy is significantly higher than that of gabapentin and pregabalin.

[0007] In the existing technology, the main clinical application form of commercially available merogabarine besylate formulations is oral solid dosage forms with relatively good stability, currently marketed as tablets and orally disintegrating tablets. Orally disintegrating tablets, as a dosage form easily taken by the elderly, children, and patients with swallowing difficulties, have promising development prospects. Besides meeting the requirement of rapid disintegration in the oral cavity, orally disintegrating tablets also need sufficient hardness to withstand physical impacts during production, transportation, and use, as well as providing a good taste. Patent CN 115803020A discloses an orally disintegrating tablet containing merogabarine besylate, but it has drawbacks such as poor taste, poor process reproducibility, and suboptimal product stability. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a powder-coated merogabaline benzyl sulfonate orally disintegrating tablet.

[0009] The technical solution of the present invention is as follows:

[0010] A powder-coated melogabalin benzylsulfonate comprises the following components by weight: 1000 parts melogabalin benzylsulfonate, 150 parts coating material, 15-30 parts plasticizer, and 5 parts flavoring agent.

[0011] Optionally, the coating material is selected from one or more combinations of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, or polyvinyl alcohol.

[0012] Optionally, the plasticizer is selected from one or more combinations of triethyl citrate and talc.

[0013] Optionally, the flavoring agent is selected from one or more combinations of acesulfame potassium (acesulfame K), aspartame, citric acid, sorbitol, or flavorings.

[0014] A powder-coated melogabalin benzylsulfonate comprises the following components by weight: 1000 parts melogabalin benzylsulfonate, 30 parts hydroxypropyl cellulose, 120 parts carboxymethyl cellulose, 15 parts triethyl citrate, and 5 parts potassium acetaminophen.

[0015] A powder-coated melogabalin benzylsulfonate comprises the following components by weight: 1000 parts melogabalin benzylsulfonate, 30 parts hydroxypropyl cellulose, 120 parts polyvinyl alcohol, 20 parts triethyl citrate, and 5 parts potassium acetaminophen.

[0016] A powder-coated melogabalin benzylsulfonate comprises the following components by weight: 1000 parts melogabalin benzylsulfonate, 30 parts hydroxypropyl cellulose, 120 parts polyvinylpyrrolidone, 30 parts triethyl citrate, and 5 parts potassium acetamidosulfonate.

[0017] A powder-coated melogabalin benzylsulfonate comprises the following components by weight: 1000 parts melogabalin benzylsulfonate, 30 parts polyvinyl alcohol, 120 parts polyvinylpyrrolidone, 30 parts triethyl citrate, and 5 parts potassium acetamidosulfonate.

[0018] A method for preparing powder-coated melogabalin benzylsulfonic acid, wherein the preparation method is a fluidized bed bottom spray powder coating method, comprising the following steps:

[0019] 1) Prepare a mixed solution with a solid content of 10% to 15% by mixing the prescribed amount of coating material and one or more of suitable plasticizers, flavoring agents, disintegrants and stabilizers with purified water.

[0020] 2) Weigh out the prescribed amount of melogabalin benzylsulfonic acid, place it in a fluidized bed, preheat it until the temperature stabilizes at 50-60℃, and adjust the process parameters such as fan frequency, air inlet temperature, air inlet volume, spray speed, and bag shaking frequency to control the material at 45-50℃ for coating.

[0021] 3) After coating is completed, control the material temperature at 50-55℃ and age the coating film for 2-6 hours;

[0022] 4) Pass the aged melegabalin benzyl sulfonate through a 40-mesh sieve to obtain powdered melegabalin benzyl sulfonate.

[0023] A powder-coated melogabalin besylate orally disintegrating tablet comprises the following components: 105-107 parts of the above-mentioned powder-coated melogabalin besylate, 1680 parts of filler, 200 parts of disintegrant, 250 parts of stabilizer, and 30 parts of lubricant.

[0024] Optionally, the filler is selected from one or more combinations of D-mannitol, microcrystalline cellulose, lactose, starch, and calcium sulfate.

[0025] Optionally, the disintegrant is selected from one or more combinations of crospovidone, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0026] Optionally, the lubricant is selected from one or more combinations of magnesium stearate, talc, and micronized silica gel.

[0027] Optionally, the stabilizer is selected from one or more combinations of L-tartaric acid, butylated hydroxyanisole (BHA), ascorbic acid, sodium bisulfite, or sodium metabisulfite.

[0028] A powder-coated merogabarine besylate orally disintegrating tablet contains the following ingredients.

[0029]

[0030] A powder-coated merogabarine besylate orally disintegrating tablet contains the following ingredients.

[0031]

[0032]

[0033] A powder-coated merogabarine besylate orally disintegrating tablet contains the following ingredients.

[0034]

[0035] A powder-coated merogabarine besylate orally disintegrating tablet contains the following ingredients.

[0036]

[0037]

[0038] A method for preparing powder-coated merogabarine besylate orally disintegrating tablets includes the following steps:

[0039] 1) Weigh out the prescribed amount of the powder-coated melogabalin benzyl sulfonate and mix it evenly with the filler, disintegrant and stabilizer by adding equal amounts of each other.

[0040] 2) Add the powder obtained in step 1) to the prescribed amount of lubricant, mix for 30 minutes and then compress into tablets to obtain melogabalin besylate orally disintegrating tablets.

[0041] The powder-coated melogabalin orally disintegrating tablets provided by this invention have the following effects: 1) The obtained powder-coated melogabalin has good stability, especially wet stability; 2) This process can effectively mask the bitterness of the raw drug, and the taste of the resulting orally disintegrating tablets is significantly improved; 3) The final product, the orally disintegrating tablets, has good dissolution behavior, exhibiting extremely rapid dissolution in key media, which is beneficial to the body's absorption of melogabalin besylate. Detailed Implementation

[0042] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0043] Example 1

[0044] Prescription composition:

[0045] Merogabalin benzyl sulfonate 1000g Hydroxypropyl cellulose 30.0g Carboxymethyl cellulose 120.0g Triethyl citrate 15.0g Potassium acetaminophen 5.0g

[0046] Coating process:

[0047] (1) Prepare a mixed solution with a solid content of 10% by mixing the prescribed amounts of hydroxypropyl cellulose, carboxymethyl cellulose, triethyl citrate and potassium acetaminophen with purified water;

[0048] (2) Weigh the prescribed amount of melogabalin benzylsulfonic acid, place it in a fluidized bed, preheat it to a stable temperature of 55°C, and adjust the process parameters such as fan frequency, air inlet temperature, air inlet volume, spray speed, and bag shaking frequency to control the material at 45-50°C for coating.

[0049] (3) After coating is completed, the material temperature is controlled at 50-55℃, and the coating film is aged for 2 hours.

[0050] (4) The aging-coated melogabalin benzenesulfonic acid is passed through a 40-mesh sieve to obtain powdered melogabalin benzenesulfonic acid.

[0051] Example 2

[0052] Prescription composition:

[0053] Merogabalin benzyl sulfonate 1000g Hydroxypropyl cellulose 30.0g polyvinyl alcohol 120.0g Triethyl citrate 20.0g Potassium acetaminophen 5.0g

[0054] Coating process:

[0055] 1) Prepare a homogeneous mixed solution with a solid content of 12% by mixing the prescribed amounts of hydroxypropyl cellulose, polyvinyl alcohol, triethyl citrate, and potassium acetamidosulfonate with purified water.

[0056] 2) Weigh out the prescribed amount of melogabalin benzylsulfonic acid, place it in a fluidized bed, preheat it to a stable temperature of 52°C, and adjust the process parameters such as fan frequency, air inlet temperature, air inlet volume, spraying speed, and bag shaking frequency to control the material at 45-50°C for coating.

[0057] 3) After coating is completed, the material temperature is controlled at 50-55℃, and the coating film is aged for 3.0 hours.

[0058] 4) Pass the aged melegabalin benzyl sulfonate through a 40-mesh sieve to obtain powdered melegabalin benzyl sulfonate.

[0059] Example 3

[0060] Prescription composition:

[0061] Merogabalin benzyl sulfonate 1000g Hydroxypropyl cellulose 30.0g Polyvinylpyrrolidone 120.0g Triethyl citrate 30.0g Potassium acetaminophen 5.0g

[0062] Coating process:

[0063] 1) Prepare a homogeneous mixed solution with a solid content of 15% by mixing the prescribed amounts of hydroxypropyl cellulose, polyvinylpyrrolidone, triethyl citrate, and potassium acetamidosulfonate with purified water.

[0064] 2) Weigh out the prescribed amount of melogabalin benzylsulfonic acid, place it in a fluidized bed, preheat it to a stable temperature of 58°C, and adjust the process parameters such as fan frequency, air inlet temperature, air inlet volume, spraying speed, and bag shaking frequency to control the material at 45-50°C for coating.

[0065] 3) After coating is completed, the material temperature is controlled at 50-55℃, and the coating film is aged for 6.0 hours.

[0066] 4) Pass the aged melegabalin benzyl sulfonate through a 40-mesh sieve to obtain powdered melegabalin benzyl sulfonate.

[0067] Example 4

[0068] Prescription composition:

[0069] Merogabalin benzyl sulfonate 1000g polyvinyl alcohol 30.0g Polyvinylpyrrolidone 120.0g Triethyl citrate 30.0g Potassium acetaminophen 5.0g

[0070] Coating process:

[0071] 1) Prepare a homogeneous mixed solution with a solid content of 13% by dissolving the prescribed amounts of polyvinylpyrrolidone, polyvinyl alcohol, triethyl citrate, and potassium acetamidosulfonate in purified water.

[0072] 2) Weigh out the prescribed amount of melogabalin benzylsulfonic acid, place it in a fluidized bed, preheat it to a stable temperature of 55°C, and adjust the process parameters such as fan frequency, air inlet temperature, air inlet volume, spraying speed, and bag shaking frequency to control the material at 45-50°C for coating.

[0073] 3) After coating is completed, the material temperature is controlled at 50-55℃, and the coating film is aged for 4.0 hours.

[0074] 4) Pass the aged melegabalin benzyl sulfonate through a 40-mesh sieve to obtain powdered melegabalin benzyl sulfonate.

[0075] Comparative Example 1

[0076] Prescription composition:

[0077] Merogabalin benzyl sulfonate 1000g Hydroxypropyl cellulose 30.0g Carboxymethyl cellulose 120.0g Triethyl citrate 20.0g Potassium acetaminophen 5.0g

[0078] Direct mixing process:

[0079] 1) Mix the prescribed amounts of hydroxypropyl cellulose, carboxymethyl cellulose, triethyl citrate, and potassium acetaminophen evenly;

[0080] 2) Weigh out the prescribed amount of melogabalin besylate and mix it thoroughly with the material obtained in 1) in the fluidized bed to obtain a uniformly mixed material;

[0081] 3) The temperature of the uniformly mixed material obtained in 2) is controlled at 45-50℃ and maintained for 3.0h;

[0082] 4) Pass the material obtained in 3) through a 40-mesh sieve to obtain melogabalin benzenesulfonic acid, which is directly mixed with the coating material and other components.

[0083] Comparative Example 2

[0084] Prescription composition:

[0085] Merogabalin benzyl sulfonate 1000g Hydroxypropyl cellulose 30.0g Carboxymethyl cellulose 120.0g Triethyl citrate 20.0g Aspartan 5.0g

[0086] The process is the same as in Example 1.

[0087] Comparative Example 3

[0088] Prescription composition:

[0089] Merogabalin benzyl sulfonate 1000g Hydroxypropyl cellulose 30.0g Carboxymethyl cellulose 120.0g Triethyl citrate 20.0g Potassium acetaminophen 10.0g

[0090] The process is the same as in Example 1.

[0091] Formulation Example 1

[0092] Preparation of orally disintegrating merogbalin besylate tablets:

[0093] Formulation prescription:

[0094] raw materials Prescription quantity (10,000 tablets) Example 1: Powder-coated melogabalin benzylsulfonic acid 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Cross-linked polyvinylpyrrolidone 200g L-tartaric acid 200g BHA 50g magnesium stearate 30g

[0095] Preparation process:

[0096] 1) Weigh out the amount of the powder-coated melogabalin benzyl sulfonate obtained in Example 1 and mix it evenly with D-mannitol, microcrystalline cellulose and crospovidone by adding equal amounts of each other.

[0097] 2) Add the powder obtained in step 1) to the prescribed amount of magnesium stearate, mix for 30 minutes and then compress into tablets to obtain melogabalin besylate orally disintegrating tablets.

[0098] Formulation Example 2

[0099] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0100] raw materials Prescription quantity (10,000 tablets) Example 2 Powder-coated melogabalin benzylsulfonic acid 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Cross-linked polyvinylpyrrolidone 200g L-tartaric acid 200g BHA 50g magnesium stearate 30g

[0101] Preparation process:

[0102] The process is the same as in Formulation Example 1.

[0103] Formulation Example 3

[0104] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0105] raw materials Prescription quantity (10,000 tablets) Example 3: Powder-coated melogabalin benzylsulfonic acid 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Cross-linked polyvinylpyrrolidone 200g L-tartaric acid 200g BHA 50g magnesium stearate 30g

[0106] Preparation process:

[0107] The process is the same as in Formulation Example 1.

[0108] Formulation Example 4

[0109] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0110] raw materials Prescription quantity (10,000 tablets) Example 4: Powder-coated melogabalin benzylsulfonic acid 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Cross-linked polyvinylpyrrolidone 200g L-tartaric acid 200g BHA 50g magnesium stearate 30g

[0111] Preparation process:

[0112] The process is the same as in Formulation Example 1.

[0113] Formulation Example 5

[0114] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0115] raw materials Prescription quantity (10,000 tablets) direct-mixed powder of melogabalin benzyl sulfonate 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Cross-linked polyvinylpyrrolidone 200g L-tartaric acid 200g BHA 50g magnesium stearate 30g

[0116] Preparation process:

[0117] The process is the same as in Formulation Example 1.

[0118] Formulation Example 6

[0119] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0120]

[0121]

[0122] Preparation process:

[0123] The process is the same as in Formulation Example 1.

[0124] Formulation Example 7

[0125] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0126] raw materials Prescription quantity (10,000 tablets) Powder-coated melogabalin benzyl sulfonate 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Croscarmellose sodium 200g L-tartaric acid 200g BHA 50g magnesium stearate 30g

[0127] Formulation process:

[0128] The process is the same as in Formulation Example 1.

[0129] Formulation Example 8

[0130] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0131] raw materials Prescription quantity (10,000 tablets) Powder-coated melogabalin benzyl sulfonate 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Low-substituted hydroxypropyl cellulose 200g L-tartaric acid 200g BHA 50g magnesium stearate 30g

[0132] Formulation process:

[0133] The process is the same as in Formulation Example 1.

[0134] Formulation Example 9

[0135] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0136] raw materials Prescription quantity (10,000 tablets) Powder-coated melogabalin benzyl sulfonate 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Sodium carboxymethyl starch 200g L-tartaric acid 200g BHA 50g magnesium stearate 30g

[0137] The process is the same as in Formulation Example 1.

[0138] Formulation Example 10

[0139] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0140] raw materials Prescription quantity (10,000 tablets) Powder-coated melogabalin benzyl sulfonate 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Cross-linked polyvinylpyrrolidone 200g ascorbic acid 200g BHA 50g magnesium stearate 30g

[0141] The process is the same as in Formulation Example 1.

[0142] Formulation Example 11

[0143] Preparation of Merogabalin Besylate Orally Disintegrating Tablets: Formulation:

[0144]

[0145]

[0146] The process is the same as in Formulation Example 1.

[0147] Formulation Example 12

[0148] Preparation of orally disintegrating merogbalin besylate tablets:

[0149] Formulation prescription:

[0150] raw materials Prescription quantity (10,000 tablets) Powder-coated melogabalin benzyl sulfonate 90g (calculated as melogabrine) D-Mannitol 420g microcrystalline cellulose 1260g Cross-linked polyvinylpyrrolidone 200g Sodium metabisulfite 200g magnesium stearate 30g

[0151] The process is the same as in Formulation Example 1.

[0152] Before proceeding with the following test examples, it should be explained that in each of the following test examples, the term "single impurity" refers to the largest unknown single impurity detected during the analytical testing process, the term "total impurities" refers to the total amount of impurities including the largest unknown single impurity and other impurities, and the term "related substances inspection" refers to the testing and inspection of the largest unknown single impurity and the total impurities.

[0153] Test Example 1

[0154] Stability tests of melogabalin benzylsulfonic acid obtained in Examples 1-4 and Comparative Examples 1-3 under high humidity conditions:

[0155] Referring to the methods and testing conditions in the current "Technical Guidelines for Stability Studies of Chemical Drugs", and following the content and related substance testing methods under the Merogabalin Besylate Orally Disintegrating Tablets section of the 2020 Chinese Pharmacopoeia, high humidity tests were conducted on the materials obtained in Examples 1-4 and Comparative Examples 1-3, as well as commercially available Merogabalin Besylate. The results are shown in Table 1 below:

[0156] Table 1. Results of high humidity stability test for merogbalin benzyl sulfonate:

[0157]

[0158]

[0159] As shown in Table 1, the following results were obtained: 1) The powder-coated melogabalin besylate described in Examples 1-4 maintained good stability under high humidity conditions for 10 and 30 days, with no significant changes in content, maximum unknown single impurity, and total impurities; 2) After 30 days of high humidity, the content of commercially available melogabalin besylate raw material decreased by 3.1% (99.2%-96.1%), the maximum unknown single impurity was 2.61 times that of day 0 (0.094% / 0.036%), and the total impurities were 3.22 times that of day 0 (0.457% / 0.142%). The quality stability changed significantly (%). 3) The direct-mixed melogabalin benzyl sulfonate obtained in Comparative Example 1 showed slightly improved stability compared to commercially available melogabalin benzyl sulfonate, but not significantly. The melogabalin benzyl sulfonate content decreased by 1.8% (99.6%-97.8%) after 30 days of high humidity. At the same time, the maximum unknown single impurity and total impurities both increased significantly. The results of the high humidity stability test show that the powder-coated melogabalin benzyl sulfonate of the present invention effectively solves the problem of the instability of melogabalin benzyl sulfonate to humidity and achieves a significantly beneficial technical effect.

[0160] Test Example 2

[0161] Stability tests of merogabarine besylate orally disintegrating tablets obtained in Formulation Examples 1-12 under high humidity conditions:

[0162] Referring to the methods and testing conditions in the current "Technical Guidelines for Stability Studies of Chemical Drugs", and following the content and related substance testing methods under the Merogabalin Besylate Orally Disintegrating Tablets section of the 2020 Chinese Pharmacopoeia, the high humidity conditions were tested on the Merogabalin Besylate Orally Disintegrating Tablets obtained in Examples 1-9. The results are shown in Table 2 below:

[0163] Table 2. Results of High-Moisture Stability Test for Merogabalin Besylate Orally Disintegrating Tablets

[0164]

[0165]

[0166] From the inspection results in Table 2 and Table 1 of Test Example 1, it can be seen that: 1) The merogalpaline besylate orally disintegrating tablets prepared by formulation examples 1-4 using the powder-coated merogalpaline besylate obtained in Examples 1-4 of this invention have merogalpaline besylate impurities at day 0 in the finished formulation that are basically consistent with those of the powder-coated merogalpaline besylate. However, the merogalpaline besylate orally disintegrating tablets prepared by formulation examples 5 and 6 using directly mixed merogalpaline besylate and commercially available merogalpaline besylate, respectively, have merogalpaline besylate impurities at day 0 in the finished formulation that are basically consistent with those of the corresponding merogalpaline besylate. Compared with the raw material, the impurities of melogabalin increased, indicating that the powder-coated melogabalin benzyl sulfonate of the present invention can reduce and avoid the degradation of melogabalin benzyl sulfonate during the formulation production process while improving its own wet stability; 2) Formulation Example 1 uses the powder-coated melogabalin benzyl sulfonate of the present invention, and maintains good stability under high humidity conditions for 10 days and 30 days, with no significant changes in content, maximum unknown single impurity and total impurities; 3) Formulation Examples 5 and 6 respectively use direct-mixed melogabalin benzyl sulfonate and commercially available melogabalin benzyl sulfonate to prepare melogabalin benzyl sulfonate oral solutions. After 30 days of exposure to high humidity, the melogabalin besylate content in the cavity disintegrating tablets decreased by 1.9% (99.7%-97.8%) and 2.6% (99.5%-96.9%), respectively. The maximum unknown single impurity was 2.42 times (0.087% / 0.036%) and 2.47 times (0.106% / 0.043%) of that on day 0, respectively. The total impurities were 2.30 times (0.328% / 0.143%) and 2.87 times (0.447% / 0.156%) of those on day 0, respectively, indicating a significant change in quality stability. 4) Formulation Examples 7-9 Merogabalin besylate orally disintegrating tablets prepared using croscarmellose sodium, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch as disintegrants showed a decrease in besylate content after 30 days under high humidity conditions, while the maximum unknown single impurity and total impurities were higher than in Formulation Example 1. 5) Merogabalin besylate orally disintegrating tablets prepared using BHA+ascorbic acid, sodium bisulfite, and sodium metabisulfite as stabilizers in Formulation Examples 10-12 showed a decrease in besylate content after 30 days under high humidity conditions, while the maximum unknown single impurity and total impurities were lower than in Formulation Example 1. The humidity stability test results of each formulation example indicate that the final product formulation prepared using the powder-coated merogabalin besylate described in this invention has good humidity stability.

[0167] Test Example 3

[0168] When the powder-coated melogabalin benzyl sulfonate of the present invention is prepared into a final product formulation after being coated by the aforementioned preparation method, it is easy to mix evenly with other materials, and a final product with good content uniformity can be obtained. This test example aims to demonstrate the good powder mechanical properties of the powder-coated melogabalin benzyl sulfonate of the present invention by checking the content uniformity.

[0169] Content uniformity checks in formulation examples 1, 5, and 6:

[0170] According to the content uniformity test method under the Merogabalin Besylate Orally Disintegrating Tablets section of the 2020 edition of the Chinese Pharmacopoeia, the content uniformity of the Merogabalin Besylate Orally Disintegrating Tablets in Formulation Examples 1, 5, and 6 was tested, and the results are shown in Table 3 below:

[0171] Table 3. Results of content uniformity test for merogabarine besylate orally disintegrating tablets in formulation examples 1, 5, and 6

[0172] Formulation Example 1 Formulation Example 5 Formulation Example 6 Average content 99.8 99.4 99.7 A = |100-X| 0.2 0.6 0.3 Standard deviation S 2.14 5.47 5.92 A+2.2S 4.91 12.63 13.32

[0173] Based on the analysis of the results in Table 3 above, it can be seen that, compared with other formulation examples, the meregabalin besylate orally disintegrating tablets of Formulation Example 1 prepared using the powder-coated meregabalin besylate obtained in Example 1 of this invention have good content uniformity, and the A+2.2S is much lower than the 15.0 requirement specified in the pharmacopoeia, indicating that the powder-coated meregabalin besylate has good powder mechanical properties.

[0174] Test Example 4

[0175] Dissolution tests for formulation examples 1-12:

[0176] According to the dissolution test method under the Merogabalin Besylate Orally Disintegrating Tablets section of the 2020 edition of the Chinese Pharmacopoeia, the dissolution of the Merogabalin Besylate Orally Disintegrating Tablets obtained in Examples 1-12 was tested, and the results are shown in Table 4 below:

[0177] Table 4. Dissolution test results of merogabarine besylate orally disintegrating tablets in Examples 1-12

[0178]

[0179] The results in Table 4 above show that the merogabalone besylate powder coated with the powder obtained in Examples 1-4 of this invention and the commercially available merogabalone besylate orally disintegrating tablets both dissolve extremely rapidly. The high dissolution rate indicates that the active ingredient has high bioavailability in vivo, thus ultimately bringing more clinical benefits to patients.

[0180] Test Example 5

[0181] Referring to the methods and testing conditions in the current "Technical Guidelines for Stability Studies of Chemical Drugs", and following the content and related substance testing methods under the section on orally disintegrating melogabalin besylate tablets in the 2020 edition of the Chinese Pharmacopoeia, the stability of melogabalin besylate obtained in Examples 1-4 and Comparative Examples 1 and 2 under accelerated conditions was investigated. The results are shown in Table 5 below:

[0182] Table 5. Accelerated stability results of merogabarine benzylsulfonic acid in Examples 1-4 and Comparative Examples 1-3

[0183]

[0184]

[0185] The analysis of the results in Table 5 shows that, under accelerated conditions for 6 months, the content, maximum unknown single impurity, and total impurities of melogabalin besylate in Examples 1-4 all exhibited good stability. In contrast, the content of melogabalin besylate in Comparative Example 1 and commercially available melogabalin besylate decreased by 3.0% (99.3%-96.3%) and 3.4% (99.2%-95.8%) respectively over 6 months. The maximum unknown single impurity increased from 0.145% to 0.648% and from 0.254% to 1.253% respectively over 6 months, and the total impurities increased from 0.249% to 1.452% and from 0.257% to 2.385% respectively over 6 months, showing a relatively obvious unstable trend. Examples 1 and Comparative Example 2 indicate that potassium acetaminophen, as a flavoring agent, did not accelerate the growth of related substances, while aspartame accelerated the growth of related substances. Potassium acetaminophen has better compatibility with APIs. Examples 1 and 3 show that potassium acetaminophen may accelerate the growth of the maximum single heterozygote if the dosage is too high, and its dosage needs to be controlled.

[0186] Test Example 6

[0187] Referring to the methods and testing conditions in the current "Technical Guidelines for Stability Studies of Chemical Drugs," and following the content and related substance testing methods under the Merogabalin Besylate Orally Disintegrating Tablets section of the 2020 Chinese Pharmacopoeia, the stability of the Merogabalin Besylate Orally Disintegrating Tablets obtained in Formulation Examples 1, 5, and 6 under accelerated conditions was investigated. The results are shown in Table 6 below:

[0188] Table 6. Accelerated stability results of Merogabalin Besylate Accelerated Oral Disintegration Tablets in Examples 1, 5, and 6

[0189]

[0190]

[0191] The results in Table 6 show that the melogabalin besylate formulation obtained in Formulation Example 1 exhibited good accelerated stability within 6 months, while the melogabalin besylate formulations obtained in Examples 5 and 6, prepared by direct mixing of melogabalin besylate and commercially available melogabalin besylate respectively, showed a significant decreasing trend in accelerated stability within 6 months.

[0192] Test Example 7

[0193] Formulation Examples 1-12 Disintegration Time Test:

[0194] According to the General Rules, Part IV of the 2020 edition of the Chinese Pharmacopoeia <0921> The disintegration time test was performed using a disintegration apparatus (basket method) with water as the medium (37±1℃). The disintegration time of the orally disintegrating tablets of merogabarine besylate from formulation examples 1 to 12 was determined, and all disintegration times were recorded to determine whether they met the requirements. The results are shown in Table 7 below:

[0195] Table 7. Results of disintegration time test for Merogabalin Besylate Orally Disintegrating Tablets in Examples 1-12

[0196]

[0197] Based on the analysis of the results in Table 7 above, it can be seen that the merogabalin besylate powder-coated tablets prepared using the powder-coated merogabalin besylate obtained in Examples 1 to 4 of the present invention and commercially available merogabalin besylate, all meet the requirements of the disintegration time test method for oral disintegrating tablets.

Claims

1. A powder-coated melogabalin benzylsulfonate, comprising the following components by weight: 1000 parts melogabalin benzylsulfonate, 150 parts coating material, 15-30 parts plasticizer and 5 parts flavoring agent; The coating material is selected from one or more combinations of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, or polyvinyl alcohol; The plasticizer is selected from one or more combinations of triethyl citrate and talc. The flavoring agent is selected from one or more combinations of potassium acesulfame potassium (acesulfame K), aspartame, citric acid, sorbitol, or flavoring.

2. The powder-coated melogabalin benzylsulfonate according to claim 1, characterized in that, The product contains the following ingredients by weight: 1000 parts melogabalin benzyl sulfonate, 30 parts hydroxypropyl cellulose, 120 parts carboxymethyl cellulose, 15 parts triethyl citrate, and 5 parts potassium acetaminophen.

3. The powder-coated melogabalin benzylsulfonate according to claim 1, characterized in that, The product contains the following ingredients by weight: 1000 parts melogabalin benzyl sulfonate, 30 parts hydroxypropyl cellulose, 120 parts polyvinyl alcohol, 20 parts triethyl citrate, and 5 parts potassium acetaminophen.

4. The powder-coated melogabalin benzylsulfonate according to claim 1, characterized in that, The product contains the following ingredients by weight: 1000 parts melogabalin benzenesulfonate, 30 parts hydroxypropyl cellulose, 120 parts polyvinylpyrrolidone, 30 parts triethyl citrate, and 5 parts potassium acetamidosulfonate.

5. The powder-coated melogabalin benzylsulfonate according to claim 1, characterized in that, The product contains the following ingredients by weight: 1000 parts melogabalin benzenesulfonate, 30 parts polyvinyl alcohol, 120 parts polyvinylpyrrolidone, 30 parts triethyl citrate, and 5 parts potassium acetamidosulfonate.

6. A powder-coated melogabalin besylate orally disintegrating tablet comprising the following components: 105-107 parts of the powder-coated melogabalin besylate as described in any one of claims 1-5, 1680 parts of filler, 200 parts of disintegrant, 250 parts of stabilizer, and 30 parts of lubricant. The filler is selected from one or more combinations of D-mannitol, microcrystalline cellulose, lactose, starch, and calcium sulfate; The disintegrant is selected from one or more combinations of crospovidone, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; The lubricant is selected from one or more combinations of magnesium stearate, talc, and micronized silica gel. The stabilizer is selected from one or more combinations of L-tartaric acid, butylated hydroxyanisole, ascorbic acid, sodium bisulfite, or sodium metabisulfite.

7. The orally disintegrating melogabalin besylate tablets with powder coating according to claim 6, characterized in that, It is composed of the following ingredients, 8. The orally disintegrating melogabalin besylate tablets with powder coating according to claim 6, characterized in that, It is composed of the following ingredients, 9. The powder-coated merogabarine besylate orally disintegrating tablets according to claim 6, characterized in that, It is composed of the following ingredients, 10. The powder-coated merogabarine besylate orally disintegrating tablets according to claim 6, characterized in that, It is composed of the following ingredients,

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