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CA-3157788-C - ORAL PHARMACEUTICAL COMPOSITION COMPRISING CARBAMATE COMPOUND AND PREPARATION METHOD THEREFOR

CA3157788CCA 3157788 CCA3157788 CCA 3157788CCA-3157788-C

Abstract

The present invention relates to an oral pharmaceutical composition comprising a carbamate compound of chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof as an active ingredient, and a preparation method therefor.

Inventors

  • Ji Hye Lee
  • So Young Choi

Assignees

  • SK BIOPHARMACEUTICALS CO., LTD.

Dates

Publication Date
20260505
Application Date
20201120
Priority Date
20191122

Claims (20)

  1. CLAIMS 1. A pharmaceutical composition for oral administration compnsmg particles of a carbamate compound of the following Formula I, an isomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient; and a pharmaceutically acceptable carrier; wherein a particle diameter d(0.9) of the active ingredient particles is less than 300 μm: [Formula I] wherein, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-Cs perfluoroalk:yl, C1-Cs alkyl, C1-Cs thioalkoxy and C1-Cs alkoxy; and one of A1 and A2 is CH, and the other is N.
  2. 2. The pharmaceutical composition for oral administration according to Claim I, wherein the particle diameter d(0.9) of the active ingredient particles is 250 μm or less.
  3. 3. The pharmaceutical composition for oral administration according to Claim I, wherein the particle diameter d(0.9) of the active ingredient particles is 150 μm or less.
  4. 4. The pharmaceutical composition for oral administration according to any one of Date Re9ue/Date Received 2024-04-08 Claims 1 to 3, wherein the active ingredient is comprised in an amount of 5 mg to 400 mg.
  5. 5. The pharmaceutical composition for oral administration according to any one of Claims 1 to 4, wherein the pharmaceutically acceptable carrier is one or more selected from the group consisting of a diluent, a disintegrant and a lubricant.
  6. 6. The pharmaceutical composition for oral administration according to Claim 5, which further comprises a surfactant.
  7. 7. The pharmaceutical composition for oral administration according to Claim 5 or 6, wherein the diluent is one or more selected from the group consisting of com starch, pregelatinized starch, potato starch, wheat flour starch, glutinous rice starch, sweet potato starch, tapioca starch, rice starch, waxy com starch, sucrose, anhydrous lactose, lactose hydrate, mannitol, sorbitol, xylitol, lactitol, rnaltitol, erythritol, synthetic aluminum silicate, hydroxypropyl starch, microcrystalline cellulose and crystalline cellulose.
  8. 8. The pharmaceutical composition for oral administration according to any one of Claims 5 to 7, wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, anhydrous lactose, lactose hydrate, sodium starch glycolate, crospovidone, carboxymethyl cellulose and a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, com starch, and croscarmellose and a pharmaceutically acceptable salt thereof.
  9. 9. The pharmaceutical composition for oral administration according to any one of Date Re9ue/Date Received 2024-04-08 Claims 5 to 8, wherein the lubricant is one or more selected from the group consisting of silicon dioxide, colloidal anhydrous silica, magnesium trisilicate, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, powdered cellulose, starch, magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, mineral oil, hydrogenated vegetable oil, zinc stearate and stearic acid.
  10. 10. The pharmaceutical composition for oral administration according to any one of Claims 5 to 9, which comprises 5 to 35% by weight of the active ingredient, 55 to 90% by weight of the diluent, 2 to 6% by weight of the disintegrant and 0.1 to 4% by weight of the lubricant, based on the total weight of the pharmaceutical composition.
  11. 11. The pharmaceutical composition for oral administration according to any one of Claims 1 to 10, wherein the active ingredient is a carbamate compound of the following Formula 2, an isomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof: [Formula 2]
  12. 12. The pharmaceutical composition for oral administration according to any one of Claims 1 to 11, which is in a form of compressed tablet, multi-compressed tablet, sugar-coated tablet, film-coated tablet, hard capsule or soft capsule. Date Re9ue/Date Received 2024-04-08
  13. 13. A method for prepanng a pharmaceutical composition for oral administration comprising a step of mixing particles of a carbamate compound of the following Formula 1, an isomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient with a pharmaceutically acceptable carrier, and tableting; wherein a particle diameter d(0.9) of the active ingredient particles is less than 300 μm: [Formula l] wherein, Rt and R2 are each independently selected from the group consisting of hydrogen, halogen, Ct-Cs perfluoroalkyl, Ct-Cs alkyl, Ct-Cs thioalkoxy and Ct-Cs alkoxy; and one of At and A2 is CH, and the other is N.
  14. 14. The method for preparing a pharmaceutical composition for oral administration according to Claim 13, wherein the mixing of the active ingredient with the pharmaceutically acceptable carrier is carried out by direct compression.
  15. 15. The method for preparing a pharmaceutical composition for oral administration according to Claim 13 or 14, wherein the particle diameter d(0.9) of the active ingredient particles is 250 μm or less.
  16. 16. The method for preparing a pharmaceutical composition for oral administration Date Re9ue/Date Received 2024-04-08 according to any one of Claims 13 to 15, wherein the pharmaceutical composition comprises the active ingredient in an amount of 5 mg to 400 mg.
  17. 17. The method for preparing a pharmaceutical composition for oral administration according to any one of Claims 13 to 16, wherein the pharmaceutically acceptable carrier is one or more selected from the group consisting of a diluent, a disintegrant and a lubricant.
  18. 18. The method for preparing a pharmaceutical composition for oral administration according to Claim 17, wherein the pharmaceutically acceptable carrier further comprises a surfactant.
  19. 19. The method for preparing a pharmaceutical composition for oral administration according to any one of Claims 13 to 18, wherein the active ingredient is a carbamate compound of the following Formula 2, an isomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof: [Formula 2]
  20. 20. The method for preparing a pharmaceutical composition for oral administration according to any one of Claims 13 to 19, wherein the pharmaceutical composition is in a form of compressed tablet, multi-compressed tablet, sugar-coated tablet, film-coated tablet, hard Date Re9ue/Date Received 2024-04-08 capsule or soft capsule. Date Re9ue/Date Received 2024-04-08

Description

DESCRIPTION TITLE OF INVENTION ORAL PHARMACEUTICAL COMPOSITION COMPRISING CARBAMATE COMPOUND AND PREPARATION METHOD THEREFOR TECHNICAL FIELD The present invention relates to a pharmaceutical composition for oral administration comprising a carbamate compound of the following Formula 1, an isomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient, and a preparation method therefor: [Formula l] wherein, R1, R2, A1 and A2 are the same as defined herein. BACKGROUND ART The carbamate compound (carbamic acid aryl-2-tetrazolyl ethyl ester) represented by the following Formula 1 and the preparation method therefor are described in detail in International Patent Publication Nos. WO 2006/112685 Al, WO 2010/150946 Al and WO 2011/046380A2: Date Re9ue/Date Received 2024-04-08 CA 03157788 2022-5-9 PCT/KR2020/016427 English translation [Formula 1] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-Cs perfluoroalkyl, C1-Cs alkyl, C1-Cs thioalkoxy and C1-Cs alkoxy; and one of A1 and A2 is CH, and the other is N. A specific example of the carbamate compound of Formula 1 may be a carbamate compound of the fol lowing Formula 2 (carbami c acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-ylethyl ester): [Formula 2] The carbamate compound of Formula 2 is known as an effective anti-epileptic drug used for central nervous system diseases, but studies about a specific formulation for oral administration for applying it to the human body have not been disclosed. In order for drugs to be applied to the human body, formulation design is essential. In order to be effective as drugs, specific formulations such as tablets, capsules, injections and ointments are required. In the case of obtaining pharmacological activity by administering said compound, it CA 03157788 2022-5-9 PCT/KR2020/016427 English translation is required that the effect must appear quickly, and it must be suitable to secure a uniform concentration of the active ingredient in the blood by repeating administration over an extended treatment period. In order to obtain a quick effect, an injection preparation may be appropriate, but there is a disadvantage in that use is limited due to the route of administration. As such, there is increased demand for developing a novel oral solid dosage form for achieving this purpose. DISCLOSURE OF INVENTION TECHNICAL PROBLEM The solubility (1.8 to 2.0 mg/ml) of the carbamate compound of Formula 1 in the in vivo pH range (pH 1.2 to 6.8) does not limit the absorption of tablets having an active ingredient of 12.5 to 400 mg (BCS; Amidon, G.L. et al., Pharmaceutical research, 12: 413- 420 (1995)). In addition, based on the above dose, the particle size of the compound is not expected to have a significant effect on uniformity of dosage units. Rather, micronization is not recommended for the purpose of uniformity of dosage units since it directly affects the flowability and stability of the active pharmaceutical ingredient, thereby affecting the content uniformity and content. However, the present inventors have found that the dissolution rate of the carbamate compound of Formula 1 is variable despite its high solubility. The dissolution rate of the formulation is a necessary condition for rapid and consistent therapeutic effect, and quality control. In addition, if the dissolution rate is variable, it may cause problems in the quality control of the formulation. Therefore, the present inventors have conducted repeated studies to solve such problems. CA 03157788 2022-5-9 PCT/KR2020/016427 English translation Meanwhile, in general, micronization of particles is not adopted since it may directly affect the flowability and stability of drugs, thereby affecting the content uniformity and content of dosage forms. However, through repeated studies, the present inventors have conceived the dosage form which can consistently achieve an excellent dissolution rate by controlling the average particle size of the particles of the carbamate compound of Formula 1 included therein by micronization. That is, the present invention is surprising in that a person skilled in the art would not have easily conceived that the dissolution rate of the carbamate compound of Formula 1 can be adjusted by micronization. Accordingly, an object of the present invention is the provision of a pharmaceutical composition for oral administration comprising a carbamate compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient, and a preparation method therefor SOLUTION TO PROBLEM According to one aspect of the present invention, there is provided a pharmaceutical composition for oral administration comprising particles of a carbamate compound of the following Formula 1, an isomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient; and a pharmaceutically acceptable carr