US20130217708A1 - Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide - Google Patents

Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide Download PDF

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US20130217708A1
US20130217708A1 US13/877,037 US201113877037A US2013217708A1 US 20130217708 A1 US20130217708 A1 US 20130217708A1 US 201113877037 A US201113877037 A US 201113877037A US 2013217708 A1 US2013217708 A1 US 2013217708A1
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lyophilized
preparation
crystal
salt
solution
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Keiko Takakura
Namika Nakamatsu
Sakiko Takeshima
Takayoshi Nakashima
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Toyama Chemical Co Ltd
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Toyama Chemical Co Ltd
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Assigned to TOYAMA CHEMICAL CO., LTD. reassignment TOYAMA CHEMICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NAKAMATSU, NAMIKA, NAKASHIMA, TAKAYOSHI, TAKAKURA, KEIKO, TAKESHIMA, SAKIKO
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • 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
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/08—Solutions
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton

Definitions

  • the present invention relates to a meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (hereinafter referred to as “Compound A”), an injectable preparation containing the same and a process thereof
  • pandemic has been caused by H1N1 influenza virus and occurrence of pandemic by a further virulent virus in the future is a concern.
  • Oseltamivir cannot be administered to patients having difficulty in oral administration. It is difficult to administer Zanamivir to children and aged persons. It takes a long time to administer Peramivir. Amantadine is ineffective against Type B influenza virus and resistant viruses have emerged.
  • Laninamivir is an inhalation drug, which is not suitable to patients with dementia and a severe disease and it is difficult to administer it to children.
  • a further superior therapeutic agent for influenza has been desired.
  • an injection that can be administered to patients having difficulty in oral administration, children and aged persons has been desired.
  • Compound A or a salt thereof has a superior antiviral activity and is useful as a therapeutic agent for viral infection (PATENT DOCUMENT 2).
  • PATENT DOCUMENT 2 Compound A has low solubility in water and thus an injection of Compound A or a salt thereof has not been known yet.
  • the present inventors prepared an aqueous solution of a sodium salt of Compound A by using sodium hydroxide generally used as a base, and then produced a lyophilized preparation in accordance with a common method, for improving the water solubility of Compound A.
  • the sodium salt of Compound A obtained by this process was an amorphous dry powder, thus quick dissolution thereof in water was expected.
  • the obtained lyophilized preparation was a lyophilized cake having poor solubility and required a long time to dissolve.
  • the amorphous lyophilized preparation of a sodium salt of Compound A was a preparation needing a long time to dissolve, and was difficult to handle with significant loss of convenience in use.
  • the present inventors have intensively conducted studies with the view to attaining the above desire. As a result, they have found that
  • amorphous Salt A can be produced by lyophilizing an aqueous solution of Salt A.
  • Amorphous Salt A has high solubility and significantly high dissolution rate in water.
  • a preparation containing amorphous Salt A is superior in solubility and useful as an injectable preparation.
  • a crystal of Salt A can be produced by precipitating a crystal from a solution of Salt A.
  • the crystal has high solubility and significantly high dissolution rate in water.
  • a preparation containing a crystal of Salt A is superior in solubility and useful as an injectable preparation.
  • a milled crystal of Salt A has high solubility and significantly high dissolution rate in water.
  • a preparation containing a milled crystal of Salt A is superior in solubility and useful as an injectable preparation.
  • a powder filling method is known as a technique for filling a vial, etc. with a powder.
  • a powder filling method it is difficult to accurately control the filler content and contamination with minute foreign bodies occurs easily, when compared to a method that divides a solution into small portions. For these reasons, as a process for producing a solid injection, a process by lyophilization is the most reliable process.
  • a lyophilized preparation of a crystal of Salt A having significantly high dissolution rate can be produced in a short crystallization time by controlling the temperature (crystallization temperature) range in a temperature-increasing step after primary freezing in lyophilization. More specifically, a crystal of Salt A can be produced by providing a step of increasing temperature after the primary freezing of lyophilization.
  • the resultant crystal has high solubility in water and significantly high dissolution rate, even though it is not milled. Therefore, the preparation containing the crystal is superior in solubility and useful as an injectable preparation.
  • the crystal of Salt A of the present invention does not change to an amorphous state even if a dehydration operation is applied during lyophilization.
  • a lyophilized preparation of Salt A of the present invention has more superior solubility and much higher stability, compared to the amorphous lyophilized preparation of a sodium salt of Compound A.
  • a superior lyophilized preparation of a crystal of Salt A can be produced according to the process of the present invention.
  • the lyophilized preparation can be easily maintained in aseptic conditions and from which insoluble foreign bodies can be easily removed. Therefore, the lyophilized preparation is an injection superior in usability.
  • the present invention is as follows:
  • Salt A of the present invention is superior in solubility in water and useful as a drug substance of an injectable preparation.
  • a preparation containing Salt A of the present invention is useful as an injectable preparation which is superior in solubility and stability and even satisfactory in appearance.
  • the process for producing Salt A of the present invention is useful as a process for producing a lyophilized preparation of a crystal of Salt A which is superior in solubility and stability and even satisfactory in appearance.
  • Compound A can be produced by a method described, for example, in PATENT DOCUMENT 2.
  • Compound A has a tautomer: 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide. This tautomer is included in the present invention.
  • Salt A of the present invention and an injectable preparation containing Salt A can be produced, for example, according to the following processes.
  • a crystal of Salt A monohydrate can be produced by adding Compound A and meglumine to water, heating the mixture to dissolve, adding 2-propanol and collecting a precipitated crystal by filtration.
  • the amount of water is satisfactorily 1 to 10 times (v/w), and preferably 2 to 4 times (v/w) as large as that of Compound A.
  • the amount of meglumine is satisfactorily 1.0 time (mole) or above, and preferably 1.0 to 1.5 times (mole) as large as that of Compound A.
  • the temperature of the reaction with meglumine is satisfactorily 30 to 100° C. and preferably 40 to 80° C.
  • the amount of 2-propanol is satisfactorily 5 to 50 times (v/w), and preferably 10 to 15 times (v/w) as large as that of Compound A.
  • An injectable preparation can be produced by filling a vial, etc. with the crystal of Salt A monohydrate and/or the milled crystal of Salt A monohydrate thus obtained.
  • a crystal of Salt A anhydrate can be produced by allowing a crystal of Salt A monohydrate to stand still at ⁇ 20 to 60° C. under reduced pressure.
  • the standstill time is satisfactorily 0.5 to 120 hours and preferably 1 to 72 hours.
  • the degree of pressure reduction is not particularly limited; however it is satisfactorily 100 Pa or below and preferably 50 Pa or below.
  • a crystal of Salt A anhydrate can be produced by allowing a crystal of Salt A monohydrate to stand still under heating.
  • the heating temperature is satisfactorily 30° C. or above, preferably 50° C. to 110° C. and more preferably 50° C. to 90° C.
  • An injectable preparation can be produced by filling a vial, etc. with the crystal of Salt A anhydrate and/or the milled crystal of Salt A anhydrate thus obtained.
  • an injectable preparation of a Salt A anhydrate can be produced by grinding the crystal of Salt A monohydrate and then drying it in the same manner as mentioned above.
  • Amorphous Salt A can be produced by lyophilizing an aqueous solution of Compound A and meglumine.
  • the amount of water is satisfactorily 10 to 100 times (v/w), and preferably 10 to 50 times (v/w) as large as that of Compound A.
  • Meglumine is added such that the pH of the aqueous solution becomes satisfactorily 4.0 to 10 and preferably 7.0 to 9.0.
  • Lyophilization may be performed, for example, by freezing an aqueous solution of Compound A and meglumine at ⁇ 40° C. or below and maintaining the temperature of the resultant product at a collapse temperature or below.
  • An aqueous solution of Compound A and meglumine can be frozen to obtain an amorphous frozen product.
  • the amount of water is satisfactorily 10 to 100 times (v/w), and preferably 10 to 50 times (v/w) as large as that of Compound A.
  • Meglumine is added such that the pH of the aqueous solution becomes 4.0 to 10 and preferably 7.0 to 9.0.
  • the temperature of the primary freezing step is satisfactorily a collapse temperature or below.
  • the temperature of ⁇ 60 of ⁇ 40° C. is preferable.
  • the period of time for the primary freezing step is satisfactorily 1 to 10 hours and preferably 2 to 5 hours.
  • the temperature of the amorphous frozen product is increased and the frozen product is maintained for a preset time (annealing) to allow crystallization to proceed to obtain a crystalline frozen product.
  • the temperature, at which thawing of the frozen product dose not occur and crystallization proceeds to the extent that the frozen product maintains a frozen state, may be satisfactory in the annealing step; preferably ⁇ 20 of ⁇ 2° C., more preferably ⁇ 20 of ⁇ 5° C., and further preferably ⁇ 15 of ⁇ 5° C.
  • the period of time for maintaining the annealing step is satisfactorily 0.5 to 48 hours and preferably 1 to 24 hours.
  • the temperature of the secondary freezing step is preferably ⁇ 60 of ⁇ 30° C.
  • the period of time for the secondary freezing step is satisfactorily 1 to 10 hours and preferably 2 to 5 hours.
  • pressure reduction treatment can be performed to produce a lyophilized preparation.
  • This step can be performed in accordance with a lyophilization method usually used, for example, in two steps, i.e., a primary drying step and a secondary drying step.
  • the primary drying step is carried out under reduced pressure while product temperature is maintained at the eutectic point or below; however, since the temperature drops as the moisture sublimates from the frozen product, the preset temperature of an apparatus may be the eutectic point or above.
  • the product temperature of the frozen product is satisfactorily ⁇ 40 of ⁇ 3° C. and preferably ⁇ 30 of ⁇ 5° C.
  • the preset temperature of an apparatus is satisfactorily ⁇ 20 to 60° C. and preferably ⁇ 10 to 50° C.
  • the degree of pressure reduction in the primary drying step is not particularly limited; however it is satisfactorily 100 Pa or below and preferably 50 Pa or below.
  • the rate of temperature decrease becomes slower.
  • the product temperature increases and becomes almost equal to the preset temperature.
  • the primary drying step is determined to have completed.
  • the secondary drying step is carried out at room temperature or above and preferably 30 to 60° C.
  • the degree of pressure reduction is preferably enhanced in order to accelerate removal of water.
  • the degree of pressure reduction is satisfactorily 0.5 to 10 Pa and preferably 1 to 5 Pa.
  • the secondary drying step may be satisfactorily carried out up until the point where the product temperature becomes almost equal to the preset temperature and a product temperature virtually does not change.
  • the powder X-ray diffraction pattern of a crystal of Salt A produced by the process was the same as the powder X-ray diffraction pattern of a crystal of Salt A anhydrate produced in process 2. More specifically, a lyophilized preparation of a crystal of Salt A anhydrate can be produced by the use of the process.
  • a sterilization treatment or the like may be carried out in accordance with the procedure usually employed.
  • the lyophilized preparation since no organic solvents are used, the lyophilized preparation has no residual solvent.
  • the lyophilized preparation of the present invention is not harmful to a human body.
  • powder X-ray diffraction measurement conditions are as follows.
  • the characteristic peaks of powder X-ray diffraction sometimes varies depending on measurement conditions.
  • 2 ⁇ has a margin of error of ⁇ 0.2°.
  • the diffraction angle of X° represented by 2 ⁇ refers to “a diffraction angle of ((X ⁇ 0.2) to (X+0.2))° represented by 2 ⁇ ”.
  • the Salt A of the present invention includes a crystal of a monohydrate, a crystal of an anhydrate and amorphous anhydrate. Furthermore, various shapes of crystals are included in the crystal.
  • Additives can be added to the lyophilized preparation containing Salt A of the present invention for improving solubility and/or appearance.
  • the temperature range of the annealing step can be extended by adding additives.
  • additives examples include amino acids, saccharides, sugar alcohols, salts, urea, ethyl urea, creatinine, nicotinic acid amide and trometamol. These may be used alone or as a mixture of two or more types.
  • preferable additives include amino acids, saccharides, sugar alcohols, salts, urea, creatinine, nicotinic acid amide and trometamol.
  • amino acids examples include glycine, L-alanine, L-phenylalanine, L-leucine, L-isoleucine, taurine, DL-methionine, L-threonine, L-glutamine, sodium L-glutamate, acetyltryptophan and L-histidine.
  • Glycine, L-alanine, taurine and L-histidine are more preferable and glycine and L-alanine are further preferable.
  • saccharides examples include trehalose, maltose, glucose, lactose, purified white sugar, fructose, dextran and cyclodextrin. Trehalose, maltose, glucose, lactose and purified white sugar are more preferable and trehalose and purified white sugar are further preferable.
  • sugar alcohols examples include D-sorbitol, xylitol, inositol and D-mannitol.
  • salts examples include sodium acetate, sodium lactate, sodium L-tartrate, sodium citrate, sodium salicylate, sodium benzoate and sodium caprylate.
  • Sodium acetate, sodium lactate and sodium benzoate are more preferable.
  • a combination use of an amino acid and a saccharide, or an amino acid and a sugar alcohol is preferable and a combination use of an amino acid and a saccharide is more preferable.
  • amino acids include glycine and L-alanine.
  • saccharide examples include trehalose and purified white sugar.
  • sugar alcohol examples include D-sorbitol, xylitol and D-mannitol.
  • additives such as an osmo-regulator, a pH regulator, a buffer, a solubilizer, a stabilizer, a surfactant, a soothing agent, and/or a preservative, may be added to the preparation of the present invention.
  • osmo-regulator examples include sodium chloride, glycerin and propylene glycol.
  • Examples of the pH regulator and/or the buffer 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; salts such as sodium bicarbonate, sodium carbonate, sodium dihydrogenphosphate, potassium dihydrogenphosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, disodium citrate and sodium sulfite; and bases such as sodium hydroxide, trometamol, monoethanolamine, diethanolamine, triethanolamine, L-arginine and L-lysine.
  • 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
  • salts such as sodium bicarbonate, sodium carbonate, sodium dihydrogenphosphate, potassium
  • solubilizer examples include Macrogol and purified soybean lecithin.
  • the stabilizer examples include sodium hydrogen sulfite, sodium pyrosulfite, potassium pyrosulfite, sodium pyrophosphate, sodium thiosulfate, sodium metasulfobenzoate, sodium formaldehyde sulfoxylate, ethylene diamine, edetate sodium, thioglycolic acid, sodium gluconate, 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.
  • Examples of the soothing agent include lidocaine, procaine, meprylcaine and benzyl alcohol.
  • preservative examples include cresol, phenol, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzalkonium chloride and benzethonium chloride.
  • the dose of an active ingredient is appropriately determined in accordance with dosage form, age and gender of a patient, conditions of a disease and other conditions; however, usually 0.1 to 100 mg/kg per adult per day may be administered.
  • the content of Compound A is 10 to 6000 mg and preferably 100 to 2000 mg.
  • the content of the additives to be added for improving solubility and/or appearance is 0.1 to 115% (w/w) and preferably 5 to 65% (w/w) relative to the content of Compound A.
  • DMSO-d 6 refers to heavy dimethylsulfoxide.
  • the water content was measured by the Karl Fischer method.
  • Example 1 The crystal obtained in Example 1 was milled and passed through No. 60 (250 ⁇ m) sieve to obtain a powder remaining on No. 282 (53 ⁇ m) sieve. Each vial was filled with the powder (1.41 g) to obtain an injectable preparation of a monohydrate crystal.
  • Example 1 The crystal (1.35 g) obtained in Example 1 was allowed to stand still at 40° C. under vacuum (50 Pa or below) for 64 hours to obtain a crystal of an anhydrate.
  • Example 1 The crystal (86 mg) obtained in Example 1 was allowed to stand still at 80 to 90° C. for 5 minutes and thereafter at 90° C. for 180 minutes to obtain a crystal of an anhydrate.
  • Example 2 The injectable preparation obtained in Example 2 was allowed to stand still at 40° C. under vacuum (50 Pa or below) for 60 hours to obtain an injectable preparation of a crystal of the anhydrate.
  • the result of powder X-ray diffraction of the lyophilized preparation is shown in FIG. 2 .
  • Example 7 To the liquid preparation (35 mL) produced in the same manner as in Example 7 was added L-histidine (0.35 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (100 mL) produced in the same manner as in Example 7 was added trehalose (1.00 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (160 mL) produced in the same manner as in Example 7 was added trehalose (3.20 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 was added D-maltose monohydrate (1.65 g), and a solution (pH 8.1) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 was added lactose (1.65 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Each vial was filled with the liquid preparation (pH 8.1, 10 mL) produced in the same manner as in Example 7, and purified white sugar (0.30 g)(manufactured by Ensuiko Sugar Refining Co., Ltd.) was added and dissolved. After lyophilization, the vials were closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (160 mL) produced in the same manner as in Example 7 was added D-sorbitol (1.60 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (35 mL) produced in the same manner as in Example 7 was added xylitol (0.35 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (160 mL) produced in the same manner as in Example 7 was added D-mannitol (1.60 g), and a solution (pH 8.1) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 was added sodium acetate trihydrate (0.55 g), and a solution (pH 8.1) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 was added sodium lactate (50% solution, 1.11 g), and a solution (pH 8.1) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 was added sodium benzoate (0.55 g), and a solution (pH 8.1) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (210 mL) produced in the same manner as in Example 7 were added glycine (2.10 g) and trehalose (2.10 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (210 mL) produced in the same manner as in Example 7 were added L-alanine (2.10 g) and trehalose (2.10 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Vials were filled with the liquid preparation (pH 8.1, 10 mL) produced in the same manner as in Example 7 and glycine (0.10 g) and purified white sugar (0.10 g, manufactured by Ensuiko Sugar Refining Co., Ltd.) were added and dissolved. After lyophilization, the vials were closed airtight to obtain a lyophilized preparation of a crystal.
  • Vials were filled with the liquid preparation (pH 8.1, 10 mL) produced in the same manner as in Example 7 and L-alanine (0.10 g) and purified white sugar (0.10 g, manufactured by Ensuiko Sugar Refining Co., Ltd.) were added and dissolved. After lyophilization, the vials were closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (90 mL) produced in the same manner as in Example 7 were added glycine (0.90 g) and D-sorbitol (0.90 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (210 mL) produced in the same manner as in Example 7 were added L-alanine (2.10 g) and D-sorbitol (2.10 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (90 mL) produced in the same manner as in Example 7 were added glycine (0.90 g) and xylitol (0.90 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (90 mL) produced in the same manner as in Example 7 were added L-alanine (0.90 g) and xylitol (0.90 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (90 mL) produced in the same manner as in Example 7 were added glycine (0.90 g) and D-mannitol (0.90 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (210 mL) produced in the same manner as in Example 7 were added L-alanine (2.10 g) and D-mannitol (2.10 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 41 Production was performed in the same manner as in Example 41 to obtain a liquid preparation (pH 7.6). Each vial was filled with the liquid preparation (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 42 Production was performed in the same manner as in Example 42 to obtain a liquid preparation (pH 8.5). Each vial was filled with the liquid preparation (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added trehalose (1.10 g) and glycine (1.10 g), and a solution (pH 7.7) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added trehalose (1.10 g) and glycine (1.10 g), and a solution (pH 7.8) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added D-mannitol (0.28 g) and glycine (0.28 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added D-mannitol (1.10 g) and glycine (1.10 g), and a solution (pH 7.8) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added purified white sugar (1.10 g, manufactured by Ensuiko Sugar Refining Co., Ltd.) and glycine (1.10 g), and a solution (pH 7.7) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added purified white sugar (1.10 g, manufactured by Ensuiko Sugar Refining Co., Ltd.) and glycine (1.10 g), and a solution (pH 7.8) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 41 To the liquid preparation (55 mL) produced in the same manner as in Example 41 were added trehalose (0.55 g) and L-alanine (0.55 g), and a solution (pH 7.4) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added trehalose (0.55 g) and L-alanine (0.55 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added trehalose (1.10 g) and L-alanine (1.10 g), and a solution (pH 7.8) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 42 To the liquid preparation (55 mL) produced in the same manner as in Example 42 were added trehalose (0.55 g) and L-alanine (0.55 g), and a solution (pH 8.4) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added trehalose (0.28 g) and L-alanine (0.28 g), and a solution (pH 8.0) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 41 To the liquid preparation (55 mL) produced in the same manner as in Example 41 were added trehalose (0.55 g) and L-alanine (0.55 g), and a solution (pH 7.5) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 42 To the liquid preparation (55 mL) produced in the same manner as in Example 42 were added trehalose (0.55 g) and L-alanine (0.55 g), and a solution (pH 8.4)was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added trehalose (1.10 g) and L-alanine (1.10 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added D-sorbitol (0.28 g) and L-alanine (0.28 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added D-sorbitol (0.28 g) and L-alanine (0.28 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added D-mannitol (1.10 g) and L-alanine (1.10 g), and a solution (pH 7.8) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added D-mannitol (1.10 g) and L-alanine (1.10 g), and a solution (pH 7.8) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added purified white sugar (0.28 g, manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine (0.28 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added purified white sugar (0.55 g, manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine (0.55 g), and a solution (pH 7.8) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added purified white sugar (1.10 g, manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine (1.10 g), and a solution (pH 7.8) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added purified white sugar (0.28 g, manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine (0.28 g), and a solution (pH 7.9) was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • Example 7 To the liquid preparation (55 mL) produced in the same manner as in Example 7 were added purified white sugar (1.10 g, manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine (1.10 g), and a solution (pH 7.8)was obtained. Each vial was filled with the solution (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal.
  • the dissolution time of an amorphous sodium salt was 60 seconds.
  • the dissolution time of an amorphous sodium salt was 65 seconds.
  • the dissolution time of a milled crystal of a meglumine salt monohydrate was 5 seconds.
  • the milled crystal of a meglumine salt exhibited more superior solubility than the amorphous sodium salt.
  • the dissolution time of an amorphous meglumine salt was 5 seconds.
  • the amorphous meglumine salt exhibited more superior solubility than the amorphous sodium salt.
  • the dissolution time of preparations (Examples 6 to 9, 41 to 44) produced by lyophilization including an annealing step was 10 to 31 seconds.
  • the preparation produced by this process exhibited more superior solubility than the amorphous sodium salt even though it is not milled.
  • the dissolution time of preparations (Examples 10 to 13) containing amino acids as an additive; preparations (Examples 14 to 19) containing saccharides as an additive; preparations (Examples 20 to 23) containing sugar alcohols as an additive; preparations (Examples 24 to 26) containing salts as an additive; a preparation (Example 27) containing creatinine as an additive, a preparation (Example 28) containing urea as an additive; a preparation (Example 29) containing nicotinic acid amide as an additive; and a preparation (Example 30) containing trometamol as an additive demonstrate that these preparations exhibit much more superior solubility than an amorphous sodium salt.
  • lyophilized preparations of Examples 7 and 8 looked uniform without a melting mark. Furthermore, the preparations of Examples 12, 15, 27, 31 to 33, 36, 38, 51, 55 and 59 were uniform cakes without a melting mark. The surface of the preparations was smooth and appearance was more satisfactory. Lyophilized preparations having more preferable appearance were obtained by blending additives.
  • Example 69 and Comparative Example 1 were irradiated (1,200,000 lx ⁇ hr) by a D65 lamp (FLR20S-D-EDL-D65/M) and then their appearance was observed. As a result, appearance change was not observed in the preparation of Example 69; whereas the preparation of Comparative Example 1 turned into orange-yellow.
  • FIG. 1 is a powder X-ray diffraction pattern of a crystal of a meglumine salt (monohydrate) of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide;
  • FIG. 2 is a powder X-ray diffraction pattern of an amorphous meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
  • FIG. 3 is a powder X-ray diffraction pattern of a crystal of an anhydrous meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.
  • a preparation filled with a meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide of the present invention is superior in solubility and useful as an injectable preparation.

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US9090571B2 (en) 2015-07-28
RS54642B1 (en) 2016-08-31
CN103209967B (zh) 2015-04-08
TWI507397B (zh) 2015-11-11
SMT201600184B (it) 2016-08-31
EP2623497A4 (fr) 2014-03-26
US20150266832A1 (en) 2015-09-24
WO2012043696A1 (fr) 2012-04-05
CN103209967A (zh) 2013-07-17
HRP20160218T1 (hr) 2016-03-25
MY161757A (en) 2017-05-15
PL2623497T3 (pl) 2016-07-29
PH12015501328A1 (en) 2015-09-21
CY1117218T1 (el) 2017-04-05

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