Search

BR-122026002969-A2 - METHOD FOR PRODUCING FROZEN FORMULATIONS

BR122026002969A2BR 122026002969 A2BR122026002969 A2BR 122026002969A2BR-122026002969-A2

Abstract

This method for producing a lyophilized formulation, including an amorphous form of sodium salt 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, is useful as a method for producing a lyophilized formulation with uniform quality.

Inventors

  • Makoto Ono
  • Takafumi Hirota
  • IORI MIZOGAKI

Assignees

  • FUJIFILM TOYAMA CHEMICAL CO., LTD.

Dates

Publication Date
20260317
Application Date
20181214
Priority Date
20171228

Claims (19)

  1. 1. Method for producing a lyophilized preparation containing amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide, characterized in that it comprises the steps of: (1) adjusting the temperature of an aqueous solution containing a sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide to between 30 °C and 70 °C, excluding the exact value of 70 °C; (2) cooling the aqueous solution obtained in step (1) between -70 °C and -40 °C within 1 hour to produce a frozen product; and (3) lyophilizing the frozen product obtained in step (2).
  2. 2. Method according to claim 1, characterized in that the temperature in step (1) is between 30 °C and 60 °C, excluding the exact value of 60 °C.
  3. 3. Method according to claim 1, characterized in that the temperature in step (1) is between 30 °C and 50 °C, excluding the exact value of 50 °C.
  4. 4. Production method according to claim 1, characterized in that the temperature in step (1) is between 30 °C and 40 °C, excluding the exact value of 40 °C.
  5. 5. Method according to claim 1, characterized in that the temperature in step (1) is between 40 °C and 70 °C, excluding the exact value of 70 °C.
  6. 6. Method according to claim 1, characterized in that the temperature in step (1) is between 40 °C and 60 °C, excluding the exact value of 60 °C.
  7. 7. Production method according to claim 1, characterized in that the temperature in step (1) is between 40 °C and 50 °C, excluding the exact value of 50 °C.
  8. 8. Method according to claim 1, characterized in that the temperature in step (1) is between 50 °C and 70 °C, excluding the exact value of 70 °C.
  9. 9. Production method according to claim 1, characterized in that the temperature in step (1) is between 50 °C and 60 °C, excluding the exact value of 60 °C.
  10. 10. Production method according to claim 1, characterized in that the temperature in step (1) is between 60 °C and 70 °C, excluding the exact value of 70 °C.
  11. 11. Method for producing a lyophilized preparation containing amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide, characterized in that it comprises the steps of: (1) adjusting the temperature of an aqueous solution containing a sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide to between 40 °C and 70 °C, excluding the exact value of 70 °C; (2) cooling the aqueous solution obtained in step (1) to -70 °C to -40 °C over a period of 3 hours to produce a frozen product; and (3) lyophilizing the frozen product obtained in step (2).
  12. 12. Method according to claim 11, characterized in that the temperature in step (1) is between 40 °C and 70 °C, excluding the exact value of 70 °C.
  13. 13. Method according to claim 11, characterized in that the temperature in step (1) is between 40 °C and 60 °C, excluding the exact value of 60 °C.
  14. 14. Production method according to claim 11, characterized in that the temperature in step (1) is between 40 °C and 50 °C, excluding the exact value of 50 °C.
  15. 15. Method according to claim 11, characterized in that the temperature in step (1) is between 50 °C and 70 °C, excluding the exact value of 70 °C.
  16. 16. Production method according to claim 11, characterized in that the temperature in step (1) is between 50 °C and 60 °C, excluding the exact value of 60 °C.
  17. 17. Production method according to claim 11, characterized in that the temperature in step (1) is between 60 °C and 70 °C, excluding the exact value of 70 °C.
  18. 18. Production method according to any one of claims 1 to 17, characterized in that the temperature of the frozen product during water sublimation in the primary drying step (3) is between -30 °C and 0 °C, excluding the exact value of 0 °C, and the degree of vacuum (absolute pressure) is between 15 Pa and 25 Pa, excluding the exact value of 25 Pa.
  19. 19. Production method, according to any one of claims 1 to 17, characterized in that the temperature of the frozen product during water sublimation in the primary drying step (3) is between -40 °C and -15 °C, excluding the exact value of -15 °C.

Description

TECHNICAL FIELD [0001] The present invention relates to a method for producing a lyophilized preparation containing an amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide (hereinafter also referred to as "Compound A"). BACKGROUND [0002] Recently, there has been a noted fear of a highly virulent influenza pandemic. For example, oseltamivir, zanamivir, laninamivir, and amantadine are currently used as influenza medications. However, these medications have the disadvantage of not being able to be administered to patients with difficulty swallowing orally. [0003] Compound A, or its salt, has excellent antiviral activity and is useful as a therapeutic drug for viral infection (Patent Literature 1). There have been reports of an injectable solution of the sodium salt and meglumine salt of Compound A (Patent Literature 2 and 3). [0004] A method based on lyophilization, for example, is known as a method for producing an injectable solution. [0005] A general freeze-drying process includes a freezing step, a primary drying step, and a secondary drying step. The freezing step is one of the important steps that determine the quality of the product. [0006] In the freezing stage, water does not freeze spontaneously and remains in a supercooled state. When the degree of supercooling is increased due to a specific cause, the initial freezing temperature decreases and the size of the ice crystals formed by rapid freezing becomes smaller. The small size of the ice crystals does not allow water vapor to be efficiently sublimated in the primary drying stage, causing the frozen product to melt and foam, resulting in a product with an abnormal appearance and therefore products of non-uniform quality. [0007] To obtain uniform product quality, it is preferable to control the freezing stage and suppress over-cooling. [0008] In this regard, freeze-drying is easily influenced by a scale difference between a test device and a production device. This is because test and production devices are not necessarily identical in terms of shape and material quality, and cooling and heating transfer efficiencies vary according to scale differences (Non-Patent Literature 1). It is desirable that the method of suppressing supercooling be suitable for scale-up that can be achieved in the production device, similarly to the test device. [0009] Techniques such as pre-cooling, gradual cooling, annealing, or the addition of additives have been examined as existing methods for controlling the freezing step (Patent Literature 4, 5, and 6). However, none of these methods is necessarily satisfactory in terms of certainty of control, simplicity of operation, and suitability for scale-up. LIST OF QUOTES Patent Literature [0010] PATENT LITERATURE 1: International Publication No. 00/10569 [0011] PATENT LITERATURE 2: International Publication No. 2012/043696 [0012] PATENT LITERATURE 3: International Publication No. 2012/043700 [0013] PATENT LITERATURE 4: Japanese Patent Application No. 2008/231067 [0014] PATENT LITERATURE 5: Japanese Patent No. 4753717 [0015] PATENT LITERATURE 6: Japanese Patent Application No. 2012 214525 NON-PATENT LITERATURE [0016] NON-PATENTORY LITERATURE 1: Journal of Japan Society of Pharmaceutical Machinery and Engineering, vol. 24, no. 2, pp. 39-51,2015 SUMMARY OF THE INVENTION TECHNICAL PROBLEM [0017] There is a need for a scalable production method for a freeze-dried preparation containing a compound or its salt that is of uniform quality. SOLUTION TO THE PROBLEM [0018] Under such circumstances, the present inventors engaged in repetitive studies and, consequently, determined a scalable production method for a freeze-dried preparation of uniform quality containing a sodium salt of Compound A (hereinafter also referred to as "Salt A"). [0019] The present inventors determined that the freezing step affects the variation in the appearance of the lyophilized preparation. They then determined that a whole solution in a heated state is once rapidly cooled, so as to facilitate the convective flow associated with a temperature difference between a part closer to and a part further from a cooling source (a large temperature difference results in an increase in the density difference of water and therefore convective flow occurs easily), cooling the entire solution quickly and uniformly. In other words, they discovered that it is possible to freeze water with little supercooling. [0020] Furthermore, the present inventors have engaged in repetitive studies. As a result, they have determined that (1) the temperature of an aqueous solution of salt A before cooling (hereinafter also referred to as the "initial cooling temperature") is adjusted to 20 °C or more, cooled within a certain period of time and lyophilized, producing a lyophilized preparation containing amorphous salt A, (2) the lyophilized preparation obtained has a uniform quality, so that the variation in appearance is very small, and (3) it is possible to easily increase