WO2018003946A1 - Method for producing lyophilized preparation - Google Patents

Method for producing lyophilized preparation Download PDF

Info

Publication number
WO2018003946A1
WO2018003946A1 PCT/JP2017/024032 JP2017024032W WO2018003946A1 WO 2018003946 A1 WO2018003946 A1 WO 2018003946A1 JP 2017024032 W JP2017024032 W JP 2017024032W WO 2018003946 A1 WO2018003946 A1 WO 2018003946A1
Authority
WO
WIPO (PCT)
Prior art keywords
temperature
freeze
water
sodium hydroxide
added
Prior art date
Application number
PCT/JP2017/024032
Other languages
French (fr)
Japanese (ja)
Inventor
大野　誠
貴文 廣田
伊織 溝垣
Original Assignee
富山化学工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 富山化学工業株式会社 filed Critical 富山化学工業株式会社
Publication of WO2018003946A1 publication Critical patent/WO2018003946A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the present invention relates to a method for producing a freeze-dried preparation containing an amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (hereinafter sometimes referred to as “compound A”).
  • pandemics due to highly toxic influenza viruses.
  • oseltamivir, zanamivir, peramivir, laninamivir, amantadine and the like are used as therapeutic agents for influenza.
  • these drugs have drawbacks such as being unable to be administered to patients who are difficult to administer orally.
  • Compound A or a salt thereof has excellent antiviral activity and is useful as a therapeutic agent for viral infection (Patent Document 1). Injectable preparations of sodium salt and meglumine salt of Compound A have been reported (Patent Documents 2 and 3).
  • a typical lyophilization process includes a freezing step, a primary drying step, a secondary drying step, and the like.
  • the freezing process is one of the important processes for determining product quality. In the freezing process, water does not freeze spontaneously and maintains a supercooled state. If the degree of supercooling increases for some reason, the freezing start temperature decreases, and the size of ice crystals formed by rapid freezing decreases. If the size of the ice crystals is small, the water vapor cannot be sublimated efficiently in the primary drying process, and the frozen body will melt and foam, resulting in a product with an abnormal appearance.
  • Non-Patent Document 1 The method for suppressing overcooling is desired to have a scale-up suitability that can be realized in a production machine as well as a test machine.
  • Patent Document 4 Patent Document 5
  • Patent Document 6 Patent Document 6
  • Salt A a sodium salt of Compound A
  • the process affected. Then, by rapidly cooling the entire solution once it has been heated, convection associated with a temperature difference between the vicinity of the cooling source and a distance is promoted (if the temperature difference is large, the density difference of water increases and it is easy to convect) It was found that the entire solution can be cooled quickly and uniformly. And it discovered that water could be frozen almost without generating supercooling.
  • cooling start temperature The temperature of the aqueous solution of salt A before cooling (hereinafter also referred to as “cooling start temperature”) is set to 20 ° C. or higher, cooled within a certain time, and then freeze-dried, thereby The ability to produce lyophilized formulations containing crystalline material; (2) The obtained freeze-dried preparation has uniform quality with very little variation in appearance, (3) This freezing process can be easily scaled up; The present invention has been completed.
  • the present invention provides the following. [1] (1) adjusting the temperature of an aqueous solution containing a sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide to 20 ° C. or higher; (2) A step of producing a frozen body by cooling the aqueous solution obtained in the step (1) to ⁇ 40 ° C. or less within 1 hour, (3) A step of freeze-drying the frozen body obtained in the step (2), A process for producing a freeze-dried preparation containing an amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, [2] The production method according to [1], wherein the temperature in the step (1) is in a range of 20 ° C. or higher and lower than 30 ° C.
  • the frozen body temperature during water sublimation in the primary drying of the step (3) is in the range of ⁇ 30 ° C. or more and less than 0 ° C., and the degree of vacuum (absolute pressure) is in the range of 15 Pa or more and less than 25 Pa.
  • the method for producing a lyophilized preparation containing an amorphous salt A according to the present invention can be scaled up and is useful as a method for producing a lyophilized preparation of uniform quality.
  • Compound A can be produced, for example, by the method described in Patent Document 1.
  • Compound A has tautomer 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide.
  • the present invention also includes this compound.
  • This step is a step of adjusting the temperature of the aqueous solution containing the salt A to 20 ° C. or higher.
  • the aqueous solution containing the salt A can be obtained, for example, by mixing the compound A, a base and water.
  • the amount of water may be 10 to 100 times (v / w) with respect to Compound A, and preferably 10 to 50 times (v / w).
  • Examples of the base include sodium hydroxide, sodium hydrogen carbonate, sodium carbonate and the like.
  • the amount of the base is not particularly limited as long as the pH of the aqueous solution is 4 to 10, and preferably 6.5 to 9.
  • the aqueous solution containing the salt A can be obtained by mixing an aqueous solution such as sodium hydroxide, sodium bicarbonate or sodium carbonate and the compound A as an alternative method.
  • the aqueous solution containing the salt A can also be obtained by dissolving the salt A in water as an alternative method.
  • the aqueous solution containing the salt A is preferably obtained in a state of being filled in a container that can be sealed later.
  • the aqueous solution containing the salt A filled in a container that can be sealed later can be obtained by filling an aqueous solution containing the separately prepared salt A into the sealable container.
  • compound A, base and water can be obtained by dissolving in a container that can be sealed later.
  • the cooling start temperature is preferably 20 ° C. or higher, and more preferably in the range of 20 ° C. or higher and lower than 30 ° C.
  • the cooling start temperature is preferably 20 ° C. or higher, and more preferably in the range of 30 ° C. or higher and lower than 40 ° C.
  • the cooling start temperature is preferably 20 ° C.
  • the cooling start temperature is preferably 20 ° C. or higher, and more preferably in the range of 50 ° C. or higher and lower than 60 ° C.
  • This step is a step of manufacturing a frozen body by cooling the aqueous solution obtained in the step (1) to ⁇ 40 ° C. or lower.
  • the time required for cooling to ⁇ 40 ° C. or lower is not particularly limited, but is preferably within 1 hour.
  • the cooling start temperature is in the range of 40 ° C. or higher and lower than 50 ° C., or when it is 50 ° C. or higher
  • the time required for cooling to ⁇ 40 ° C. or lower is within 3 hours. It is preferable that it is within 1 hour.
  • the aqueous solution may be cooled to ⁇ 40 ° C. or lower. Specifically, for example, ⁇ 40 ° C. or lower, ⁇ 41 ° C.
  • the cooling rate is not particularly limited, but is preferably 28 ° C./hour or more, more preferably 55 ° C./hour or more, and still more preferably 85 ° C./hour or more.
  • This step is a step of freeze-drying the frozen body obtained in step (2).
  • This step may be performed in accordance with a commonly practiced freeze-drying method, and can be performed, for example, by two steps, a primary drying step and a secondary drying step.
  • the primary drying process is performed under reduced pressure while maintaining the frozen body below the eutectic point.However, since the temperature decreases with the sublimation of moisture from the frozen body, the set temperature of the freeze-drying equipment is the same. You may set more than a crystal point.
  • the temperature of the frozen body is kept substantially constant (hereinafter, also referred to as “the frozen body temperature during moisture sublimation”).
  • the frozen body temperature during moisture sublimation may be ⁇ 40 ° C. or higher and lower than 0 ° C., and preferably ⁇ 30 ° C. or higher and lower than 0 ° C.
  • the degree of reduced pressure (absolute pressure) in the primary drying step is not particularly limited, but may be 50 Pa or less, preferably 30 Pa or less, and more preferably in the range of 15 Pa or more and less than 25 Pa.
  • the moisture to sublimate decreases, the temperature drop becomes moderate. As a result, the temperature of the frozen body rises, and the temperature of the frozen body and the set temperature substantially coincide. Usually, this point is judged as the completion of the primary drying process.
  • the secondary drying step is performed at 20 ° C. or higher, preferably 30 to 60 ° C., more preferably 40 to 50 ° C.
  • the degree of vacuum may be 0.5 to 50 Pa, and preferably 0.5 to 5 Pa.
  • the secondary drying process may be performed until the product temperature and the set temperature are substantially equal and the change in the product temperature is almost eliminated.
  • the freeze-dried preparation containing the amorphous salt A produced by this production method has very little variation in appearance. That is, by this production method, a lyophilized preparation of uniform quality containing an amorphous salt A can be produced.
  • an additive for improving solubility and / or appearance can be added to the freeze-dried preparation containing an amorphous salt A.
  • additives include amino acids, polyethers, saccharides, sugar alcohols, salts, urea, ethylurea, creatinine, nicotinamide, trometamol, purified soy lecithin, ovalbumin, bovine serum albumin, and polysorbate 80. These may be used alone or in combination of two or more.
  • amino acids examples include glycine, L-alanine, L-phenylalanine, L-valine, L-leucine, L-isoleucine, taurine, DL-methionine, L-threonine, L-glutamine, sodium L-glutamate, acetyltryptophan And L-histidine, L-alanine, L-phenylalanine, L-valine, L-leucine, L-isoleucine, taurine, DL-methionine, L-glutamine and L-histidine are preferred, and L-leucine, L -Isoleucine and L-valine are more preferred.
  • polyethers examples include polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 4000, with polyethylene glycol 400 being preferred.
  • saccharide examples include trehalose, maltose, glucose, lactose, sucrose, fructose, dextran, and cyclodextrin, and dextran 40 is preferable.
  • sugar alcohols examples include D-sorbitol, xylitol, inositol, isomaltose and D-mannitol.
  • the salts include sodium acetate, sodium lactate, sodium L-tartrate, sodium citrate, sodium salicylate, sodium benzoate and sodium caprylate.
  • Preferred examples of the additive include amino acids, polyethers, saccharides, urea and polysorbate 80.
  • the preparation of the present invention contains, as necessary, a commonly used osmotic pressure regulator, pH regulator, buffer, solubilizer, stabilizer, surfactant, soothing agent and / or preservative. It may be added.
  • a commonly used osmotic pressure regulator include sodium chloride, glycerin and propylene glycol.
  • Examples of the pH adjusting agent and / or buffering agent include acids such as hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, lactic acid, maleic acid, citric acid, tartaric acid, ascorbic acid and benzoic acid; sodium bicarbonate, carbonic acid Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, disodium citrate, sodium deoxycholate and sodium sulfite; sodium hydroxide And bases such as trometamol, monoethanolamine, diethanolamine, triethanolamine, L-arginine and L-lysine.
  • Examples of the solubilizer include macrogol and purified soybean lecithin.
  • stabilizers include sodium bisulfite, sodium pyrosulfite, potassium pyrosulfite, sodium pyrophosphate, sodium thiosulfate, sodium metasulfobenzoate, sodium formaldehyde sulfoxylate, ethylenediamine, sodium edetate, thioglycolic acid, glucone.
  • stabilizers include sodium acid, potassium L-glutamate, L-lysine-L-glutamate, sodium chondroitin sulfate, albumin, L-aspartic acid, L-cysteine, and dibutylhydroxytoluene.
  • surfactant examples include sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene polyoxypropylene glycol, and polysorbate.
  • soothing agents include lidocaine, procaine, meprilucaine, and benzyl alcohol.
  • preservative examples include cresol, phenol, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzalkonium chloride and benzethonium chloride.
  • the dose of the active ingredient in the freeze-dried preparation obtained by the production method of the present invention is appropriately determined according to the usage, patient age, sex, disease form, other conditions, etc. It is sufficient to administer 0.1 to 200 mg / kg per day.
  • the content of Compound A in the lyophilized preparation obtained by the production method of the present invention is 10 to 6000 mg, preferably 100 to 2000 mg.
  • the additive for improving solubility and / or appearance, which is incorporated in the lyophilized preparation obtained by the production method of the present invention, is 0 to 100% (w / w), preferably 0, relative to Compound A. ⁇ 50% (w / w).
  • Non-defective product freeze-dried preparation with a yellow to pale yellow appearance and no white part
  • Defective product lyophilized preparation with a white part observed
  • the percentage of good products was determined by the following formula.
  • Non-defective product rate (%) (Number of good products / (Number of good products + Number of defective products)) ⁇ 100
  • Example 1 42.19 g of Compound A was suspended in 350 mL of water for injection with stirring. Separately, 10.66 g of sodium hydroxide was dissolved in 250 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Non-defective rate 100% Method of lyophilization
  • the shelf temperature was adjusted to 50 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours.
  • the frozen body temperature during water sublimation was -13.2 to -3.3 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
  • shelf temperature means the shelf temperature of a freeze dryer.
  • Example 2 181 g of Compound A was suspended in 1450 g of water for injection under stirring. Separately, 46 g of sodium hydroxide was dissolved in 1100 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 7.6. Water for injection was added to make the total volume 3 L, then 750 mL was taken, 0.2 mol / kg sodium hydroxide solution was added, and the pH was adjusted to 8.0. The solution was filtered through a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation.
  • Millex-GV, MERCK 0.22 ⁇ m membrane filter
  • Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Non-defective rate 100% Method of lyophilization
  • the shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the shelf temperature was raised to 25 ° C., and the pressure and temperature were maintained for 15 hours.
  • the frozen body temperature during water sublimation was -13.7 to -6.0 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 22
  • Example 3 42.16 g of Compound A was suspended in 350 mL of water for injection with stirring. Separately, 10.65 g of sodium hydroxide was dissolved in 250 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Non-defective rate 100% Method of lyophilization
  • the shelf temperature was adjusted to 30 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours.
  • the frozen body temperature during water sublimation was ⁇ 6.1 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
  • Example 4 120.41 g of Compound A was suspended in 800 mL of water for injection with stirring. Separately, 30.73 g of sodium hydroxide was dissolved in 300 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make a total volume of 2000 mL, followed by filtration through a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Non-defective rate 100% Method of lyophilization
  • the shelf temperature was adjusted to 20 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 41 minutes and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours.
  • the frozen body temperature during water sublimation was -11.9 to -3.0 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
  • Example 5 42.19 g of Compound A was suspended in 300 g of water for injection with stirring. Separately, 10.86 g of sodium hydroxide was dissolved in 299 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Non-defective rate 100% Method of lyophilization
  • the shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the shelf temperature was raised to 0 ° C., and the pressure and temperature were maintained for 66 hours.
  • the frozen body temperature during water sublimation was ⁇ 5.5 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of pressure reduction (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 20 hours.
  • Example 6 422 g of Compound A was suspended in 3001 g of water for injection with stirring. Separately, 107 g of sodium hydroxide was dissolved in 2501 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.5. Water for injection was added to make the total volume 7 L, followed by filtration with a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • DFM-05B-S, Ulvac freeze dryer
  • a broad halo pattern in a low angle region (20 ° to 30 °) peculiar to amorphous was observed.
  • This lyophilized preparation (good product) was confirmed to be amorphous.
  • Non-defective rate 99% Method of lyophilization The shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes. 2.
  • Example 7 181 g of Compound A was suspended in 1450 g of water for injection under stirring. Separately, 46 g of sodium hydroxide was dissolved in 1100 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 7.6. Water for injection was added to make the total volume 3 L, then 750 mL was taken, 0.2 mol / kg sodium hydroxide solution was added, and the pH was adjusted to 8.5. The solution was filtered through a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation.
  • Millex-GV, MERCK 0.22 ⁇ m membrane filter
  • Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Non-defective rate 100% Method of lyophilization
  • the shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the shelf temperature was raised to 25 ° C., and the pressure and temperature were maintained for 15 hours.
  • the frozen body temperature during water sublimation was -13.7 to -6.0 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 22
  • Example 8 Compound A (4.518 kg) was suspended in 36 kg of water for injection under stirring. Separately, 1.151 kg of sodium hydroxide was dissolved in 10 kg of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 77.7 kg, followed by filtration with a 0.22 ⁇ m membrane filter (OpticapXL4 Capsule, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (V10-F8W, material D713, coating RB2-40, Daikyo Seiko) into a filled vial, and freeze-dryer (DFB2000-2MS-ST / CIP, chamber volume 3.9m 3 , shelf 5
  • DFB2000-2MS-ST / CIP chamber volume 3.9m 3
  • Non-defective rate 98% Method of lyophilization
  • the shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature ⁇ 50 ° C. in 3 hours and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and maintained at the same pressure and the same temperature for 58 hours.
  • the frozen body temperature during water sublimation was ⁇ 6.0 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 0.5 Pa, and the same temperature was maintained for 26.5 hours.
  • Example 9 42.17 g of Compound A was suspended in 350 mL of water for injection with stirring. Separately, 10.65 g of sodium hydroxide was dissolved in 250 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.5. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Non-defective rate 93% Method of lyophilization
  • the shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 3 hours and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours.
  • the frozen body temperature during water sublimation was -5.1 to -4.3 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
  • Example 10 181 g of Compound A was suspended in 1450 g of water for injection under stirring. Separately, 46 g of sodium hydroxide was dissolved in 1100 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 7.6. Water for injection was added to make the total volume 3 L, then 750 mL was taken, 0.2 mol / kg sodium hydroxide solution was added, and the pH was adjusted to 9.0. The solution was filtered through a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation.
  • Millex-GV, MERCK 0.22 ⁇ m membrane filter
  • Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Non-defective rate 100% Method of lyophilization
  • the shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the shelf temperature was raised to 25 ° C., and the pressure and temperature were maintained for 15 hours.
  • the frozen body temperature during water sublimation was -13.7 to -6.0 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 22
  • Example 11 120.48 g of Compound A was suspended in 900 g of water for injection with stirring. Separately, 30.68 g of sodium hydroxide was dissolved in 700 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, a 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0, and water for injection was added to make the total volume 2 L. The solution was filtered through a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation.
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Comparative Example 1 42.18 g of Compound A was suspended in 299 g of water for injection with stirring. Separately, 10.59 g of sodium hydroxide was dissolved in 293 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Non-defective rate 82% Method of lyophilization
  • the shelf temperature was adjusted to 5 ° C and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours.
  • the frozen body temperature during water sublimation was ⁇ 6.1 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
  • Comparative Example 2 42.25 g of Compound A was suspended in 300 mL of water for injection with stirring. Separately, 10.47 g of sodium hydroxide was dissolved in 300 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Non-defective rate 53% Method of lyophilization
  • the shelf temperature was adjusted to 30 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 3 hours and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and maintained at the same pressure and the same temperature for 34 hours.
  • the frozen body temperature during water sublimation was -9.9 to -6.3 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 4 hours.
  • Comparative Example 3 42.20 g of Compound A was suspended in 350 mL of water for injection with stirring. Separately, 10.73 g of sodium hydroxide was dissolved in 250 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
  • Non-defective rate 73%
  • the shelf temperature was adjusted to 20 ° C. and held at that temperature for 180 minutes. 2. Cooled to shelf temperature -47 ° C in 3 hours and frozen contents. 3.
  • the degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours.
  • the frozen body temperature during water sublimation was -16.7 to -6.0 ° C. 4).
  • the shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.2 Pa, and the same temperature was maintained for 24 hours.
  • Comparative Example 4 60 g of Compound A was suspended in 346 g of water for injection with stirring. 198 g of 2 mol / L sodium hydroxide solution was added to the suspension of compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.1. Water for injection was added to make the total volume 800 mL, followed by filtration with a 0.22 ⁇ m membrane filter (Millex-GV, MERCK) to obtain a preparation. 8 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass).
  • Table 1 shows the production conditions and non-defective rate of the examples and comparative examples. A photograph of a good product is shown in FIG. 1, and a photograph of a defective product is shown in FIG.
  • Test example 1 The stability test of the lyophilized preparation filled in the normal vial obtained in Example 8 and the silicon-coated vial obtained in Examples 11 (1) and (2) was performed. The stability test was carried out under the following evaluation items and evaluation conditions. Evaluation items: Related substances, pH, re-solubility, moisture Evaluation conditions: Temperature: 40 ° C Period: Up to 6 months Test results: Table 2 shows the test results of the stability test. Each evaluation item was within the target range with or without silicon coating. It was confirmed that the silicon-coated vial had the same degree of stability as the non-silicon-coated vial.
  • a photograph of a non-defective product (a lyophilized preparation having an appearance of yellow to light yellow and having no white portion). It is a photograph of a defective product (lyophilized preparation in which a white part is observed).
  • the method for producing a lyophilized preparation containing an amorphous salt A according to the present invention can be scaled up and is useful as a method for producing a lyophilized preparation of uniform quality.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The purpose of the present invention is to provide a method for producing a lyophilized preparation containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof and having uniform quality, which can be scaled up. A method for producing a lyophilized preparation containing an amorphia of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide sodium salt according to the present invention is useful as a method for producing a lyophilized preparation having uniform quality.

Description

凍結乾燥製剤の製造方法Method for producing freeze-dried preparation
　本発明は、６－フルオロ－３－ヒドロキシ－２－ピラジンカルボキサミド（以下、「化合物Ａ」と称することもある。）のナトリウム塩の非晶質を含む凍結乾燥製剤の製造方法に関する。 The present invention relates to a method for producing a freeze-dried preparation containing an amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (hereinafter sometimes referred to as “compound A”).
　近年、強毒性のインフルエンザウイルスによるパンデミックの発生が危惧されている。
　現在、インフルエンザの治療剤として、例えば、オセルタミビル、ザナミビル、ペラミビル、ラニナミビルおよびアマンタジンなどが使用されている。しかし、これらの薬剤は、経口投与が困難な患者に投与できないなどの欠点を有する。 In recent years, there is a concern about the occurrence of pandemics due to highly toxic influenza viruses.
Currently, for example, oseltamivir, zanamivir, peramivir, laninamivir, amantadine and the like are used as therapeutic agents for influenza. However, these drugs have drawbacks such as being unable to be administered to patients who are difficult to administer orally.
　化合物Ａまたはその塩は、優れた抗ウイルス活性を有し、ウイルス感染の治療剤として有用である（特許文献１）。化合物Ａのナトリウム塩およびメグルミン塩の注射剤が報告されている（特許文献２、特許文献３）。 Compound A or a salt thereof has excellent antiviral activity and is useful as a therapeutic agent for viral infection (Patent Document 1). Injectable preparations of sodium salt and meglumine salt of Compound A have been reported (Patent Documents 2 and 3).
　注射剤を製造する方法として、例えば、凍結乾燥による方法が知られている。
　一般的な凍結乾燥プロセスは、凍結工程、一次乾燥工程および二次乾燥工程などを含む。凍結工程は、製品品質を決定する重要な工程の一つである。
　凍結工程において、水は自発的に凍結せず過冷却状態を維持する。何らかの原因で過冷却度が大きくなると、凍結開始温度が低くなり、急速に凍結することで形成される氷晶のサイズが小さくなる。氷晶のサイズが小さいと、一次乾燥工程で水蒸気が効率的に昇華できず、凍結体の溶融・発泡が生じ、外観異常の製品が生じるなど、品質がばらつく原因となる。 As a method for producing an injection, for example, a method by freeze drying is known.
A typical lyophilization process includes a freezing step, a primary drying step, a secondary drying step, and the like. The freezing process is one of the important processes for determining product quality.
In the freezing process, water does not freeze spontaneously and maintains a supercooled state. If the degree of supercooling increases for some reason, the freezing start temperature decreases, and the size of ice crystals formed by rapid freezing decreases. If the size of the ice crystals is small, the water vapor cannot be sublimated efficiently in the primary drying process, and the frozen body will melt and foam, resulting in a product with an abnormal appearance.
　均一な品質を実現するため、凍結工程を制御し、さらに過冷却を抑制することが好ましい。
　なお、凍結乾燥は、試験機と生産機のスケールの相違による影響を受けやすい。試験機と生産機の形状や材質が必ずしも同一ではないこと、スケールの相違により冷却・伝熱効率が異なることなどが原因である（非特許文献１）。過冷却を抑制する方法は、試験機と同様、生産機でも実現可能な、スケールアップ適性を有することが望まれる。 In order to achieve uniform quality, it is preferable to control the freezing step and further suppress overcooling.
Note that freeze-drying is easily affected by the difference in scale between the testing machine and the production machine. This is because the shape and material of the test machine and the production machine are not necessarily the same, and the cooling / heat transfer efficiency varies depending on the scale (Non-Patent Document 1). The method for suppressing overcooling is desired to have a scale-up suitability that can be realized in a production machine as well as a test machine.
　凍結工程を制御する既存の方法として、予備冷却、徐冷化、アニーリング、添加剤などの手法が検討されてきた（特許文献４、特許文献５、特許文献６）。しかし、いずれの方法も、制御の確実さ、操作の簡便さ、スケールアップ適性などから、必ずしも満足いくものではなかった。 As an existing method for controlling the freezing process, methods such as pre-cooling, slow cooling, annealing, and additives have been studied (Patent Document 4, Patent Document 5, and Patent Document 6). However, none of these methods is always satisfactory because of certainty of control, ease of operation, scale-up suitability, and the like.
国際公開第００／１０５６９号パンフレットInternational Publication No. 00/1010569 Pamphlet 国際公開第２０１２／０４３６９６号パンフレットInternational Publication No. 2012/043696 Pamphlet 国際公開第２０１２／０４３７００号パンフレットInternational Publication No. 2012/043700 Pamphlet 特開第２００８－２３１０６７号公報JP 2008-231067 A 特許第４７５３７１７号公報Japanese Patent No. 4753717 特開第２０１２－２１４５２５号公報JP 2012-214525 A
　化合物Ａまたはその塩を含む、均一な品質の凍結乾燥製剤の、スケールアップ可能な製造方法が、求められている。 There is a need for a production method capable of scaling up a uniform quality lyophilized preparation containing Compound A or a salt thereof.
　このような状況下、本発明者らは、鋭意検討を重ねた結果、化合物Ａのナトリウム塩（以下、「塩Ａ」と称することもある。）を含む凍結乾燥製剤の外観上のばらつきに凍結工程が影響することを見出した。そして、一度溶液全体を昇温した状態から、急速に冷却することにより、冷却源の近傍と遠方の温度差に伴う対流を促進する（温度差が大きいと水の密度差が大きくなり対流しやすくする）ことで、溶液全体を速やか、かつ均一に冷却できることを見出した。そして、過冷却をほとんど発生させることなく水を凍結できることを見出した。
　本発明者らは、さらに鋭意検討を重ねた結果、
（１）冷却前における塩Ａの水溶液の温度（以下、「冷却開始温度」と称することもある。）を２０℃以上にし、一定時間以内で冷却後、凍結乾燥することで、塩Ａの非晶質を含む凍結乾燥製剤を製造できること、
（２）得られる凍結乾燥製剤は、外観上のばらつきが極めて少ない、均一な品質を有すること、
（３）本凍結工程は、容易にスケールアップ可能であること、
を見出し、本発明を完成した。 Under such circumstances, as a result of intensive investigations, the present inventors have frozen the appearance variation of a lyophilized preparation containing a sodium salt of Compound A (hereinafter sometimes referred to as “Salt A”). We found that the process affected. Then, by rapidly cooling the entire solution once it has been heated, convection associated with a temperature difference between the vicinity of the cooling source and a distance is promoted (if the temperature difference is large, the density difference of water increases and it is easy to convect) It was found that the entire solution can be cooled quickly and uniformly. And it discovered that water could be frozen almost without generating supercooling.
As a result of further intensive studies, the present inventors have
(1) The temperature of the aqueous solution of salt A before cooling (hereinafter also referred to as “cooling start temperature”) is set to 20 ° C. or higher, cooled within a certain time, and then freeze-dried, thereby The ability to produce lyophilized formulations containing crystalline material;
(2) The obtained freeze-dried preparation has uniform quality with very little variation in appearance,
(3) This freezing process can be easily scaled up;
The present invention has been completed.
　本発明は、以下を提供する。
［１］（１）６－フルオロ－３－ヒドロキシ－２－ピラジンカルボキサミドのナトリウム塩を含む水溶液の温度を、２０℃以上に調整する工程、
（２）（１）工程で得られた水溶液を、１時間以内で、－４０℃以下に冷却して凍結体を製造する工程、
（３）（２）工程で得られた凍結体を凍結乾燥する工程、
を含むことを特徴とする、６－フルオロ－３－ヒドロキシ－２－ピラジンカルボキサミドのナトリウム塩の非晶質を含む凍結乾燥製剤の製造方法。
［２］前記（１）工程の温度が、２０℃以上３０℃未満の範囲である、［１］に記載の製造方法。
［３］前記（１）工程の温度が、３０℃以上４０℃未満の範囲である、［１］に記載の製造方法。
［４］前記（１）工程の温度が、４０℃以上５０℃未満の範囲である、［１］に記載の製造方法。
［５］前記（１）工程の温度が、５０℃以上６０℃未満の範囲である、［１］に記載の製造方法。
［６］（１）６－フルオロ－３－ヒドロキシ－２－ピラジンカルボキサミドのナトリウム塩を含む水溶液の温度を、４０℃以上に調整する工程、
（２）（１）工程で得られた水溶液を、３時間以内で、－４０℃以下に冷却して凍結体を製造する工程、
（３）（２）工程で得られた凍結体を凍結乾燥する工程、
を含むことを特徴とする、６－フルオロ－３－ヒドロキシ－２－ピラジンカルボキサミドのナトリウム塩の非晶質を含む凍結乾燥製剤の製造方法。
［７］前記（１）工程の温度が、４０℃以上５０℃未満の範囲である、［６］に記載の製造方法。
［８］前記（１）工程の温度が、５０℃以上６０℃未満の範囲である、［６］に記載の製造方法。
［９］前記（３）工程の一次乾燥における水分昇華中の凍結体温度が、－３０℃以上０℃未満の範囲であり、減圧度（絶対圧力）が、１５Ｐａ以上２５Ｐａ未満の範囲である、［１］～［８］のいずれか一に記載の製造方法。 The present invention provides the following.
[1] (1) adjusting the temperature of an aqueous solution containing a sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide to 20 ° C. or higher;
(2) A step of producing a frozen body by cooling the aqueous solution obtained in the step (1) to −40 ° C. or less within 1 hour,
(3) A step of freeze-drying the frozen body obtained in the step (2),
A process for producing a freeze-dried preparation containing an amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide,
[2] The production method according to [1], wherein the temperature in the step (1) is in a range of 20 ° C. or higher and lower than 30 ° C.
[3] The production method according to [1], wherein the temperature in the step (1) is in a range of 30 ° C. or higher and lower than 40 ° C.
[4] The production method according to [1], wherein the temperature in the step (1) is in a range of 40 ° C. or higher and lower than 50 ° C.
[5] The production method according to [1], wherein the temperature in the step (1) is in a range of 50 ° C. or more and less than 60 ° C.
[6] (1) adjusting the temperature of an aqueous solution containing a sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide to 40 ° C. or higher;
(2) A step of producing a frozen body by cooling the aqueous solution obtained in step (1) to −40 ° C. or less within 3 hours,
(3) A step of freeze-drying the frozen body obtained in the step (2),
A process for producing a freeze-dried preparation containing an amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide,
[7] The production method according to [6], wherein the temperature in the step (1) is in a range of 40 ° C. or more and less than 50 ° C.
[8] The production method according to [6], wherein the temperature in the step (1) is in a range of 50 ° C. or more and less than 60 ° C.
[9] The frozen body temperature during water sublimation in the primary drying of the step (3) is in the range of −30 ° C. or more and less than 0 ° C., and the degree of vacuum (absolute pressure) is in the range of 15 Pa or more and less than 25 Pa. [1] The production method according to any one of [8].
　本発明の、塩Ａの非晶質を含む凍結乾燥製剤の製造方法は、スケールアップが可能であり、均一な品質の凍結乾燥製剤の製造方法として有用である。 The method for producing a lyophilized preparation containing an amorphous salt A according to the present invention can be scaled up and is useful as a method for producing a lyophilized preparation of uniform quality.
　以下、本発明について詳述する。 Hereinafter, the present invention will be described in detail.
　化合物Ａは、例えば、特許文献１に記載の方法によって製造することができる。なお、化合物Ａには、互変異性体である６－フルオロ－３－オキソ－３，４－ジヒドロ－２－ピラジンカルボキサミドが存在する。本発明は、この化合物も包含する。 Compound A can be produced, for example, by the method described in Patent Document 1. Compound A has tautomer 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide. The present invention also includes this compound.
　本発明の、塩Ａの非晶質を含む凍結乾燥製剤の製造方法について、以下に説明する。 The method for producing a freeze-dried preparation containing an amorphous salt A according to the present invention will be described below.
製造方法１
＜（１）工程＞
　この工程は、塩Ａを含む水溶液の温度を、２０℃以上に調整する工程である。
　塩Ａを含む水溶液は、例えば、化合物Ａ、塩基および水を混合することによって得ることができる。
　水の量は、化合物Ａに対して１０～１００倍量（ｖ/ｗ）であればよく、１０～５０倍量（ｖ/ｗ）が好ましい。
　塩基としては、例えば水酸化ナトリウム、炭酸水素ナトリウムまたは炭酸ナトリウム等が挙げられる。
　塩基の量は、水溶液のｐＨが４～１０になる量であればよく、６．５～９になる量が好ましい。
　また、塩Ａを含む水溶液は、別法として、水酸化ナトリウム、炭酸水素ナトリウムまたは炭酸ナトリウム等の水溶液および化合物Ａを混合することによって得ることもできる。
　さらに、塩Ａを含む水溶液は、別法として、塩Ａを水に溶解することによって得ることもできる。
　塩Ａを含む水溶液は、後に密封可能な容器に充填した状態で得ることが好ましい。後に密封可能な容器に充填した塩Ａを含む水溶液は、別途調整した塩Ａを含む水溶液を、密封可能な容器に充填することによって得ることができる。また、化合物Ａ、塩基および水を、後に密封可能な容器中で溶解することによって得ることもできる。
　後に密封可能な容器としては、バイアル、アンプル、シリンジまたはカートリッジ等が挙げられる。容器の内表面は、シリコンコート加工されていることが好ましい。容器の内表面がシリコンコート加工されていることで、凍結乾燥製剤の製造中に、容器が割れるのを抑制することができる。
　本発明の一態様として、冷却開始温度は、２０℃以上が好ましく、２０℃以上３０℃未満の範囲であることがより好ましい。
　本発明の別の一態様として、冷却開始温度は、２０℃以上が好ましく、３０℃以上４０℃未満の範囲であることがより好ましい。
　また、本発明の別の一態様として、冷却開始温度は、２０℃以上が好ましく、４０℃以上５０℃未満の範囲であることがより好ましい。
　さらに、本発明の別の一態様として、冷却開始温度は、２０℃以上が好ましく、５０℃以上６０℃未満の範囲であることがより好ましい。 Manufacturing method 1
<(1) Process>
This step is a step of adjusting the temperature of the aqueous solution containing the salt A to 20 ° C. or higher.
The aqueous solution containing the salt A can be obtained, for example, by mixing the compound A, a base and water.
The amount of water may be 10 to 100 times (v / w) with respect to Compound A, and preferably 10 to 50 times (v / w).
Examples of the base include sodium hydroxide, sodium hydrogen carbonate, sodium carbonate and the like.
The amount of the base is not particularly limited as long as the pH of the aqueous solution is 4 to 10, and preferably 6.5 to 9.
Alternatively, the aqueous solution containing the salt A can be obtained by mixing an aqueous solution such as sodium hydroxide, sodium bicarbonate or sodium carbonate and the compound A as an alternative method.
Furthermore, the aqueous solution containing the salt A can also be obtained by dissolving the salt A in water as an alternative method.
The aqueous solution containing the salt A is preferably obtained in a state of being filled in a container that can be sealed later. The aqueous solution containing the salt A filled in a container that can be sealed later can be obtained by filling an aqueous solution containing the separately prepared salt A into the sealable container. Alternatively, compound A, base and water can be obtained by dissolving in a container that can be sealed later.
Examples of containers that can be sealed later include vials, ampoules, syringes, and cartridges. The inner surface of the container is preferably silicon coated. Since the inner surface of the container is silicon-coated, the container can be prevented from cracking during the production of the freeze-dried preparation.
As one embodiment of the present invention, the cooling start temperature is preferably 20 ° C. or higher, and more preferably in the range of 20 ° C. or higher and lower than 30 ° C.
As another aspect of the present invention, the cooling start temperature is preferably 20 ° C. or higher, and more preferably in the range of 30 ° C. or higher and lower than 40 ° C.
As another aspect of the present invention, the cooling start temperature is preferably 20 ° C. or higher, and more preferably in the range of 40 ° C. or higher and lower than 50 ° C.
Furthermore, as another aspect of the present invention, the cooling start temperature is preferably 20 ° C. or higher, and more preferably in the range of 50 ° C. or higher and lower than 60 ° C.
＜（２）工程＞
　この工程は、（１）工程で得られた水溶液を、－４０℃以下に冷却して凍結体を製造する工程である。
　－４０℃以下まで冷却するのに要する時間は、特に限定されないが、１時間以内であることが好ましい。
　本発明の別の一態様として、冷却開始温度が４０℃以上５０℃未満の範囲である場合、または、５０℃以上である場合、－４０℃以下まで冷却するのに要する時間は、３時間以内であることが好ましく、１時間以内であることがより好ましい。
　水溶液は－４０℃以下まで冷却すればよく、具体的には例えば、－４０℃以下、－４１℃以下、－４２℃以下、－４３℃以下、－４４℃以下、－４５℃以下、－４６℃以下および－４７℃以下を挙げることができ、－４０℃以下－７０℃以上の範囲まで冷却することが好ましく、－４５℃以下－７０℃以上の範囲まで冷却することがより好ましい。
　冷却速度は、特に限定されないが、２８℃／時以上であることが好ましく、５５℃／時以上であることがより好ましく、８５℃／時以上であることがよりさらに好ましい。 <(2) Process>
This step is a step of manufacturing a frozen body by cooling the aqueous solution obtained in the step (1) to −40 ° C. or lower.
The time required for cooling to −40 ° C. or lower is not particularly limited, but is preferably within 1 hour.
As another aspect of the present invention, when the cooling start temperature is in the range of 40 ° C. or higher and lower than 50 ° C., or when it is 50 ° C. or higher, the time required for cooling to −40 ° C. or lower is within 3 hours. It is preferable that it is within 1 hour.
The aqueous solution may be cooled to −40 ° C. or lower. Specifically, for example, −40 ° C. or lower, −41 ° C. or lower, −42 ° C. or lower, −43 ° C. or lower, −44 ° C. or lower, −45 ° C. or lower, And lower than −40 ° C., preferably −40 ° C. or lower and −70 ° C. or higher, more preferably −45 ° C. or lower and −70 ° C. or higher.
The cooling rate is not particularly limited, but is preferably 28 ° C./hour or more, more preferably 55 ° C./hour or more, and still more preferably 85 ° C./hour or more.
＜（３）工程＞
　この工程は、（２）工程で得られた凍結体を凍結乾燥する工程である。
　この工程は、通常実施される凍結乾燥の方法に従って行えばよいが、例えば、一次乾燥工程および二次乾燥工程の２つの工程により、行うことができる。
　一次乾燥工程は、減圧下、凍結体を共晶点以下に維持して実施されるが、凍結体からの水分の昇華に伴って温度低下が起きるため、凍結乾燥の機器の設定温度は、共晶点以上に設定してもよい。
　水分の昇華中、凍結体の温度は、ほぼ一定に保たれる（以下、「水分昇華中の凍結体温度」と称することもある）。
　水分昇華中の凍結体温度は、－４０℃以上０℃未満であればよく、－３０℃以上０℃未満が好ましい。
　一次乾燥工程の減圧度（絶対圧力）は、特に限定されないが、５０Ｐａ以下であればよく、３０Ｐａ以下が好ましく、１５Ｐａ以上２５Ｐａ未満の範囲がより好ましい。
　昇華する水分が減少するに伴い、温度低下が緩和になり、この結果として凍結体の温度が上昇し、凍結体の温度と設定温度がほぼ一致する。通常、この時点を一次乾燥工程の完了と判断する。 <(3) Process>
This step is a step of freeze-drying the frozen body obtained in step (2).
This step may be performed in accordance with a commonly practiced freeze-drying method, and can be performed, for example, by two steps, a primary drying step and a secondary drying step.
The primary drying process is performed under reduced pressure while maintaining the frozen body below the eutectic point.However, since the temperature decreases with the sublimation of moisture from the frozen body, the set temperature of the freeze-drying equipment is the same. You may set more than a crystal point.
During the sublimation of moisture, the temperature of the frozen body is kept substantially constant (hereinafter, also referred to as “the frozen body temperature during moisture sublimation”).
The frozen body temperature during moisture sublimation may be −40 ° C. or higher and lower than 0 ° C., and preferably −30 ° C. or higher and lower than 0 ° C.
The degree of reduced pressure (absolute pressure) in the primary drying step is not particularly limited, but may be 50 Pa or less, preferably 30 Pa or less, and more preferably in the range of 15 Pa or more and less than 25 Pa.
As the moisture to sublimate decreases, the temperature drop becomes moderate. As a result, the temperature of the frozen body rises, and the temperature of the frozen body and the set temperature substantially coincide. Usually, this point is judged as the completion of the primary drying process.
　次いで、二次乾燥工程を実施する。
　二次乾燥工程は、２０℃以上で実施され、３０～６０℃が好ましく、４０～５０℃がより好ましい。
　二次乾燥工程では水分の脱離を促進させるために減圧度を高めることが好ましい。減圧度（絶対圧力）は、０．５～５０Ｐaであればよく、０．５～５Ｐａが好ましい。
　二次乾燥工程は、品温と設定温度がほぼ一致し、品温の変化がほぼなくなる時点まで行えばよい。 Next, a secondary drying step is performed.
The secondary drying step is performed at 20 ° C. or higher, preferably 30 to 60 ° C., more preferably 40 to 50 ° C.
In the secondary drying step, it is preferable to increase the degree of vacuum in order to promote moisture desorption. The degree of vacuum (absolute pressure) may be 0.5 to 50 Pa, and preferably 0.5 to 5 Pa.
The secondary drying process may be performed until the product temperature and the set temperature are substantially equal and the change in the product temperature is almost eliminated.
　この製造方法で製造された塩Ａの非晶質を含む凍結乾燥製剤は、外観上のばらつきがきわめて少ない。すなわち、この製造方法により、塩Ａの非晶質を含む、均一な品質の凍結乾燥製剤を製造することができる。 The freeze-dried preparation containing the amorphous salt A produced by this production method has very little variation in appearance. That is, by this production method, a lyophilized preparation of uniform quality containing an amorphous salt A can be produced.
　本発明の、塩Ａの非晶質を含む凍結乾燥製剤には、溶解性および／または外観の改良のための添加物を加えることができる。添加物としては、例えば、アミノ酸類、ポリエーテル類、糖類、糖アルコール類、塩類、尿素、エチル尿素、クレアチニン、ニコチン酸アミド、トロメタモール、精製大豆レシチン、卵白アルブミン、ウシ血清アルブミンおよびポリソルベート８０などが挙げられ、これらは、一種または二種以上を混合して用いることができる。 In the present invention, an additive for improving solubility and / or appearance can be added to the freeze-dried preparation containing an amorphous salt A. Examples of additives include amino acids, polyethers, saccharides, sugar alcohols, salts, urea, ethylurea, creatinine, nicotinamide, trometamol, purified soy lecithin, ovalbumin, bovine serum albumin, and polysorbate 80. These may be used alone or in combination of two or more.
　アミノ酸類としては、例えば、グリシン、Ｌ－アラニン、Ｌ－フェニルアラニン、Ｌ－バリン、Ｌ－ロイシン、Ｌ－イソロイシン、タウリン、ＤＬ－メチオニン、Ｌ－トレオニン、Ｌ－グルタミン、Ｌ－グルタミン酸ナトリウム、アセチルトリプトファンおよびＬ－ヒスチジンなどが挙げられ、Ｌ－アラニン、Ｌ－フェニルアラニン、Ｌ－バリン、Ｌ－ロイシン、Ｌ－イソロイシン、タウリン、ＤＬ－メチオニン、Ｌ－グルタミンおよびＬ－ヒスチジンが好ましく、Ｌ－ロイシン、Ｌ－イソロイシンおよびＬ－バリンがより好ましい。
　ポリエーテル類としては、例えば、ポリエチレングリコール３００、ポリエチレングリコール４００、ポリエチレングリコール６００およびポリエチレングリコール４０００が挙げられ、ポリエチレングリコール４００が好ましい。
　糖類としては、例えば、トレハロース、マルトース、ブドウ糖、乳糖、白糖、果糖、デキストランおよびシクロデキストリンなどが挙げられ、デキストラン４０が好ましい。
　糖アルコール類としては、例えば、Ｄ－ソルビトール、キシリトール、イノシトール、イソマルトースおよびＤ－マンニトールなどが挙げられる。
　塩類としては、例えば、酢酸ナトリウム、乳酸ナトリウム、Ｌ－酒石酸ナトリウム、クエン酸ナトリウム、サリチル酸ナトリウム、安息香酸ナトリウムおよびカプリル酸ナトリウムなどが挙げられる。 Examples of amino acids include glycine, L-alanine, L-phenylalanine, L-valine, L-leucine, L-isoleucine, taurine, DL-methionine, L-threonine, L-glutamine, sodium L-glutamate, acetyltryptophan And L-histidine, L-alanine, L-phenylalanine, L-valine, L-leucine, L-isoleucine, taurine, DL-methionine, L-glutamine and L-histidine are preferred, and L-leucine, L -Isoleucine and L-valine are more preferred.
Examples of polyethers include polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 4000, with polyethylene glycol 400 being preferred.
Examples of the saccharide include trehalose, maltose, glucose, lactose, sucrose, fructose, dextran, and cyclodextrin, and dextran 40 is preferable.
Examples of sugar alcohols include D-sorbitol, xylitol, inositol, isomaltose and D-mannitol.
Examples of the salts include sodium acetate, sodium lactate, sodium L-tartrate, sodium citrate, sodium salicylate, sodium benzoate and sodium caprylate.
　好ましい添加物としては、例えば、アミノ酸類、ポリエーテル類、糖類、尿素およびポリソルベート８０が挙げられる。 Preferred examples of the additive include amino acids, polyethers, saccharides, urea and polysorbate 80.
　また、本発明の製剤は、必要に応じ、通常使用される浸透圧調節剤、pH調節剤、緩衝剤、可溶化剤、安定化剤、界面活性剤、無痛化剤および／または保存剤などを添加してもよい。
　浸透圧調節剤としては、例えば、塩化ナトリウム、グリセリンおよびプロピレングリコールなどが挙げられる。
　pH調節剤および／または緩衝剤としては、例えば、塩酸、リン酸、硫酸、メタンスルホン酸、酢酸、乳酸、マレイン酸、クエン酸、酒石酸、アスコルビン酸および安息香酸などの酸；炭酸水素ナトリウム、炭酸ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、リン酸水素二ナトリウム、リン酸水素二カリウム、リン酸三ナトリウム、クエン酸二ナトリウム、デオキシコール酸ナトリウムおよび亜硫酸ナトリウムなどの塩；水酸化ナトリウム、トロメタモール、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、Ｌ－アルギニンおよびＬ－リジンなどの塩基が挙げられる。
　可溶化剤としては、例えば、マクロゴールおよび精製大豆レシチンなどが挙げられる。 In addition, the preparation of the present invention contains, as necessary, a commonly used osmotic pressure regulator, pH regulator, buffer, solubilizer, stabilizer, surfactant, soothing agent and / or preservative. It may be added.
Examples of the osmotic pressure regulator include sodium chloride, glycerin and propylene glycol.
Examples of the pH adjusting agent and / or buffering agent include acids such as hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, lactic acid, maleic acid, citric acid, tartaric acid, ascorbic acid and benzoic acid; sodium bicarbonate, carbonic acid Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, disodium citrate, sodium deoxycholate and sodium sulfite; sodium hydroxide And bases such as trometamol, monoethanolamine, diethanolamine, triethanolamine, L-arginine and L-lysine.
Examples of the solubilizer include macrogol and purified soybean lecithin.
　安定化剤としては、例えば、亜硫酸水素ナトリウム、ピロ亜硫酸ナトリウム、ピロ亜硫酸カリウム、ピロリン酸ナトリウム、チオ硫酸ナトリウム、メタスルホ安息香酸ナトリウム、ナトリウムホルムアルデヒドスルホキシレート、エチレンジアミン、エデト酸ナトリウム、チオグリコール酸、グルコン酸ナトリウム、Ｌ－グルタミン酸カリウム、Ｌ－リジン－Ｌ－グルタマート、コンドロイチン硫酸ナトリウム、アルブミン、Ｌ－アスパラギン酸、Ｌ－システインおよびジブチルヒドロキシトルエンなどが挙げられる。
　界面活性剤としては、例えば、ソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンポリオキシプロピレングリコールおよびポリソルベートなどが挙げられる。
　無痛化剤としては、例えば、リドカイン、プロカイン、メプリルカインおよびベンジルアルコールなどが挙げられる。
　保存剤としては、例えば、クレゾール、フェノール、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、ベンザルコニウム塩化物およびベンゼトニウム塩化物などが挙げられる。 Examples of stabilizers include sodium bisulfite, sodium pyrosulfite, potassium pyrosulfite, sodium pyrophosphate, sodium thiosulfate, sodium metasulfobenzoate, sodium formaldehyde sulfoxylate, ethylenediamine, sodium edetate, thioglycolic acid, glucone. Examples thereof include sodium acid, potassium L-glutamate, L-lysine-L-glutamate, sodium chondroitin sulfate, albumin, L-aspartic acid, L-cysteine, and dibutylhydroxytoluene.
Examples of the surfactant include sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene polyoxypropylene glycol, and polysorbate.
Examples of soothing agents include lidocaine, procaine, meprilucaine, and benzyl alcohol.
Examples of the preservative include cresol, phenol, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzalkonium chloride and benzethonium chloride.
　本発明の製造方法で得られる凍結乾燥製剤中の有効成分の投与量は、用法、患者の年齢、性別、疾患の形態、その他の条件などに応じて適宜決定されるが、通常成人に対して１日０．１～２００ｍｇ/ｋｇを投与すればよい。
　本発明の製造方法で得られる凍結乾燥製剤中の化合物Ａの含有量は、１０～６０００ｍｇ、好ましくは、１００～２０００ｍｇである。
　本発明の製造方法で得られる凍結乾燥製剤中に配合される、溶解性および／または外観の改良のための添加物は、化合物Ａに対し、０～１００％（ｗ/ｗ）、好ましくは０～５０％（ｗ/ｗ）である。 The dose of the active ingredient in the freeze-dried preparation obtained by the production method of the present invention is appropriately determined according to the usage, patient age, sex, disease form, other conditions, etc. It is sufficient to administer 0.1 to 200 mg / kg per day.
The content of Compound A in the lyophilized preparation obtained by the production method of the present invention is 10 to 6000 mg, preferably 100 to 2000 mg.
The additive for improving solubility and / or appearance, which is incorporated in the lyophilized preparation obtained by the production method of the present invention, is 0 to 100% (w / w), preferably 0, relative to Compound A. ~ 50% (w / w).
　以下、本発明を実施例および試験例で説明するが、本発明はこれらに限定されるものではない。 Hereinafter, although an example and a test example explain the present invention, the present invention is not limited to these.
＜凍結乾燥製剤の品質（外観）確認方法＞
　すべての凍結乾燥製剤（品温を測定したバイアルは除く）の外観を目視観察し、以下の通り２段階で判定した。
　　　良品：外観が黄色～淡黄色で、白色部分が認められない凍結乾燥製剤
　　　不良品：白色部分が認められる凍結乾燥製剤
　下式により良品率を求めた。
　　　良品率（％）＝（良品の数／（良品の数＋不良品の数））×１００ <Quality (appearance) confirmation method of freeze-dried preparation>
The appearance of all lyophilized preparations (excluding vials whose product temperature was measured) was visually observed and judged in two stages as follows.
Non-defective product: freeze-dried preparation with a yellow to pale yellow appearance and no white part Defective product: lyophilized preparation with a white part observed The percentage of good products was determined by the following formula.
Non-defective product rate (%) = (Number of good products / (Number of good products + Number of defective products)) × 100
実施例１
　化合物Ａ 42.19gを注射用水350mLに撹拌下、懸濁させた。別途、水酸化ナトリウム10.66gを注射用水250mLに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とした。注射用水を加え、全量を700mLとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：100%
　凍結乾燥の方法
１．棚温度を50℃に調整し、同温度で180分間保持した。
２．53分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で35時間保持した。水分昇華中の凍結体温度は、－13.2～－3.3℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で24時間保持した。
なお、実施例において、棚温度とは、凍結乾燥機の棚温度を意味する。 Example 1
42.19 g of Compound A was suspended in 350 mL of water for injection with stirring. Separately, 10.66 g of sodium hydroxide was dissolved in 250 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 100%
Method of lyophilization The shelf temperature was adjusted to 50 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours. The frozen body temperature during water sublimation was -13.2 to -3.3 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
In addition, in an Example, shelf temperature means the shelf temperature of a freeze dryer.
実施例２
　化合物Ａ 181gを注射用水1450gに撹拌下、懸濁させた。別途、水酸化ナトリウム46gを注射用水1100gに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを7.6とした。注射用水を加え、全量を3Lとした後、750mL分取し、0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とした。0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：100%
　凍結乾燥の方法
１．棚温度を40℃に調整し、同温度で180分間保持した。
２．53分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で15時間保持した。水分昇華中の凍結体温度は、－13.7～－6.0℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で22時間保持した。 Example 2
181 g of Compound A was suspended in 1450 g of water for injection under stirring. Separately, 46 g of sodium hydroxide was dissolved in 1100 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 7.6. Water for injection was added to make the total volume 3 L, then 750 mL was taken, 0.2 mol / kg sodium hydroxide solution was added, and the pH was adjusted to 8.0. The solution was filtered through a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 100%
Method of lyophilization The shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the shelf temperature was raised to 25 ° C., and the pressure and temperature were maintained for 15 hours. The frozen body temperature during water sublimation was -13.7 to -6.0 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 22 hours.
実施例３
　化合物Ａ 42.16gを注射用水350mLに撹拌下、懸濁させた。別途、水酸化ナトリウム10.65gを注射用水250mLに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とした。注射用水を加え、全量を700mLとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：100%
　凍結乾燥の方法
１．棚温度を30℃に調整し、同温度で180分間保持した。
２．53分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で35時間保持した。水分昇華中の凍結体温度は、－6.1℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で24時間保持した。 Example 3
42.16 g of Compound A was suspended in 350 mL of water for injection with stirring. Separately, 10.65 g of sodium hydroxide was dissolved in 250 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 100%
Method of lyophilization The shelf temperature was adjusted to 30 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours. The frozen body temperature during water sublimation was −6.1 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
実施例４
　化合物Ａ 120.41gを注射用水800mLに撹拌下、懸濁させた。別途、水酸化ナトリウム30.73gを注射用水300mLに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とした。注射用水を加え、全量を2000mLとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：100%
　凍結乾燥の方法
１．棚温度を20℃に調整し、同温度で180分間保持した。
２．41分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で35時間保持した。水分昇華中の凍結体温度は、－11.9～－3.0℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で24時間保持した。 Example 4
120.41 g of Compound A was suspended in 800 mL of water for injection with stirring. Separately, 30.73 g of sodium hydroxide was dissolved in 300 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make a total volume of 2000 mL, followed by filtration through a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 100%
Method of lyophilization The shelf temperature was adjusted to 20 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 41 minutes and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours. The frozen body temperature during water sublimation was -11.9 to -3.0 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
実施例５
　化合物Ａ 42.19gを注射用水300gに撹拌下、懸濁させた。別途、水酸化ナトリウム10.86gを注射用水299gに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とした。注射用水を加え、全量を700mLとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：100%
　凍結乾燥の方法
１．棚温度を40℃に調整し、同温度で180分間保持した。
２．53分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度0℃に昇温し、同圧力、同温度で66時間保持した。水分昇華中の凍結体温度は、－5.5℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で20時間保持した。 Example 5
42.19 g of Compound A was suspended in 300 g of water for injection with stirring. Separately, 10.86 g of sodium hydroxide was dissolved in 299 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 100%
Method of lyophilization The shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the shelf temperature was raised to 0 ° C., and the pressure and temperature were maintained for 66 hours. The frozen body temperature during water sublimation was −5.5 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of pressure reduction (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 20 hours.
実施例６
　化合物Ａ 422gを注射用水3001gに撹拌下、懸濁させた。別途、水酸化ナトリウム107gを注射用水2501gに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.5とした。注射用水を加え、全量を7Lとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　得られた凍結乾燥製剤（良品）の粉末Ｘ線回折で、非晶質に特有の、低角度領域(20°～30°)におけるブロードなハローパターンを認めた。本凍結乾燥製剤（良品）は非晶質であることを確認した。
　良品率：99%
　凍結乾燥の方法
１．棚温度を40℃に調整し、同温度で180分間保持した。
２．53分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度を（絶対圧力）20Paに設定し、棚温度30℃に昇温し、同圧力、同温度で27時間保持した。水分昇華中の凍結体温度は、－15.0～－7.4℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.2Paで、同温度で23時間保持した。 Example 6
422 g of Compound A was suspended in 3001 g of water for injection with stirring. Separately, 107 g of sodium hydroxide was dissolved in 2501 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.5. Water for injection was added to make the total volume 7 L, followed by filtration with a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
In the powder X-ray diffraction of the obtained freeze-dried preparation (good product), a broad halo pattern in a low angle region (20 ° to 30 °) peculiar to amorphous was observed. This lyophilized preparation (good product) was confirmed to be amorphous.
Non-defective rate: 99%
Method of lyophilization The shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents.
3. The degree of vacuum was set to 20 Pa (absolute pressure), the shelf temperature was raised to 30 ° C., and the pressure and temperature were maintained for 27 hours. The frozen body temperature during water sublimation was -15.0 to -7.4 ° C.
4). The shelf temperature was raised to 50 ° C., and the pressure was reduced to 1.2 Pa (absolute pressure) at the same temperature for 23 hours.
実施例７
　化合物Ａ 181gを注射用水1450gに撹拌下、懸濁させた。別途、水酸化ナトリウム46gを注射用水1100gに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを7.6とした。注射用水を加え、全量を3Lとした後、750mL分取し、0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.5とした。0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：100%
　凍結乾燥の方法
１．棚温度を40℃に調整し、同温度で180分間保持した。
２．53分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で15時間保持した。水分昇華中の凍結体温度は、－13.7～－6.0℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で22時間保持した。 Example 7
181 g of Compound A was suspended in 1450 g of water for injection under stirring. Separately, 46 g of sodium hydroxide was dissolved in 1100 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 7.6. Water for injection was added to make the total volume 3 L, then 750 mL was taken, 0.2 mol / kg sodium hydroxide solution was added, and the pH was adjusted to 8.5. The solution was filtered through a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 100%
Method of lyophilization The shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the shelf temperature was raised to 25 ° C., and the pressure and temperature were maintained for 15 hours. The frozen body temperature during water sublimation was -13.7 to -6.0 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 22 hours.
実施例８
　化合物Ａ 4.518kgを注射用水36kgに撹拌下、懸濁させた。別途、水酸化ナトリウム1.151kgを注射用水10kgに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とした。注射用水を加え、全量を77.7kgとした後、0.22μmメンブランフィルター(OpticapXL4 Capsule、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(V10-F8W、材質D713、コーティングRB2-40、大協精工)を半打栓し、凍結乾燥機(DFB2000-2MS-ST/CIP、チャンバー容積3.9m3、棚5段仕様、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：98%
　凍結乾燥の方法
１．棚温度を40℃に調整し、同温度で180分間保持した。
２．3時間で棚温度－50℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で58時間保持した。水分昇華中の凍結体温度は、－6.0℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）0.5Paで、同温度で26.5時間保持した。 Example 8
Compound A (4.518 kg) was suspended in 36 kg of water for injection under stirring. Separately, 1.151 kg of sodium hydroxide was dissolved in 10 kg of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 77.7 kg, followed by filtration with a 0.22 μm membrane filter (OpticapXL4 Capsule, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (V10-F8W, material D713, coating RB2-40, Daikyo Seiko) into a filled vial, and freeze-dryer (DFB2000-2MS-ST / CIP, chamber volume 3.9m 3 , shelf 5 A freeze-dried preparation was obtained after freeze-drying using a tiered specification (Ulvac) and sealed.
Non-defective rate: 98%
Method of lyophilization The shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature −50 ° C. in 3 hours and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and maintained at the same pressure and the same temperature for 58 hours. The frozen body temperature during water sublimation was −6.0 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 0.5 Pa, and the same temperature was maintained for 26.5 hours.
実施例９
　化合物Ａ 42.17gを注射用水350mLに撹拌下、懸濁させた。別途、水酸化ナトリウム10.65gを注射用水250mLに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.5とした。注射用水を加え、全量を700mLとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：93%
　凍結乾燥の方法
１．棚温度を40℃に調整し、同温度で180分間保持した。
２．3時間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で35時間保持した。水分昇華中の凍結体温度は、－5.1～－4.3℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で24時間保持した。 Example 9
42.17 g of Compound A was suspended in 350 mL of water for injection with stirring. Separately, 10.65 g of sodium hydroxide was dissolved in 250 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.5. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 93%
Method of lyophilization The shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 3 hours and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours. The frozen body temperature during water sublimation was -5.1 to -4.3 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
実施例１０
　化合物Ａ 181gを注射用水1450gに撹拌下、懸濁させた。別途、水酸化ナトリウム46gを注射用水1100gに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを7.6とした。注射用水を加え、全量を3Lとした後、750mL分取し、0.2mol/kg水酸化ナトリウム溶液を添加し、pHを9.0とした。0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：100%
　凍結乾燥の方法
１．棚温度を40℃に調整し、同温度で180分間保持した。
２．53分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で15時間保持した。水分昇華中の凍結体温度は、－13.7～－6.0℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で22時間保持した。 Example 10
181 g of Compound A was suspended in 1450 g of water for injection under stirring. Separately, 46 g of sodium hydroxide was dissolved in 1100 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 7.6. Water for injection was added to make the total volume 3 L, then 750 mL was taken, 0.2 mol / kg sodium hydroxide solution was added, and the pH was adjusted to 9.0. The solution was filtered through a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 100%
Method of lyophilization The shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the shelf temperature was raised to 25 ° C., and the pressure and temperature were maintained for 15 hours. The frozen body temperature during water sublimation was -13.7 to -6.0 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 22 hours.
実施例１１
　化合物Ａ 120.48gを注射用水900gに撹拌下、懸濁させた。別途、水酸化ナトリウム30.68gを注射用水700gに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とし、注射用水を加え、全量を2Lとした。0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　実施例１１（１）
　　実施例１１で得た調製液を10 mL、東京高分子製 (C0036)のシリコンコート加工されているバイアルに充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
実施例１１（２）
　実施例１１で得た調製液を10 mL、ナミコス製 (271116)のシリコンコート加工されているバイアルに充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　実施例１１（１）及び（２）の凍結乾燥の方法
１．棚温度を40℃に調整し、同温度で180分間保持した。
２．53分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で33時間保持した。水分昇華中の凍結体温度は、-15.1～-8.5℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で23時間保持した。
　シリコンコート加工されたバイアル（実施例１１（１）及び（２））は、シリコンコート加工されていないバイアル（実施例８）と同等の良品率を有することが確認できた。また、シリコンコート加工されたバイアルに破瓶はなかった。 Example 11
120.48 g of Compound A was suspended in 900 g of water for injection with stirring. Separately, 30.68 g of sodium hydroxide was dissolved in 700 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, a 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0, and water for injection was added to make the total volume 2 L. The solution was filtered through a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Example 11 (1)
10 mL of the prepared solution obtained in Example 11 was filled into a silicon-coated vial made of Tokyo Polymer (C0036). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Example 11 (2)
10 mL of the preparation obtained in Example 11 was filled into a silicon-coated vial made by Namikos (271116). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Method of freeze-drying of Example 11 (1) and (2) The shelf temperature was adjusted to 40 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and maintained at the same pressure and the same temperature for 33 hours. The frozen body temperature during sublimation of water was -15.1 to -8.5 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of decompression (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 23 hours.
It was confirmed that the silicon-coated vials (Examples 11 (1) and (2)) had the same non-defective rate as the non-silicon-coated vials (Example 8). There were no broken bottles in the silicon coated vials.
比較例１
　化合物Ａ 42.18gを注射用水299gに撹拌下、懸濁させた。別途、水酸化ナトリウム10.59gを注射用水293gに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とした。注射用水を加え、全量を700mLとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：82%
　凍結乾燥の方法
１．棚温度を5℃に調整し、同温度で180分間保持した。
２．53分間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で35時間保持した。水分昇華中の凍結体温度は、－6.1℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で24時間保持した。 Comparative Example 1
42.18 g of Compound A was suspended in 299 g of water for injection with stirring. Separately, 10.59 g of sodium hydroxide was dissolved in 293 g of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 82%
Method of lyophilization The shelf temperature was adjusted to 5 ° C and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 53 minutes and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours. The frozen body temperature during water sublimation was −6.1 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 24 hours.
比較例２
　化合物Ａ 42.25gを注射用水300mLに撹拌下、懸濁させた。別途、水酸化ナトリウム10.47gを注射用水300mLに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とした。注射用水を加え、全量を700mLとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：53%
　凍結乾燥の方法
１．棚温度を30℃に調整し、同温度で180分間保持した。
２．3時間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で34時間保持した。水分昇華中の凍結体温度は、－9.9～－6.3℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.1Pa、同温度で4時間保持した。 Comparative Example 2
42.25 g of Compound A was suspended in 300 mL of water for injection with stirring. Separately, 10.47 g of sodium hydroxide was dissolved in 300 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 53%
Method of lyophilization The shelf temperature was adjusted to 30 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 3 hours and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and maintained at the same pressure and the same temperature for 34 hours. The frozen body temperature during water sublimation was -9.9 to -6.3 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.1 Pa, and the same temperature was maintained for 4 hours.
比較例３
　化合物Ａ 42.20gを注射用水350mLに撹拌下、懸濁させた。別途、水酸化ナトリウム10.73gを注射用水250mLに撹拌下、溶解させた。前記水酸化ナトリウム溶液を、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.0とした。注射用水を加え、全量を700mLとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を10mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　良品率：73%
　凍結乾燥の方法
１．棚温度を20℃に調整し、同温度で180分間保持した。
２．3時間で棚温度－47℃まで冷却し、内容物を凍結した。
３．減圧度（絶対圧力）を20Paに設定し、棚温度25℃に昇温し、同圧力、同温度で35時間保持した。水分昇華中の凍結体温度は、－16.7～－6.0℃だった。
４．棚温度を50℃に昇温し、減圧度（絶対圧力）1.2Pa、同温度で24時間保持した。 Comparative Example 3
42.20 g of Compound A was suspended in 350 mL of water for injection with stirring. Separately, 10.73 g of sodium hydroxide was dissolved in 250 mL of water for injection with stirring. The sodium hydroxide solution was added to the suspension of Compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.0. Water for injection was added to make the total volume 700 mL, followed by filtration with a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
Each 10 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
Non-defective rate: 73%
Method of lyophilization The shelf temperature was adjusted to 20 ° C. and held at that temperature for 180 minutes.
2. Cooled to shelf temperature -47 ° C in 3 hours and frozen contents.
3. The degree of vacuum (absolute pressure) was set to 20 Pa, the temperature was raised to a shelf temperature of 25 ° C., and the pressure and temperature were maintained for 35 hours. The frozen body temperature during water sublimation was -16.7 to -6.0 ° C.
4). The shelf temperature was raised to 50 ° C., and the degree of vacuum (absolute pressure) was 1.2 Pa, and the same temperature was maintained for 24 hours.
比較例４
　化合物Ａ 60gを注射用水346gに撹拌下、懸濁させた。２mol/L水酸化ナトリウム溶液198gを、化合物Ａの懸濁液に加えた。撹拌下、溶解を確認した後に0.2mol/kg水酸化ナトリウム溶液を添加し、pHを8.1とした。注射用水を加え、全量を800mLとした後、0.22μmメンブランフィルター(Millex-GV、MERCK)で濾過し、調製液を得た。
　調製液を8mLずつバイアル(V-K 20ML、不二硝子)に充填した。充填済バイアルに、ゴム栓(F10-91-3、住友ゴム工業)を半打栓し、凍結乾燥機(DFM-05B-S、Ulvac)を用いて凍結乾燥後、密栓し、凍結乾燥製剤を得た。
　得られた凍結乾燥製剤（良品）の粉末Ｘ線回折で、非晶質に特有の、低角度領域(20°～30°)におけるブロードなハローパターンを認めた。本凍結乾燥製剤（良品）は非晶質であることを確認した。
　良品率：72%
　凍結乾燥の方法
１．25℃より2時間で棚温度－45℃まで冷却し、内容物を凍結した。
２．減圧度（絶対圧力）を1.1Paに設定し、棚温度40℃に昇温し、同圧力、同温度で53時間保持した。水分昇華中の凍結体温度は、－13.1～－2.2℃だった。 Comparative Example 4
60 g of Compound A was suspended in 346 g of water for injection with stirring. 198 g of 2 mol / L sodium hydroxide solution was added to the suspension of compound A. After confirming dissolution under stirring, 0.2 mol / kg sodium hydroxide solution was added to adjust the pH to 8.1. Water for injection was added to make the total volume 800 mL, followed by filtration with a 0.22 μm membrane filter (Millex-GV, MERCK) to obtain a preparation.
8 mL of the prepared solution was filled into a vial (VK 20ML, Fuji Glass). Half-plug a rubber stopper (F10-91-3, Sumitomo Rubber Industries) into a filled vial, freeze-dry using a freeze dryer (DFM-05B-S, Ulvac), seal tightly, and prepare a freeze-dried preparation. Obtained.
In the powder X-ray diffraction of the obtained freeze-dried preparation (good product), a broad halo pattern in a low angle region (20 ° to 30 °) peculiar to amorphous was observed. This lyophilized preparation (good product) was confirmed to be amorphous.
Non-defective rate: 72%
Method of lyophilization 1. The contents were cooled to a shelf temperature of −45 ° C. in 2 hours from 25 ° C., and the contents were frozen.
2. The decompression degree (absolute pressure) was set to 1.1 Pa, the shelf temperature was raised to 40 ° C., and the same pressure and temperature were maintained for 53 hours. The frozen body temperature during water sublimation was -13.1 to -2.2 ° C.
実施例および比較例の製造条件、良品率を表１に示す。良品の写真を図１に、不良品の写真を図２に示す。 Table 1 shows the production conditions and non-defective rate of the examples and comparative examples. A photograph of a good product is shown in FIG. 1, and a photograph of a defective product is shown in FIG.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
試験例１
　実施例８で得られた通常バイアル及び実施例１１（１）、（２）で得られたシリコンコート加工バイアルに充填された凍結乾燥製剤の安定性試験を実施した。安定性試験は、以下の評価項目、評価条件で実施した。
　評価項目：類縁物質、pH、再溶解性、水分
　評価条件：温度： 40℃　期間：最長6カ月
　試験結果：安定性試験の試験結果を表２に示す。
　シリコンコート加工の有無にかかわらず、各評価項目は目標の範囲内だった。シリコンコート加工されたバイアルは、シリコンコート加工されていないバイアルと同程度の安定性を有することが確認できた。
Figure JPOXMLDOC01-appb-T000002
  Test example 1
The stability test of the lyophilized preparation filled in the normal vial obtained in Example 8 and the silicon-coated vial obtained in Examples 11 (1) and (2) was performed. The stability test was carried out under the following evaluation items and evaluation conditions.
Evaluation items: Related substances, pH, re-solubility, moisture Evaluation conditions: Temperature: 40 ° C Period: Up to 6 months Test results: Table 2 shows the test results of the stability test.
Each evaluation item was within the target range with or without silicon coating. It was confirmed that the silicon-coated vial had the same degree of stability as the non-silicon-coated vial.
Figure JPOXMLDOC01-appb-T000002
良品（外観が黄色～淡黄色で、白色部分が認められない凍結乾燥製剤）の写真である。A photograph of a non-defective product (a lyophilized preparation having an appearance of yellow to light yellow and having no white portion). 不良品（白色部分が認められる凍結乾燥製剤）の写真である。It is a photograph of a defective product (lyophilized preparation in which a white part is observed).
　本発明の、塩Ａの非晶質を含む凍結乾燥製剤の製造方法は、スケールアップが可能であり、均一な品質の凍結乾燥製剤の製造方法として有用である。 The method for producing a lyophilized preparation containing an amorphous salt A according to the present invention can be scaled up and is useful as a method for producing a lyophilized preparation of uniform quality.

Claims (9)

  1. （１）６－フルオロ－３－ヒドロキシ－２－ピラジンカルボキサミドのナトリウム塩を含む水溶液の温度を、２０℃以上に調整する工程、
    （２）（１）工程で得られた水溶液を、１時間以内で、－４０℃以下に冷却して凍結体を製造する工程、
    （３）（２）工程で得られた凍結体を凍結乾燥する工程、
    を含むことを特徴とする、６－フルオロ－３－ヒドロキシ－２－ピラジンカルボキサミドのナトリウム塩の非晶質を含む凍結乾燥製剤の製造方法。     (1) adjusting the temperature of an aqueous solution containing a sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide to 20 ° C. or higher;
    (2) A step of producing a frozen body by cooling the aqueous solution obtained in the step (1) to −40 ° C. or less within 1 hour,
    (3) A step of freeze-drying the frozen body obtained in the step (2),
    A process for producing a freeze-dried preparation containing an amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide,
  2. 前記（１）工程の温度が、２０℃以上３０℃未満の範囲である、請求項１に記載の製造方法。 The manufacturing method of Claim 1 whose temperature of the said (1) process is the range of 20 to 30 degreeC.
  3. 前記（１）工程の温度が、３０℃以上４０℃未満の範囲である、請求項１に記載の製造方法。 The manufacturing method of Claim 1 whose temperature of the said (1) process is the range of 30 to 40 degreeC.
  4. 前記（１）工程の温度が、４０℃以上５０℃未満の範囲である、請求項１に記載の製造方法。 The manufacturing method of Claim 1 whose temperature of the said (1) process is the range of 40 to 50 degreeC.
  5. 前記（１）工程の温度が、５０℃以上６０℃未満の範囲である、請求項１に記載の製造方法。 The manufacturing method of Claim 1 whose temperature of the said (1) process is the range of 50 to 60 degreeC.
  6. （１）６－フルオロ－３－ヒドロキシ－２－ピラジンカルボキサミドのナトリウム塩を含む水溶液の温度を、４０℃以上に調整する工程、
    （２）（１）工程で得られた水溶液を、３時間以内で、－４０℃以下に冷却して凍結体を製造する工程、
    （３）（２）工程で得られた凍結体を凍結乾燥する工程、
    を含むことを特徴とする、６－フルオロ－３－ヒドロキシ－２－ピラジンカルボキサミドのナトリウム塩の非晶質を含む凍結乾燥製剤の製造方法。     (1) adjusting the temperature of an aqueous solution containing a sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide to 40 ° C. or higher;
    (2) A step of producing a frozen body by cooling the aqueous solution obtained in step (1) to −40 ° C. or less within 3 hours,
    (3) A step of freeze-drying the frozen body obtained in the step (2),
    A process for producing a freeze-dried preparation containing an amorphous sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide,
  7. 前記（１）工程の温度が、４０℃以上５０℃未満の範囲である、請求項６に記載の製造方法。 The manufacturing method of Claim 6 whose temperature of the said (1) process is the range of 40 to 50 degreeC.
  8. 前記（１）工程の温度が、５０℃以上６０℃未満の範囲である、請求項６に記載の製造方法。 The manufacturing method of Claim 6 whose temperature of the said (1) process is the range of 50 to 60 degreeC.
  9. 前記（３）工程の一次乾燥における水分昇華中の凍結体温度が、－３０℃以上０℃未満の範囲であり、減圧度（絶対圧力）が、１５Ｐａ以上２５Ｐａ未満の範囲である、請求項１～８のいずれか一項に記載の製造方法。 The frozen body temperature during water sublimation in the primary drying of the step (3) is in the range of −30 ° C. or more and less than 0 ° C., and the degree of vacuum (absolute pressure) is in the range of 15 Pa or more and less than 25 Pa. The production method according to any one of 1 to 8.
PCT/JP2017/024032 2016-06-30 2017-06-29 Method for producing lyophilized preparation WO2018003946A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2016130374 2016-06-30
JP2016-130374 2016-06-30

Publications (1)

Publication Number Publication Date
WO2018003946A1 true WO2018003946A1 (en) 2018-01-04

Family

ID=60787250

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2017/024032 WO2018003946A1 (en) 2016-06-30 2017-06-29 Method for producing lyophilized preparation

Country Status (2)

Country Link
TW (1) TW201808291A (en)
WO (1) WO2018003946A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019131223A1 (en) * 2017-12-28 2019-07-04 富士フイルム富山化学株式会社 Method for producing freeze-dried formulation
WO2022131112A1 (en) * 2020-12-18 2022-06-23 富士フイルム富山化学株式会社 Pharmaceutical composition
WO2022131117A1 (en) * 2020-12-18 2022-06-23 富士フイルム富山化学株式会社 Pharmaceutical composition

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111228226B (en) * 2020-03-06 2021-12-28 瑞阳制药有限公司 Freeze-dried preparation of pyrrosia faberi for injection and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012043696A1 (en) * 2010-09-30 2012-04-05 富山化学工業株式会社 Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide
WO2012043700A1 (en) * 2010-09-30 2012-04-05 富山化学工業株式会社 Sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012043696A1 (en) * 2010-09-30 2012-04-05 富山化学工業株式会社 Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide
WO2012043700A1 (en) * 2010-09-30 2012-04-05 富山化学工業株式会社 Sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019131223A1 (en) * 2017-12-28 2019-07-04 富士フイルム富山化学株式会社 Method for producing freeze-dried formulation
CN111556752A (en) * 2017-12-28 2020-08-18 富士胶片富山化学株式会社 Method for producing lyophilized preparation
JPWO2019131223A1 (en) * 2017-12-28 2020-12-17 富士フイルム富山化学株式会社 Manufacturing method of lyophilized preparation
EP3733182A4 (en) * 2017-12-28 2021-09-01 FUJIFILM Toyama Chemical Co., Ltd. Method for producing freeze-dried formulation
JP7218305B2 (en) 2017-12-28 2023-02-06 富士フイルム富山化学株式会社 Method for producing lyophilized formulation
US11679083B2 (en) 2017-12-28 2023-06-20 Fujifilm Toyama Chemical Co., Ltd. Method for producing freeze-dried formulation
WO2022131112A1 (en) * 2020-12-18 2022-06-23 富士フイルム富山化学株式会社 Pharmaceutical composition
WO2022131117A1 (en) * 2020-12-18 2022-06-23 富士フイルム富山化学株式会社 Pharmaceutical composition

Also Published As

Publication number Publication date
TW201808291A (en) 2018-03-16

Similar Documents

Publication Publication Date Title
US9096547B2 (en) Sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide
US9090571B2 (en) Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide
JP7218305B2 (en) Method for producing lyophilized formulation
WO2018003946A1 (en) Method for producing lyophilized preparation
US10253031B2 (en) Stable pemetrexed arginine salt and compositions comprising it
WO2017002030A1 (en) Stable liquid formulations of melphalan
EP3013316A1 (en) Stable intravenous formulation
RU2772613C2 (en) Method for production of lyophilized drug
JP6706988B2 (en) Pharmaceutical composition containing bortezomib

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17820300

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17820300

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP