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WO2018003946A1 - Procédé de production d'une préparation lyophilisée - Google Patents

Procédé de production d'une préparation lyophilisée Download PDF

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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
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WIPO (PCT)
Prior art keywords
temperature
freeze
water
sodium hydroxide
added
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Ceased
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PCT/JP2017/024032
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English (en)
Japanese (ja)
Inventor
大野　誠
貴文 廣田
伊織 溝垣
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Toyama Chemical Co Ltd
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Toyama Chemical Co Ltd
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    • 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.

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Abstract

Le but de la présente invention est de fournir un procédé de production d'une préparation lyophilisée contenant du 6-fluoro-3-hydroxy-2-pyrazinecarboxamide ou d'un sel de celui-ci et ayant une qualité uniforme, qui peut être mis à l'échelle. Selon la présente invention, un procédé de production d'une préparation lyophilisée contenant un amorphe de sel de sodium 6-fluoro-3-hydroxy-2-pyrazinecarboxamide est utile en tant que procédé de production d'une préparation lyophilisée ayant une qualité uniforme.
PCT/JP2017/024032 2016-06-30 2017-06-29 Procédé de production d'une préparation lyophilisée Ceased WO2018003946A1 (fr)

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WO2019131223A1 (fr) * 2017-12-28 2019-07-04 富士フイルム富山化学株式会社 Procédé de production de préparation lyophilisée
WO2022131112A1 (fr) * 2020-12-18 2022-06-23 富士フイルム富山化学株式会社 Composition pharmaceutique
WO2022131117A1 (fr) * 2020-12-18 2022-06-23 富士フイルム富山化学株式会社 Composition pharmaceutique

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CN111228226B (zh) * 2020-03-06 2021-12-28 瑞阳制药有限公司 一种供注射用法匹拉韦的冻干制剂及其制备方法

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WO2012043700A1 (fr) * 2010-09-30 2012-04-05 富山化学工業株式会社 Sel sodique de 6-fluoro-3-hydroxy-2-pyrazine carboxamide

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WO2012043696A1 (fr) * 2010-09-30 2012-04-05 富山化学工業株式会社 Sel de méglumine de 6-fluoro-3-hydroxy-2-pyrazine carboxamide
WO2012043700A1 (fr) * 2010-09-30 2012-04-05 富山化学工業株式会社 Sel sodique de 6-fluoro-3-hydroxy-2-pyrazine carboxamide

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Publication number Priority date Publication date Assignee Title
WO2019131223A1 (fr) * 2017-12-28 2019-07-04 富士フイルム富山化学株式会社 Procédé de production de préparation lyophilisée
CN111556752A (zh) * 2017-12-28 2020-08-18 富士胶片富山化学株式会社 冻干制剂的制造方法
JPWO2019131223A1 (ja) * 2017-12-28 2020-12-17 富士フイルム富山化学株式会社 凍結乾燥製剤の製造方法
EP3733182A4 (fr) * 2017-12-28 2021-09-01 FUJIFILM Toyama Chemical Co., Ltd. Procédé de production de préparation lyophilisée
JP7218305B2 (ja) 2017-12-28 2023-02-06 富士フイルム富山化学株式会社 凍結乾燥製剤の製造方法
US11679083B2 (en) 2017-12-28 2023-06-20 Fujifilm Toyama Chemical Co., Ltd. Method for producing freeze-dried formulation
WO2022131112A1 (fr) * 2020-12-18 2022-06-23 富士フイルム富山化学株式会社 Composition pharmaceutique
WO2022131117A1 (fr) * 2020-12-18 2022-06-23 富士フイルム富山化学株式会社 Composition pharmaceutique

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