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KR-20260066125-A - Pharmaceutical composition having enhanced properties, method of preparation thereof, and use

KR20260066125AKR 20260066125 AKR20260066125 AKR 20260066125AKR-20260066125-A

Abstract

The present application relates to a composition and a method for preparing a spray-dried amorphous solid dispersion comprising 5-{3-[4-(3-methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidin-2,4-dione and hydroxypropyl beta-cyclodextrin. In particular, the present application relates to an improved spray-drying method for producing an amorphous solid dispersion having enhanced properties by the use of a co-solvent system and/or an antioxidant.

Inventors

  • 리, 위화
  • 황, 자팅

Assignees

  • 포시 파마슈티컬스 유에스에이 인코포레이티드

Dates

Publication Date
20260512
Application Date
20240905
Priority Date
20230906

Claims (20)

  1. A solid dispersion having improved stability comprising (i) 5-{3-[4-(3-methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidin-2,4-dione (IVO) compound, (ii) hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) acetone.
  2. In claim 1, A solid dispersion in which acetone is in the range of 100 ppm to 5,000 ppm.
  3. In claim 1, A solid dispersion in which the ratio of IVO to HPBCD in the solid dispersion is 1:99 to 99:1 (w/w), preferably 10:90 to 90:10 (w/w), more preferably 20:80 to 80:20 (w/w), and most preferably 25:75 to 75:25 (w/w).
  4. In claim 1, A solid dispersion having a particle size in the range of 0.1 to 25 μm, preferably 1 to 20 μm, more preferably 2 to 15 μm, and most preferably 2 to 10 μm, expressed as Dv50.
  5. In claim 1, A solid dispersion having a particle size distribution of less than 15, expressed as Dv90/Dv10.
  6. In claim 1, A solid dispersion comprising one or more residual solvents, wherein each individual residual solvent is less than 5000 ppm.
  7. In claim 1, A solid dispersion having a relative weight loss of less than 90% as measured by thermogravimetric analysis at 100°C.
  8. In claim 1, A solid dispersion further comprising an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotene, and ascorbyl palmitate.
  9. In claim 8, A solid dispersion in which the antioxidant is butylated hydroxyanisole (BHA).
  10. In claim 1, A solid dispersion in which the total IVO-related impurities generated from the solid dispersion stored at 60°C for one month are less than 0.5% based on the weight of IVO.
  11. In claim 1, A solid dispersion is prepared by a method comprising the step of spray-drying a solution to obtain a powder composition, and Herein, a solid dispersion comprising a solution comprising (i) a 5-{3-[4-(3-methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidin-2,4-dione (IVO) compound, (ii) hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.
  12. A method for manufacturing a solid dispersion having improved stability, The method includes the step of obtaining a powder composition by spray-drying the solution, A method wherein the solution comprises (i) a 5-{3-[4-(3-methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidin-2,4-dione (IVO) compound, (ii) hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.
  13. In claim 12, A method in which the organic solvent is selected from the group consisting of acetone, tetrahydrofuran, methanol, ethanol, dichloromethane, and ethyl acetate.
  14. In claim 12, A method in which a solvent mixture comprises methanol and acetone.
  15. In claim 14, A method in which the ratio of methanol to acetone is 70:30 to 50:50 (v/v).
  16. In claim 15, A method in which the ratio of methanol to acetone is 60:40 (v/v).
  17. In claim 12, A method in which the solubility of IVO in a solvent mixture is greater than 15 mg/mL at 25±5℃.
  18. In claim 12, A method in which the solubility of the IVO/HPBCD complex in a solvent mixture is about 2 to 5.4 times higher than the solubility in a methanol-only solvent system.
  19. In claim 12, A method in which the ratio of IVO to HPBCD in the solution is 1:99 to 99:1 (w/w), preferably 10:90 to 90:10 (w/w), more preferably 20:80 to 80:20 (w/w), and most preferably 25:75 to 75:25 (w/w).
  20. In claim 12, A method in which the solid dispersion is an amorphous solid dispersion (ASD) of an IVO/HPBCD complex.

Description

Pharmaceutical composition having enhanced properties, method of preparation thereof, and use Cross-reference regarding related applications This application claims priority based on U.S. Provisional Application No. 63/580,742 filed on September 6, 2023, the entire contents of which are incorporated herein by reference. Field of application The present application relates to a composition and a method for preparing a spray-dried amorphous solid dispersion comprising 5-{3-[4-(3-methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidin-2,4-dione (hereinafter referred to as IVO compound) and hydroxypropyl beta-cyclodextrin (HPBCD). In particular, the present application relates to an improved spray-drying method for producing an amorphous solid dispersion having enhanced properties by the use of a co-solvent system and/or an antioxidant. Background of the application A series of 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2,4-dione compounds and analogs thereof are disclosed in U.S. Patent Application No. 2006/0041000. These compounds are designed to be used as inhibitors of macrophage elastase. All of these compounds are hydantoin derivatives and have been tested in vitro for use as matrix metalloproteinase (MMP) inhibitors. According to the method disclosed in U.S. Patent Application Publication No. 2019/0054178, approximately 10.0 g of an IVO compound was weighed into a volumetric flask and then completely dissolved in 660 mL of methanol (MeOH) using sonication at 25 ± 5 °C to obtain a clear solution (15.2 mg/mL). The solubility of IVO in methanol is approximately 15.2 mg/mL. To remove any potentially remaining residual crystalline solid, the solution was filtered through a 0.45 μm filter membrane, after which approximately 30.05 g of HPBCD was added to the solution to achieve an IVO/HPBCD ratio of 25:75 (w/w). The sample was stirred for 60 minutes to form a clear solution before spray drying to obtain an amorphous solid dispersion. The maximum solid content of the 1:3 (w/w) complex of IVO compound/HPBCD prepared in MeOH solution (hereinafter referred to as ASD-01) was limited to only 60 mg/ml in the spray drying process. The low solubility of IVO in methanol requires a large amount of methanol to dissolve IVO and HPBCD. A large amount of methanol would make the large-scale production of the IVO/HPBCD complex impractical. Therefore, it would be desirable to find an appropriate approach to prepare solutions with higher solid content for the optimization of the spray drying process while using a smaller amount of organic solvent. Using a smaller amount of organic solvent is advantageous as it reduces process costs and waste. According to the method disclosed in U.S. Patent Application Publication No. 2019/0054178, the spray-dried powder of a 1:3 (w/w) complex of IVO compound/HPBCD (ASD-01) is amorphous, and the composition can induce a larger area under the plasma concentration versus time curve (AUC) for the compound than is achieved when the compound is administered in the absence of cyclodextrin under the same amount and under the same conditions. However, the IVO/HPBCD powder prepared using the disclosed method is not very stable, and therefore it is very difficult to develop pharmaceutical products using such IVO/HPBCD powder. Therefore, there is still a need to develop a method for manufacturing IVO/HPBCD powder with superior stability to enable scale-up and reduce waste and costs. Summary of the application The present application provides a method for improving the process of preparing a pharmaceutical composition comprising a 5-{3-[4-(3-methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidin-2,4-dione (IVO) compound and hydroxypropyl beta-cyclodextrin (HPBCD). Additionally, the application provides a co-solvent system comprising at least two different organic solvents, and a method for producing a spray-dried amorphous solid dispersion (ASD) comprising IVO and HPBCD, wherein the ASD has superior physical and chemical properties compared to that obtained using a single solvent, e.g., methanol. In one general aspect, the present application provides a method for preparing a solid dispersion, the method comprising the step of spray-drying a solution comprising (i) a 5-{3-[4-(3-methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidin-2,4-dione (IVO) compound, (ii) hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents. In some embodiments, the solubility of the IVO compound in the solvent mixture is greater than 15 mg/mL at 25±5℃. In some embodiments, the ratio of IVO compound to HPBCD in solution is 1:99 to 99:1 (w/w), preferably 10:90 to 90:10 (w/w), more preferably 20:80 to 80:20 (w/w), and most preferably 25:75 to 75:25 (w/w). In a specific embodiment, the ratio of IVO compound to HPBCD is about 25:75 (w/w). In some embodiments, the organic solvent is selected from the group consisting of acetone, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), dichlor