WO2012043696A1 - 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩 - Google Patents
6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩 Download PDFInfo
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- WO2012043696A1 WO2012043696A1 PCT/JP2011/072329 JP2011072329W WO2012043696A1 WO 2012043696 A1 WO2012043696 A1 WO 2012043696A1 JP 2011072329 W JP2011072329 W JP 2011072329W WO 2012043696 A1 WO2012043696 A1 WO 2012043696A1
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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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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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
- A61K9/0012—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
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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
- A61K9/08—Solutions
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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
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- 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
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- 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
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- 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
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- 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 method for producing the same.
- Compound A 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
- Compound A or a salt thereof has excellent antiviral activity and is useful as a therapeutic agent for viral infection (Patent Document 2).
- Compound A has low solubility in water, and an injection of Compound A or a salt thereof is not known.
- the present inventors prepared an aqueous solution of a sodium salt of Compound A using sodium hydroxide, which is widely used as a base, and then produced a freeze-dried preparation by a conventional method. did.
- the sodium salt of Compound A obtained by this production was an amorphous dry powder and was expected to dissolve quickly.
- the obtained freeze-dried preparation was a hardly-soluble freeze-dried cake that required a long time for dissolution.
- the amorphous lyophilized preparation of the sodium salt of Compound A was a difficult-to-handle preparation that took a long time to dissolve and the use convenience was significantly impaired.
- Non-Patent Document 1 a method of providing an annealing step is known as a method for preparing a freeze-dried preparation.
- a method for preparing a freeze-dried preparation is known as a method for preparing a freeze-dried preparation.
- the effect of the annealing process on the solubility of the lyophilized formulation varies from substance to substance. For this reason, research has been conducted by trial and error (Non-Patent Document 1).
- a meglumine salt of Compound A (hereinafter referred to as “Salt A”) having an amorphous state and a crystal
- Salt A A meglumine salt of Compound A having an amorphous state and a crystal
- the solubility of salt A in water is high
- the dissolution rate of salt A in amorphous water, the dissolution rate of salt A crystals in water, and the dissolution rate of ground salt A crystals in water are significantly high
- This amorphous material has a high solubility in water and a remarkably high dissolution rate. Therefore, a preparation filled with an amorphous salt A is excellent in solubility and is useful as an injectable preparation.
- Crystals of salt A can be produced by precipitating crystals from a solution of salt A. This crystal has a high solubility in water and a remarkably high dissolution rate. Therefore, a preparation filled with crystals of salt A is excellent in solubility and is useful as an injectable preparation.
- the ground salt A crystals have a high solubility in water and a remarkably high dissolution rate. Therefore, a preparation filled with pulverized salt A crystals is excellent in solubility and is useful as an injectable preparation.
- a powder filling method is known as a method of filling powder into a vial or the like.
- it is difficult to accurately control the filling amount as compared with the method of dividing the solution, and minute foreign matters are easily mixed. Therefore, as a method for producing a solid injection, a production method by freeze drying is the most reliable method.
- the inventors of the present invention controlled the temperature range (temperature of crystallization) at the time of temperature rise after primary freezing in lyophilization, thereby achieving a short crystallization time and a dissolution rate. It has been found that a lyophilized formulation of extremely large salt A crystals can be produced.
- the salt A crystal can be produced by providing a step of raising the temperature after primary freeze-freezing. Even if this crystal is not pulverized, the solubility in water is high and the dissolution rate is remarkably high. Therefore, the preparation filled with the crystals has excellent solubility and is useful as an injectable preparation. As a result of further intensive studies, the present inventors have found that a more excellent lyophilized preparation can be produced by adding an additive to an aqueous solution of salt A to be lyophilized, leading to the completion of the present invention. It was.
- the present invention is as follows. 1. Salt A or a hydrate thereof. Salt A or its hydrate has a high solubility in water and a very high dissolution rate. 2. Crystal of salt A or its hydrate. This crystal has a high solubility in water and a remarkably high dissolution rate. 3. Amorphous salt A. This amorphous material has a high solubility in water and a remarkably high dissolution rate. 4). An injectable preparation containing salt A or a hydrate thereof. This injectable preparation is excellent in solubility. 5. An injectable preparation containing crystals of salt A or a hydrate thereof. This injectable preparation is excellent in solubility. 6). An injectable preparation containing an amorphous form of salt A or a hydrate thereof.
- This injectable preparation is excellent in solubility. 7. 6.
- This injectable preparation is excellent in solubility. 8).
- This freeze-dried preparation has excellent solubility.
- This freeze-dried preparation has excellent solubility.
- It is a lyophilized formulation containing an amorphous salt A. This freeze-dried preparation has excellent solubility.
- the freeze-dried preparation according to the above 8 or 9 comprising an amino acid and a saccharide, or an amino acid and a sugar alcohol.
- This freeze-dried preparation has excellent solubility. 12
- a step of cooling an aqueous solution containing Compound A and meglumine to produce a frozen body (2) a step of raising the temperature of the frozen body, (3) a step of cooling the frozen body again, (4) freeze-drying A method for producing a lyophilized preparation containing crystals of salt A.
- the temperature reached by the frozen body in the step of raising the temperature of the frozen body is in the range of ⁇ 20 to ⁇ 5 ° C.
- the ultimate temperature of the frozen body in the range of ⁇ 20 to ⁇ 5 ° C.
- the salt A of the present invention has excellent solubility in water and is useful as a drug substance for injectable preparations.
- the preparation filled with the salt A of the present invention is useful as an injectable preparation having excellent solubility and stability and a good appearance.
- the method for producing salt A of the present invention is useful as a method for producing a freeze-dried preparation of salt A crystals having excellent solubility and stability and having a good appearance.
- Compound A can be produced, for example, by the method described in Patent Document 2.
- Compound A has tautomer 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide.
- the present invention also includes this compound.
- the salt A of the present invention and an injectable preparation containing the same can be produced, for example, by the following production method.
- the amount of water may be 1 to 10 times the amount of compound A (v / w), and preferably 2 to 4 times the amount (v / w).
- the amount of meglumine may be 1.0 times mol or more with respect to Compound A, and preferably 1.0 to 1.5 times mol.
- the reaction temperature with meglumine may be 30 to 100 ° C, preferably 40 to 80 ° C.
- the amount of 2-propanol may be 5 to 50 times (v / w) with respect to Compound A, and preferably 10 to 15 times (v / w).
- Anhydrous Crystal of Salt A can be produced by allowing the monohydrate crystal of Salt A to stand at ⁇ 20 to 60 ° C. under reduced pressure.
- the standing time may be 0.5 to 120 hours, preferably 1 to 72 hours.
- the degree of reduced pressure is not particularly limited, but may be 100 Pa or less, and preferably 50 Pa or less.
- the salt A monohydrate crystals can be left standing under heating to produce salt A anhydride crystals.
- the heating temperature may be 30 ° C or higher, preferably 50 ° C to 110 ° C, and more preferably 50 ° C to 90 ° C.
- An injection preparation can be produced by filling a vial or the like with the anhydrous crystals of salt A and / or the crushed anhydrous crystals of salt A thus obtained.
- an injectable preparation of an anhydrous salt A can also be produced by pulverizing crystals of the monohydrate of salt A and drying in the same manner as described above.
- Amorphous salt A (freeze-dried) Amorphous salt A can be produced by lyophilizing an aqueous solution of compound A and meglumine.
- the amount of water may be 10 to 100 times the amount of compound A (v / w), and preferably 10 to 50 times (v / w).
- Meglumine is added so that the pH of the aqueous solution is 4.0 to 10, preferably 7.0 to 9.0. Freeze-drying may be performed, for example, by freezing an aqueous solution of Compound A and meglumine at ⁇ 40 ° C. or lower and then maintaining the product temperature below the collapse temperature.
- First step An amorphous frozen body can be obtained by freezing an aqueous solution of Compound A and meglumine.
- the amount of water may be 10 to 100 times the amount of compound A (v / w), and preferably 10 to 50 times (v / w).
- Meglumine is added so that the pH of the aqueous solution is 4.0 to 10, preferably 7.0 to 9.0.
- the temperature of a primary freezing process should just be below a collapse temperature. In the present invention, -60 to -40 ° C is preferable.
- the time of the primary freezing step may be 1 to 10 hours, and preferably 2 to 5 hours.
- Second step By heating the amorphous frozen body and holding it for a certain period of time (annealing), crystallization proceeds and a crystalline frozen body can be obtained.
- the temperature of the annealing step may be any temperature that does not cause melting of the amorphous frozen body and allows crystallization to proceed as long as the frozen body can maintain freezing, and is preferably ⁇ 20 to ⁇ 2 ° C., ⁇ 20 to -5 ° C is more preferable, and -15 to -5 ° C is more preferable.
- the holding time in the annealing step may be 0.5 to 48 hours, and preferably 1 to 24 hours.
- the temperature in the secondary freezing step is preferably -60 to -30 ° C.
- the time of the secondary freezing step may be 1 to 10 hours, and preferably 2 to 5 hours.
- a freeze-dried preparation can be produced by performing a reduced pressure treatment.
- This step may be carried out in accordance with a commonly practiced freeze-drying method, and can be carried out, for example, by two steps, a primary drying step and a secondary drying step.
- the primary drying process is carried out under reduced pressure while maintaining the product temperature below the eutectic point, but since the temperature lowers with the sublimation of moisture from the frozen body, the set temperature of the equipment is above the eutectic point. But you can.
- the product temperature of the frozen body may be -40 to -3 ° C, preferably -30 to -5 ° C.
- the set temperature of the device at this time may be -20 to 60 ° C, and preferably -10 to 50 ° C.
- the degree of reduced pressure in the primary drying step is not particularly limited, but may be 100 Pa or less, and preferably 50 Pa or less.
- the temperature decrease becomes milder.
- the product temperature rises, and the product temperature and the set temperature are almost the same. Usually, this point is judged as the completion of the primary drying process.
- a secondary drying process is performed.
- the secondary drying step is performed at room temperature or higher, and preferably 30 to 60 ° C. In the secondary drying step, it is preferable to increase the degree of vacuum in order to promote the desorption of moisture.
- the degree of vacuum may be 0.5 to 10 Pa, and preferably 1 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 powder X-ray diffraction pattern of the salt A crystal produced by this production method was identical to the powder X-ray diffraction pattern of the salt A anhydride crystal produced by Production Method 2. That is, by this production method, a freeze-dried preparation of anhydrous crystals of salt A can be produced.
- sterilization and the like may be performed according to a commonly performed procedure. Since the production method of the present invention does not use an organic solvent, there is no residual solvent in the lyophilized preparation.
- the freeze-dried preparation of the present invention is safe for the human body.
- the characteristic peak by powder X-ray diffraction may change with measurement conditions. In general, 2 ⁇ causes an error within a range of ⁇ 0.2 °. Therefore, “the diffraction angle of X ° represented by 2 ⁇ ” means “the diffraction angle of ((X ⁇ 0.2) to (X + 0.2)) ° represented by 2 ⁇ ”.
- the salt A of the present invention includes monohydrate crystals, anhydride crystals and amorphous.
- crystals include crystals of various shapes.
- Additives for improving solubility and / or appearance can be added to the freeze-dried preparation containing salt A of the present invention.
- an additive By adding an additive, the temperature range of the annealing process can be expanded.
- the additive include amino acids, saccharides, sugar alcohols, salts, urea, ethylurea, creatinine, nicotinamide, and trometamol, and these can be used alone or in combination of two or more.
- Preferred additives include amino acids, sugars, sugar alcohols, salts, urea, creatinine, nicotinamide 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. And glycine, L-alanine, taurine and L-histidine are more preferred, and glycine and L-alanine are more preferred.
- the saccharide 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 more preferable.
- sugar alcohols include D-sorbitol, xylitol, inositol and D-mannitol.
- the salts include sodium acetate, sodium lactate, sodium L-tartrate, sodium citrate, sodium salicylate, sodium benzoate and sodium caprylate, and sodium acetate, sodium lactate and sodium benzoate are more preferable.
- amino acids and saccharides preferably include glycine and L-alanine.
- saccharide trehalose and purified sucrose are preferably used.
- sugar alcohols preferably include D-sorbitol, xylitol, and D-mannitol.
- an osmotic pressure regulator in the preparation of the present invention, an osmotic pressure regulator, a pH regulator, a buffer, a solubilizer, a stabilizer, a surfactant, a soothing agent, and / or a preservative, which are usually used, are used as necessary. May be added.
- the osmotic pressure regulator include sodium chloride, glycerin and propylene glycol.
- pH adjusters and / or buffers 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, sodium carbonate, Salts such as sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, disodium citrate and sodium sulfite; sodium hydroxide, trometamol, monoethanolamine, And bases such as diethanolamine, triethanolamine, L-arginine and L-lysine.
- 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, 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.
- soothing agents include lidocaine, procaine, meprilucaine, and benzyl alcohol.
- preservatives include cresol, phenol, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzalkonium chloride, and benzethonium chloride.
- the dose of the active ingredient in the injectable preparation of the present invention is appropriately determined according to the usage, the patient's age, sex, disease form, other conditions, etc., but is usually 0.1-100 mg per day for an adult. / kg should be administered.
- the content of Compound A in the injectable preparation of the present invention is 10 to 6000 mg, preferably 100 to 2000 mg.
- Additives for improving solubility and / or appearance incorporated in the injectable preparation of the present invention are 0.1 to 115% (w / w), preferably 5 to 65% (w) of Compound A. / w).
- DMSO-d 6 means deuterated dimethyl sulfoxide.
- the water content was measured by the Karl Fischer method.
- Example 1 A 30 mL suspension of Compound A 10.0 g and meglumine 15.0 g in water was heated to 50 ° C. and dissolved. After 120 mL of 2-propanol was added dropwise at 40 ° C., the mixture was cooled to 5 ° C. and stirred at the same temperature for 1 hour. The solid was collected by filtration to obtain 21.3 g of light yellow salt A monohydrate crystals.
- Example 2 The crystals obtained in Example 1 were pulverized and passed through a No. 60 (250 ⁇ m) sieve to obtain a powder remaining on the No. 282 (53 ⁇ m) sieve. 1.41 g of this powder was filled in a vial to obtain a monohydrate crystal injection preparation.
- Example 3-1 1.35 g of the crystals obtained in Example 1 were allowed to stand at 40 ° C. under vacuum (50 Pa or less) for 64 hours to obtain anhydrous crystals. Moisture content: 0.07% In the powder X-ray diffraction pattern of the obtained crystals, peaks were observed at 2 ⁇ (°): 11.3, 13.0, 17.0, 19.7, 20.5, 22.0, 24.2, 26.4, 28.1.
- Example 3-2 86 mg of the crystals obtained in Example 1 were allowed to stand at 80 to 90 ° C. for 5 minutes, and then allowed to stand at 90 ° C. for 180 minutes to obtain anhydrous crystals.
- the powder X-ray diffraction of the anhydride crystals is shown in FIG. The powder X-ray diffraction pattern was consistent with Example 3-1.
- Example 4 The injectable preparation obtained in Example 2 was allowed to stand at 40 ° C. under vacuum (50 Pa or less) for 60 hours to obtain an anhydrous crystal injectable preparation.
- Example 5 Meglumine (55.9 g) was added to a suspension of Compound A (45.1 g) in water for injection (500 mL) and dissolved by stirring. Water for injection was added to make a total volume of 600 mL, followed by filtration through a 0.22 ⁇ m membrane filter to obtain a preparation (pH 7.6). 8 mL of the prepared solution was filled into vials, freeze-dried and sealed, to obtain an amorphous freeze-dried preparation. Moisture content: 0.17% The powder X-ray diffraction of the lyophilized formulation is shown in FIG. Method of lyophilization The vial was cooled at a shelf temperature of ⁇ 60 ° C. and the contents were frozen. 2.
- the shelf temperature was raised to ⁇ 20 ° C. and kept at the same pressure and temperature for 64 hours. 3. The shelf temperature was raised to -10 ° C, and the same pressure and temperature were maintained for 7 hours. 4). The shelf temperature was raised to 0 ° C. and maintained at the same pressure and temperature for 11 hours. 5. The shelf temperature was raised to 20 ° C. and held at the same pressure and temperature for 10 hours. 6). The shelf temperature was raised to 40 ° C. and maintained at the same pressure and temperature for 17 hours.
- Example 6 90.7 g of meglumine was added to a 1000 mL suspension of water for injection of 72.0 g of Compound A, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 1200 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 8.0). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.01% In the powder X-ray diffraction pattern of the lyophilized preparation, a salt peak of the salt A anhydride observed in Example 3 was observed.
- the vial was cooled at a shelf temperature of ⁇ 60 ° C. and the contents were frozen. 2. The shelf temperature was raised to -5 ° C and the temperature was maintained for 25 hours. 3. The shelf temperature was cooled to ⁇ 55 ° C. or lower and held at that temperature for 3 hours. 4). Under vacuum (50 Pa or less), the temperature was raised to a shelf temperature of 40 ° C. and kept at the same pressure and temperature for 60 hours.
- Example 7 166 g of meglumine was added to 1900 mL of water for injection of 132 g of Compound A, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 2200 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 8.0). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.01% In the powder X-ray diffraction pattern of the lyophilized preparation, a salt peak of the salt A anhydride observed in Example 3 was observed.
- the vial was cooled at a shelf temperature of ⁇ 60 ° C. and the contents were frozen. 2. The shelf temperature was raised to ⁇ 10 ° C. and kept at the same temperature for 24 hours. 3. The shelf temperature was cooled to ⁇ 55 ° C. or lower and held at that temperature for 2 hours. 4). Under vacuum (50 Pa or less), the temperature was raised to a shelf temperature of 40 ° C. and kept at the same pressure and temperature for 48 hours.
- Example 8 166 g of meglumine was added to 1800 mL of water for injection of 132 g of Compound A, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 2200 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 8.0). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.00% In the powder X-ray diffraction pattern of the lyophilized preparation, a salt peak of the salt A anhydride observed in Example 3 was observed.
- the vial was cooled at a shelf temperature of ⁇ 60 ° C. and the contents were frozen. 2. The shelf temperature was raised to -15 ° C and held at that temperature for 24 hours. 3. The shelf temperature was cooled to ⁇ 55 ° C. or lower and held at that temperature for 2 hours. 4). Under vacuum (50 Pa or less), the temperature was raised to a shelf temperature of 40 ° C. and maintained at the same pressure and temperature for 46 hours.
- Example 9 68.0 g of meglumine was added to a suspension of 750 mL of water for injection of 54.0 g of Compound A, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 900 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 8.0). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.02% In the powder X-ray diffraction pattern of the lyophilized preparation, a salt peak of the salt A anhydride observed in Example 3 was observed.
- the vial was cooled at a shelf temperature of ⁇ 60 ° C. and the contents were frozen. 2. The shelf temperature was raised to ⁇ 30 ° C. and held at that temperature for 14 hours. 3. The shelf temperature was raised to -25 ° C and held at that temperature for 25 hours. 4). The shelf temperature was raised to ⁇ 20 ° C. and kept at that temperature for 25 hours. 5. The shelf temperature was cooled to ⁇ 55 ° C. or lower and held at that temperature for 2 hours. 6). Under vacuum (50 Pa or less), the temperature was raised to a shelf temperature of 40 ° C. and held at the same pressure and the same temperature for 50 hours.
- Example 10 91.9 g of meglumine was added to a 1000 mL suspension of water for injection of 73.2 g of compound A, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 1220 mL. To 200 mL of this solution, 2.00 g of glycine was added and dissolved, followed by filtration through a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 7.8). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.03% In the powder X-ray diffraction pattern of the lyophilized preparation, a salt peak of the salt A anhydride observed in Example 3 was observed. Lyophilization method: as in Example 7
- Example 11 91.9 g of meglumine was added to a 1000 mL suspension of water for injection of 73.2 g of compound A, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 1220 mL. To 200 mL of this solution, 2.00 g of L-alanine was added and dissolved, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 7.9). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.03% In the powder X-ray diffraction pattern of the lyophilized preparation, a salt peak of the salt A anhydride observed in Example 3 was observed. Lyophilization method: as in Example 7
- Example 12 0.35 g of L-histidine was added to 35 mL of the prepared solution produced in the same manner as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 13 85.8 g of meglumine was added to a suspension of 69.0 g of Compound A in 760 mL of water for injection, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 920 mL. To 240 mL of this solution, 1.20 g of taurine was added and dissolved, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 7.6). 8 mL of the prepared solution was filled into a vial, freeze-dried, and sealed up to obtain a freeze-dried crystalline product. Moisture content: 0.02% Lyophilization method: as in Example 7
- Example 14 1.00 g of trehalose was added to 100 mL of the preparation solution produced by the same method as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.05% Freeze-drying method: as in Example 7. The powder X-ray diffraction pattern of the freeze-dried preparation showed the crystal peak of the salt A anhydride observed in Example 3.
- Example 15 Trehalose (3.20 g) was added to 160 mL of the preparation solution produced by the same method as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 16 1.55 g of D-maltose monohydrate was added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 8.1). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 17 91.9 g of meglumine was added to a 1000 mL suspension of water for injection of 73.2 g of compound A, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 1220 mL. To 200 mL of this solution, 2.00 g of glucose was added and dissolved, followed by filtration through a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 8.0). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.04% Lyophilization method: as in Example 7
- Example 18 Lactose (1.65 g) was added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 19 10 mL of a preparation solution (pH 8.1) produced by the same method as in Example 7 was filled in a vial, and 0.30 g of purified sucrose (manufactured by Shisui Minato Sugar Co., Ltd.) was added and dissolved. After freeze-drying, it was sealed and a crystal freeze-dried preparation was obtained. Lyophilization method: as in Example 7
- Example 20 1.60 g of D-sorbitol was added to 160 mL of the prepared solution produced in the same manner as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 21 0.35 g of xylitol was added to 35 mL of a preparation solution produced by the same method as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 22 85.8 g of meglumine was added to a suspension of 69.0 g of Compound A in 760 mL of water for injection, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 920 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 7.6). 8 mL of the prepared solution was filled in a vial, and 0.10 g of inositol was added and dissolved. After freeze-drying, it was sealed and a crystal freeze-dried preparation was obtained. Lyophilization method: as in Example 7
- Example 23 1.60 g of D-mannitol was added to 160 mL of the preparation solution produced in the same manner as in Example 7, to obtain a solution (pH 8.1). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 24 0.55 g of sodium acetate trihydrate was added to 55 mL of the preparation solution prepared in the same manner as in Example 7 to obtain a solution (pH 8.1). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 25 1.11 g of sodium lactate (50% solution) was added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 8.1). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 26 0.55 g of sodium benzoate was added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 8.1). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 27 Creatinine (0.35 g) was added to 35 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 28 85.8 g of meglumine was added to a suspension of 69.0 g of Compound A in 760 mL of water for injection, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 920 mL. To 240 mL of this solution, 1.50 g of urea was added and dissolved, followed by filtration through a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 7.7). 8 mL of the prepared solution was filled into a vial, freeze-dried, and sealed up to obtain a freeze-dried crystalline product. Moisture content: 0.02% Lyophilization method: as in Example 7
- Example 29 18.6 g of meglumine and 1.25 g of nicotinamide were added to a suspension of Compound A 15.0 g of water for injection and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 200 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 7.8). 8 mL of the prepared solution was filled into a vial, freeze-dried, and sealed up to obtain a freeze-dried crystalline product. Moisture content: 0.02% Method of lyophilization The vial was cooled at a shelf temperature of ⁇ 60 ° C. and the contents were frozen. 2. The shelf temperature was raised to ⁇ 10 ° C.
- the shelf temperature was cooled to ⁇ 55 ° C. or lower and held at that temperature for 2 hours. 4). Under a vacuum (50 Pa or less), the shelf temperature was raised to 10 ° C. and kept at the same pressure and the same temperature for 30 hours. 5. The shelf temperature was raised to 20 ° C. and held at the same pressure and temperature for 2 hours. 6). The shelf temperature was raised to 40 ° C. and maintained at the same pressure and temperature for 10 hours.
- Example 30 0.55 g of trometamol was added to 55 mL of the preparation solution produced by the same method as in Example 7 to obtain a solution (pH 8.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 31 2. 210 g of glycine and 2.10 g of trehalose were added to 210 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 32 2.10 g of L-alanine and 2.10 g of trehalose were added to 210 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Freeze-drying method: as in Example 7 Moisture content: 0.05% In the powder X-ray diffraction pattern of the lyophilized preparation, a salt peak of the salt A anhydride observed in Example 3 was observed.
- Example 33 10 mL of a prepared solution (pH 8.1) produced by the same method as in Example 7 was filled in a vial, and 0.10 g of glycine and 0.10 g of purified sucrose (manufactured by Shisui Minato Sugar Co., Ltd.) were added and dissolved. After freeze-drying, it was sealed and a crystal freeze-dried preparation was obtained. Lyophilization method: as in Example 7
- Example 34 10 mL of a preparation solution (pH 8.1) produced by the same method as in Example 7 was filled in a vial, and 0.10 g of L-alanine and 0.10 g of purified sucrose (manufactured by Shisui Minato Sugar Co., Ltd.) were added and dissolved. After freeze-drying, it was sealed and a crystal freeze-dried preparation was obtained. Lyophilization method: as in Example 7
- Example 35 0.990 g of glycine and 0.90 g of D-sorbitol were added to 90 mL of a preparation solution produced by the same method as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 36 L-alanine (2.10 g) and D-sorbitol (2.10 g) were added to 210 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 37 0.990 g of glycine and 0.90 g of xylitol were added to 90 mL of a preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 38 L-alanine 0.90 g and xylitol 0.90 g were added to 90 mL of a preparation solution produced by the same method as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 39 0.990 g of glycine and 0.90 g of D-mannitol were added to 90 mL of a preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 40 L-alanine (2.10 g) and D-mannitol (2.10 g) were added to 210 mL of the preparation solution prepared in the same manner as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Lyophilization method: as in Example 7
- Example 41 Meglumine (14.9 g) was added to a suspension of Compound A (12.0 g) in water for injection (180 mL) and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 200 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 7.4). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.03% Freeze-drying method: as in Example 6
- Example 42 15.7 g of meglumine was added to a 170 mL suspension of water for injection of Compound A 12.0 g, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 200 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 8.5). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.02% Freeze-drying method: as in Example 6
- Example 43 Manufactured in the same manner as in Example 41 to obtain a preparation solution (pH 7.6). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.01% Lyophilization method: as in Example 7
- Example 44 Manufactured in the same manner as in Example 42 to obtain a preparation solution (pH 8.5). Each 10 mL of the prepared solution was filled into a vial, freeze-dried and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.00% Lyophilization method: as in Example 7
- Example 45 Trehalose (1.10 g) and glycine (1.10 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.7). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.12% Freeze-drying method: as in Example 6
- Example 46 Trehalose (1.10 g) and glycine (1.10 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.8). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.03% Lyophilization method: as in Example 7
- Example 47 D-mannitol 0.28 g and glycine 0.28 g were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.07% Freeze-drying method: as in Example 6
- Example 48 D-mannitol (1.10 g) and glycine (1.10 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7, to obtain a solution (pH 7.8). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.04% Lyophilization method: as in Example 7
- Example 49 1.55 g of purified sucrose (manufactured by Shisui Minato Seimitsu Co., Ltd.) and 1.10 g of glycine were added to 55 mL of the preparation solution produced in the same manner as in Example 7, to obtain a solution (pH 7.7). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.14% Freeze-drying method: as in Example 6
- Example 50 1.55 g of purified sucrose (manufactured by Shimizu Minato Seimitsu Co., Ltd.) and 1.10 g of glycine were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.8). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.02% Lyophilization method: as in Example 7
- Example 51 Trehalose (0.55 g) and L-alanine (0.55 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 41 to obtain a solution (pH 7.4). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.03% Freeze-drying method: as in Example 6
- Example 52 Trehalose 0.28 g and L-alanine 0.28 g were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.04% Freeze-drying method: as in Example 6
- Example 53 Trehalose (0.55 g) and L-alanine (0.55 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.04% Freeze-drying method: as in Example 6
- Example 54 Trehalose (1.10 g) and L-alanine (1.10 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7, to obtain a solution (pH 7.8). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.04% Freeze-drying method: as in Example 6
- Example 55 Trehalose (0.55 g) and L-alanine (0.55 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 42 to obtain a solution (pH 8.4). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.03% Freeze-drying method: as in Example 6
- Example 56 Trehalose 0.28 g and L-alanine 0.28 g were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 8.0). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.02% Lyophilization method: as in Example 7
- Example 57 Trehalose (0.55 g) and L-alanine (0.55 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 41 to obtain a solution (pH 7.5). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.01% Lyophilization method: as in Example 7
- Example 58 Trehalose (0.55 g) and L-alanine (0.55 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 42 to obtain a solution (pH 8.4). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.02% Lyophilization method: as in Example 7
- Example 59 Trehalose (1.10 g) and L-alanine (1.10 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.02% Lyophilization method: as in Example 7
- Example 60 0.25 g of D-sorbitol and 0.28 g of L-alanine were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.03% Freeze-drying method: as in Example 6
- Example 61 0.25 g of D-sorbitol and 0.28 g of L-alanine were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.04% Lyophilization method: as in Example 7
- Example 62 D-mannitol (1.10 g) and L-alanine (1.10 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7, to obtain a solution (pH 7.8). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.07% Freeze-drying method: as in Example 6
- Example 63 D-mannitol (1.10 g) and L-alanine (1.10 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7, to obtain a solution (pH 7.8). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.04% Lyophilization method: as in Example 7
- Example 64 Purified sucrose (manufactured by Shimizu Minato Seimitsu Co., Ltd.) (0.28 g) and L-alanine (0.28 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7, to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.03% Freeze-drying method: as in Example 6
- Example 65 Purified sucrose (manufactured by Shimizu Minato Seimitsu Co., Ltd.) (0.55 g) and L-alanine (0.55 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.8). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.02% Freeze-drying method: as in Example 6
- Example 66 1.55 g of purified sucrose (manufactured by Shimizu Minato Seimitsu Co., Ltd.) and 1.10 g of L-alanine were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.8). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.03% Freeze-drying method: as in Example 6
- Example 67 Purified sucrose (manufactured by Shimizu Minato Seimitsu Co., Ltd.) (0.28 g) and L-alanine (0.28 g) were added to 55 mL of the preparation solution produced in the same manner as in Example 7, to obtain a solution (pH 7.9). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.02% Lyophilization method: as in Example 7
- Example 68 1.55 g of purified sucrose (manufactured by Shimizu Minato Seimitsu Co., Ltd.) and 1.10 g of L-alanine were added to 55 mL of the preparation solution produced in the same manner as in Example 7 to obtain a solution (pH 7.8). Each 10 mL of the lysate was filled in a vial, freeze-dried, and sealed up to obtain a crystalline freeze-dried preparation. Moisture content: 0.02% Lyophilization method: as in Example 7
- Example 69 46.2 g of meglumine was added to 400 mL of water for injection of 36.0 g of Compound A, and dissolved by stirring. Water for injection was added to the resulting solution to make a total volume of 480 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 8.6). 8 mL of the prepared solution was filled into a vial, freeze-dried, and sealed up to obtain a freeze-dried crystalline product. Moisture content: 0.02% Freeze-drying method: as in Example 6
- Comparative Example 1 A 1 mol / L aqueous sodium hydroxide solution was added to a suspension of 13.8 g of compound A in 50 mL of water for injection, stirred and dissolved, and then a 1 mol / L aqueous sodium hydroxide solution was added to adjust the pH to 8.5. Water for injection was added to make a total volume of 161 mL, followed by filtration with a 0.22 ⁇ m membrane filter to obtain a preparation solution (pH 8.4). Each 7 mL of the prepared solution was filled in a vial, freeze-dried and sealed, to obtain an amorphous freeze-dried preparation. Moisture content: 2.2% Method of lyophilization The vial was cooled at a shelf temperature of ⁇ 60 ° C.
- the shelf temperature was raised to ⁇ 10 ° C. and maintained at the same pressure and temperature for 37 hours. 3. The shelf temperature was raised to 0 ° C, and the same pressure and temperature were maintained for 9 hours. 4). The shelf temperature was raised to 10 ° C. and held at the same pressure and temperature for 4 hours. 5. The shelf temperature was raised to 20 ° C. and held at the same pressure and temperature for 4 hours. 6). The shelf temperature was raised to 40 ° C. and maintained at the same pressure and temperature for 15 hours.
- Comparative Example 2 A 1 mol / L sodium hydroxide aqueous solution was added to a suspension of compound A (12.0 g) in 70 mL of water for injection, and the mixture was stirred to dissolve. Then, a 1 mol / L sodium hydroxide aqueous solution was added to adjust the pH to 8.5. Water for injection was added to make a total volume of 160 mL, followed by filtration through a 0.22 ⁇ m membrane filter to obtain a preparation (pH 8.5). 8 mL of the prepared solution was filled into vials, freeze-dried and sealed, to obtain an amorphous freeze-dried preparation. Method of lyophilization The vial was cooled at a shelf temperature of ⁇ 60 ° C. and the contents were frozen. 2. Under vacuum (50 Pa or less), the temperature was raised to a shelf temperature of 50 ° C. and maintained at the same pressure and temperature for 39 hours.
- Test Example 1 Solubility 10 mL of water for injection was added to the vials obtained in Comparative Examples and Examples, and shaken by hand, and the time until the solid was dissolved was measured. The results are shown in Table 3.
- the dissolution time of amorphous sodium salt was 60 seconds.
- the dissolution time of amorphous sodium salt was 65 seconds.
- the dissolution time of the ground product of the meglumine salt monohydrate was 5 seconds.
- the ground product of meglumine salt showed better solubility than the sodium salt amorphous.
- the dissolution time of the amorphous meglumine salt was 5 seconds.
- the meglumine salt amorphous showed better solubility than the sodium salt amorphous.
- the dissolution time of the preparations (Examples 6 to 9, 41 to 44) produced by lyophilization including the annealing step was 10 to 31 seconds.
- the preparation produced by this production method showed better solubility than the amorphous sodium salt without grinding.
- Preparations containing amino acids as additives (Examples 10 to 13), preparations containing saccharides (Examples 14 to 19), preparations containing sugar alcohols (Examples 20 to 23), preparations containing salts (Examples 24 to 26), a preparation containing creatinine (Example 27), a preparation containing urea (Example 28), a preparation containing nicotinamide (Example 29), and a preparation containing trometamol (Execution)
- the dissolution time of Example 30) showed much better solubility than the sodium salt amorphous.
- preparations containing amino acids and saccharides (Examples 31 to 34, 45, 46, 49 to 59, 64 to 68) and preparations containing amino acids and sugar alcohols (Examples 35 to 40, 47, 60).
- the dissolution times of -63) were all within 10 seconds and showed extremely excellent solubility.
- Example 2 Appearance As a result of observing the appearance, the freeze-dried preparations of Examples 7 and 8 were uniform freeze-dried preparations with no melting marks. In Examples 12, 15, 27, 31 to 33, 36, 38, 51, 55 and 59, no melt marks were observed and the cakes were uniform, the surface was smooth and the appearance was better. A freeze-dried preparation having a better appearance was obtained by blending the additive.
- Test Example 3 Stability (1) The freeze-dried preparations of Examples 7, 8, 10, 11, 13, 15, 20, 23, 31, 32, 36, and 40 were allowed to stand at 40 ° C. for 6 months, and the appearance and the residual ratio of Compound A were examined. It was. As a result, a change in appearance and a decrease in the content of Compound A were not observed.
- Test Example 4 Stability (2) The freeze-dried preparations of Example 69 and Comparative Example 1 were irradiated (1.2 million lx ⁇ hr) using a D65 lamp (FLR20S-D-EDL-D65 / M), and the appearance was observed. As a result, no change was found in Example 69. On the other hand, Comparative Example 1 was colored orange-yellow.
- 6 is a powder X-ray diffraction pattern of a monohydrate crystal of meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.
- 6 is an amorphous powder X-ray diffraction pattern of meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.
- 6 is a powder X-ray diffraction pattern of an anhydrous crystal of meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.
- the preparation filled with the meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide of the present invention has excellent solubility and is useful as an injectable preparation.
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Abstract
Description
現在、インフルエンザの治療剤として、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、たとえば、次のような欠点を有している。オセルタミビルは、経口投与が困難な患者には投与できない。ザナミビルは、小児や高齢者へ投与し難い。ペラミビルは、投与時間がかかる。アマンタジンは、B型インフルエンザウイルスに無効であり、耐性ウイルスが出現している。ラニナミビルは、吸入薬であり、認知症患者および重症者には不向きであり、小児へも投与し難い。
さらに優れたインフルエンザの治療剤が、求められている。特に、経口投与が困難な患者、小児および高齢者へ投与できる注射剤が求められている。
本発明者らは、化合物Aの水溶解性を向上させる目的で、塩基として汎用されている水酸化ナトリウムを用いて化合物Aのナトリウム塩の水溶液を調製した後、常法によって凍結乾燥製剤を製造した。この製造によって得られる化合物Aのナトリウム塩は、非晶質の乾燥粉末であり、速やかに溶解することが期待された。しかし、予想に反して、得られた凍結乾燥製剤は、溶解に長時間を要する難溶解性の凍結乾燥ケーキであった。すなわち、凍結乾燥製剤に溶解液を加えると、凍結乾燥ケーキは難溶性の塊状物質に変化し、溶解に長時間を要した。化合物Aのナトリウム塩の非晶質の凍結乾燥製剤は、溶解に長時間を要し、使用利便性が著しく損なわれた取り扱い難い製剤であった。
(1)化合物Aのメグルミン塩(以下、「塩A」とする)に非晶質および結晶が存在すること、
(2)塩Aの水に対する溶解度が高いこと、
(3)塩Aの非晶質の水に対する溶解速度、塩Aの結晶の水に対する溶解速度および粉砕した塩Aの結晶の水に対する溶解速度が著しく大きいこと、
(4)塩Aの非晶質、塩Aの結晶および/または粉砕した塩Aの結晶が充填された製剤が、溶解性に優れていることを見出した。
すなわち、塩Aの水溶液を凍結乾燥することにより、塩Aの非晶質を製造することができる。この非晶質は、水に対する溶解度が高く、溶解速度が著しく大きい。そのため、塩Aの非晶質が充填された製剤は、溶解性に優れ、注射用製剤として有用である。
塩Aの溶液から結晶を析出させることにより、塩Aの結晶を製造することができる。この結晶は、水に対する溶解度が高く、溶解速度が著しく大きい。そのため、塩Aの結晶が充填された製剤は、溶解性に優れ、注射用製剤として有用である。
また、粉砕した塩Aの結晶は、水に対する溶解度が高く、溶解速度が著しく大きい。そのため、粉砕した塩Aの結晶が充填された製剤は、溶解性に優れ、注射用製剤として有用である。
本発明者らは、鋭意検討を重ねた結果、凍結乾燥において、一次凍結後の昇温時の温度(晶析温度)の範囲をコントロールすることにより、短い晶析時間で、しかも、溶解速度が著しく大きい塩Aの結晶の凍結乾燥製剤が製造できることを見出した。すなわち、凍結乾燥の一次凍結後に昇温する工程を設けることにより、塩Aの結晶を製造することができる。この結晶は、粉砕しなくても、水に対する溶解度が高く、溶解速度が著しく大きい。そのため、この結晶が充填された製剤は、溶解性に優れ、注射用製剤として有用である。
本発明者らは、さらに鋭意検討を重ねた結果、凍結乾燥に付す塩Aの水溶液に添加剤を配合することにより、さらに優れた凍結乾燥製剤が製造できることを見出し、本発明を完成するに至った。
しかし、本発明の塩Aの結晶は、凍結乾燥時に脱水操作を施しても、非晶質に変化しない。しかも、本発明の塩Aの凍結乾燥製剤は、化合物Aのナトリウム塩の非晶質の凍結乾燥製剤に比べて溶解性に優れ、安定性が極めて良好である。
本発明の製造法により、優れた塩Aの結晶の凍結乾燥製剤を製造することができる。この凍結乾燥製剤は、無菌性の確保および不溶性異物の除去が容易であり、利用価値の高い注射剤である。
1.塩Aまたはその水和物である。塩Aまたはその水和物は、水に対する溶解度が高く、溶解速度が著しく大きい。
2.塩Aまたはその水和物の結晶である。この結晶は、水に対する溶解度が高く、溶解速度が著しく大きい。
3.塩Aの非晶質である。この非晶質は、水に対する溶解度が高く、溶解速度が著しく大きい。
4.塩Aまたはその水和物を含有する注射用製剤である。この注射用製剤は、溶解性に優れている。
5.塩Aまたはその水和物の結晶を含有する注射用製剤である。この注射用製剤は、溶解性に優れている。
6.塩Aまたはその水和物の非晶質を含有する注射用製剤である。この注射用製剤は、溶解性に優れている。
7.さらに、アミノ酸類と糖類、または、アミノ酸類と糖アルコール類を含有する前記4または5に記載の注射用製剤である。この注射用製剤は、溶解性に優れている。
8.塩Aを含有する凍結乾燥製剤である。この凍結乾燥製剤は、溶解性に優れている。
9.塩Aの結晶を含有する凍結乾燥製剤である。この凍結乾燥製剤は、溶解性に優れている。
10.塩Aの非晶質を含有する凍結乾燥製剤である。この凍結乾燥製剤は、溶解性に優れている。
11.さらに、アミノ酸類と糖類、または、アミノ酸類と糖アルコール類を含有する前記8または9に記載の凍結乾燥製剤である。この凍結乾燥製剤は、溶解性に優れている。
12.(1)化合物Aおよびメグルミンを含有する水溶液を冷却して凍結体を製造する工程、(2)凍結体を昇温する工程、(3)凍結体を再度冷却する工程、(4)凍結乾燥を行う工程、を含むことを特徴とする、塩Aの結晶を含有する凍結乾燥製剤の製造法である。この製造法により、短い晶析時間で、しかも、溶解速度が著しく大きい塩Aの結晶の凍結乾燥製剤を製造することができる。
13.凍結体を昇温する工程における凍結体の到達温度が、-20~-5℃の範囲である、前記12に記載の製造法である。凍結体の到達温度を-20~-5℃の範囲にすることにより、さらに優れた塩Aの結晶の凍結乾燥製剤を製造することができる。
また、本発明の塩Aが充填された製剤は、溶解性および安定性に優れ、さらに外観の良い注射用製剤として有用である。
さらに、本発明の塩Aの製造法は、溶解性および安定性に優れ、さらに外観の良い塩Aの結晶の凍結乾燥製剤の製造法として有用である。
化合物Aは、たとえば、特許文献2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。
本発明の塩Aおよびそれを含有する注射用製剤は、たとえば、次の製造法によって製造することができる。
化合物Aおよびメグルミンを水に加え、加熱溶解した後、2-プロパノールを添加し、析出した結晶を濾取することにより、塩Aの1水和物の結晶を製造することができる。
水の量は、化合物Aに対して1~10倍量(v/w)であればよく、2~4倍量(v/w)が好ましい。
メグルミンの量は、化合物Aに対して1.0倍モル以上であればよく、1.0~1.5倍モルが好ましい。
メグルミンとの反応温度は、30~100℃であればよく、40~80℃が好ましい。
2-プロパノールの量は、化合物Aに対して5~50倍量(v/w)であればよく、10~15倍量(v/w)が好ましい。
このようにして得られた塩Aの1水和物の結晶および/または粉砕した塩Aの1水和物の結晶をバイアル等に充填することにより、注射用製剤を製造することができる。
塩Aの1水和物の結晶を-20~60℃で減圧下に静置することにより、塩Aの無水物の結晶を製造することができる。
静置する時間は、0.5~120時間であればよく、1~72時間が好ましい。
減圧度は、特に限定されないが、100Pa以下であればよく、50Pa以下が好ましい。
また、塩Aの1水和物の結晶を加熱下、静置することにより、塩Aの無水物の結晶を製造することができる。
加熱温度は、30℃以上であればよく、50℃~110℃が好ましく、50℃~90℃がより好ましい。
このようにして得られた塩Aの無水物の結晶および/または粉砕した塩Aの無水物の結晶を、バイアル等に充填することにより、注射用製剤を製造することができる。
また、塩Aの1水和物の結晶を粉砕した後、上記と同様に乾燥することによっても、塩Aの無水物の注射用製剤を製造することができる。
化合物Aおよびメグルミンの水溶液を凍結乾燥することにより塩Aの非晶質を製造することができる。
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。
メグルミンは、水溶液のpHが4.0~10、好ましくは7.0~9.0になるように添加する。
凍結乾燥は、たとえば、化合物Aおよびメグルミンの水溶液を-40℃以下で凍結させた後、崩壊温度以下の品温を維持して行えばよい。
(1)第一工程(一次凍結工程)
化合物Aおよびメグルミンの水溶液を凍結させることにより、非晶質の凍結体を得ることができる。
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。
メグルミンは、水溶液のpHが4.0~10、好ましくは7.0~9.0になるように添加する。
一次凍結工程の温度は、崩壊温度以下であればよい。本発明の場合、-60~-40℃が好ましい。
一次凍結工程の時間は、1~10時間であればよく、2~5時間が好ましい。
非晶質の凍結体を昇温し、一定時間保持する(アニーリング)ことで、結晶化が進行し、結晶性の凍結体を得ることができる。
アニーリング工程の温度は、非晶質の凍結体の融解が起きず、かつ、凍結体が凍結を維持できる範囲で結晶化が進行する温度であればよく、-20~-2℃が好ましく、-20~-5℃がより好ましく、-15~-5℃がさらに好ましい。
アニーリング工程の保持時間は、0.5~48時間であればよく、1~24時間が好ましい。
ついで、結晶性の凍結体を再度冷却する。
二次凍結工程の温度は、-60~-30℃が好ましい。
二次凍結工程の時間は、1~10時間であればよく、2~5時間が好ましい。
ついで、減圧処理を行うことにより、凍結乾燥製剤を製造することができる。
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、たとえば、一次乾燥工程および二次乾燥工程の2つの工程によって行うことができる。
一次乾燥工程は、減圧下、共晶点以下の品温を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、機器の設定温度は、共晶点以上でもよい。
凍結体の品温は、-40~-3℃であればよく-30~-5℃が好ましい。
このときの機器の設定温度は、-20~60℃であればよく、-10~50℃が好ましい。
一次乾燥工程の減圧度は、特に限定されないが、100Pa以下であればよく、50Pa以下が好ましい。
昇華する水分が減少するに伴い、温度低下が緩和になり、この結果として品温が上昇し、品温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。
ついで、二次乾燥工程を実施する。
二次乾燥工程は、室温以上で実施され、30~60℃が好ましい。
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のがよい。減圧度は、0.5~10Paであればよく、1~5Pa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。
なお、本発明の凍結乾燥製剤の製造において、滅菌処理などは、通常行われる手順に従って実施すればよい。
本発明の製造法は、有機溶媒を使用しないため、凍結乾燥製剤には残留溶媒が存在しない。
本発明の凍結乾燥製剤は、人体に対して安全である。
粉末X線回折の測定条件
使用X線:CuKα
加電圧:40kV
加電流:40mA
走査軸:2θ
走査範囲:2θ=2~40°
なお、粉末X線回折による特徴的なピークは、測定条件により変動することがある。一般に、2θは、±0.2°の範囲内で誤差が生じる。従って、「2θで表されるX°の回折角度」は、「2θで表される((X-0.2)~(X+0.2))°の回折角度」を意味する。
添加物を加えることにより、アニーリング工程の温度幅を広げることができる。
添加物としては、アミノ酸類、糖類、糖アルコール類、塩類、尿素、エチル尿素、クレアチニン、ニコチン酸アミドおよびトロメタモールなどが挙げられ、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。好ましい添加物としては、アミノ酸類、糖類、糖アルコール類、塩類、尿素、クレアチニン、ニコチン酸アミドおよびトロメタモールが挙げられる。
アミノ酸類としては、グリシン、L-アラニン、L-フェニルアラニン、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、グリシン、L-アラニン、タウリンおよびL-ヒスチジンがより好ましく、グリシンおよびL-アラニンがさらに好ましい。
糖類としては、トレハロース、マルトース、ブドウ糖、乳糖、精製白糖、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、トレハロース、マルトース、ブドウ糖、乳糖および精製白糖がより好ましく、トレハロースおよび精製白糖がさらに好ましい。
糖アルコール類としては、D-ソルビトール、キシリトール、イノシトールおよびD-マンニトールなどが挙げられる。
塩類としては、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、酢酸ナトリウム、乳酸ナトリウムおよび安息香酸ナトリウムがより好ましい。
アミノ酸類としては、好ましくは、グリシンおよびL-アラニンが挙げられる。
糖類としては、好ましくは、トレハロースおよび精製白糖が挙げられる。
糖アルコール類としては、好ましくは、D-ソルビトール、キシリトールおよびD-マンニトールが挙げられる。
浸透圧調節剤としては、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、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、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。
界面活性剤としては、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、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、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。
本発明の注射用製剤中の化合物Aの含有量は、10~6000mg、好ましくは、100~2000mgである。
本発明の注射用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、0.1~115%(w/w)、好ましくは5~65%(w/w)である。
DMSO-d6は、重ジメチルスルホキシドを意味する。
含水率は、カールフィッシャー法で測定した。
化合物A10.0gおよびメグルミン15.0gの水30mL懸濁液を50℃に加熱し、溶解した。2-プロパノール120mLを40℃で滴下した後、5℃まで冷却し、同温度で1時間撹拌した。固形物を濾取し、淡黄色の塩Aの1水和物の結晶21.3gを得た。
含水率:5.2%
1H-NMR(400MHz,DMSO-d6)δ(ppm):10.43(1H,brs),7.93(1H,d,J=9.0Hz),7.27(1H,brs),3.90-3.80(1H,m),3.70-3.55(2H,m),3.55-3.35(3H,m),3.05-2.85(2H,m),2.54(3H,s)
塩Aの1水和物の結晶の粉末X線回折を図1および表1に示す。
実施例1で得られた結晶を粉砕し、60号(250μm)ふるいを通過し、282号(53μm)ふるいに残留する粉末を得た。この粉末1.41gをバイアルに充填し、1水和物の結晶の注射用製剤を得た。
実施例1で得られた結晶1.35gを40℃で真空下(50Pa以下)に64時間静置し、無水物の結晶を得た。
含水率:0.07%
得られた結晶の粉末X線回折のパターンには、2θ(°):11.3、13.0、17.0、19.7、20.5、22.0、24.2、26.4、28.1にピークが認められた。
実施例1で得られた結晶86mgを80~90℃で5分間静置した後、90℃で180分間静置し,無水物の結晶を得た。
無水物の結晶の粉末X線回折を図3および表2に示す。
粉末X線回折のパターンは実施例3-1と一致した。
使用X線:CuKα1,CuKα2,CuKβ
加電圧:45kV
加電流:40mA
走査軸:2θ
走査範囲:2θ=2~40°
測定温度:90℃
実施例2で得られた注射用製剤を40℃で真空下(50Pa以下)に60時間静置し、無水物の結晶の注射用製剤を得た。
含水率:0.17%
化合物A45.1gの注射用水500mL懸濁液にメグルミン55.9gを添加し、撹拌して溶解した。注射用水を加え、全量600mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH7.6)を得た。調製液を8mLずつバイアルに充填し、凍結乾燥後、密栓し、非晶質の凍結乾燥製剤を得た。
含水率:0.17%
凍結乾燥製剤の粉末X線回折を図2に示す。
凍結乾燥の方法
1.棚温度-60℃でバイアルを冷却し、内容物を凍結した。
2.真空下(50Pa以下)、棚温度-20℃に昇温し、同圧力、同温度で64時間保持した。
3.棚温度-10℃に昇温し、同圧力、同温度で7時間保持した。
4.棚温度0℃に昇温し、同圧力、同温度で11時間保持した。
5.棚温度20℃に昇温し、同圧力、同温度で10時間保持した。
6.棚温度40℃に昇温し、同圧力、同温度で17時間保持した。
化合物A72.0gの注射用水1000mL懸濁液にメグルミン90.7gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量1200mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH8.0)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.01%
凍結乾燥製剤の粉末X線回折のパターンには、実施例3で認められた塩Aの無水物の結晶のピークが認められた。
凍結乾燥の方法
1.棚温度-60℃でバイアルを冷却し、内容物を凍結した。
2.棚温度-5℃に昇温し、同温度で25時間保持した。
3.棚温度-55℃以下に冷却し、同温度で3時間保持した。
4.真空下(50Pa以下)、棚温度40℃に昇温し、同圧力、同温度で60時間保持した。
化合物A132gの注射用水1900mL懸濁液にメグルミン166gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量2200mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH8.0)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.01%
凍結乾燥製剤の粉末X線回折のパターンには、実施例3で認められた塩Aの無水物の結晶のピークが認められた。
凍結乾燥の方法
1.棚温度-60℃でバイアルを冷却し、内容物を凍結した。
2.棚温度-10℃に昇温し、同温度で24時間保持した。
3.棚温度-55℃以下に冷却し、同温度で2時間保持した。
4.真空下(50Pa以下)、棚温度40℃に昇温し、同圧力、同温度で48時間保持した。
化合物A132gの注射用水1800mL懸濁液にメグルミン166gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量2200mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH8.0)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.00%
凍結乾燥製剤の粉末X線回折のパターンには、実施例3で認められた塩Aの無水物の結晶のピークが認められた。
凍結乾燥の方法
1.棚温度-60℃でバイアルを冷却し、内容物を凍結した。
2.棚温度-15℃に昇温し、同温度で24時間保持した。
3.棚温度-55℃以下に冷却し、同温度で2時間保持した。
4.真空下(50Pa以下)、棚温度40℃に昇温し、同圧力、同温度で46時間保持した。
化合物A54.0gの注射用水750mL懸濁液にメグルミン68.0gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量900mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH8.0)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥製剤の粉末X線回折のパターンには、実施例3で認められた塩Aの無水物の結晶のピークが認められた。
凍結乾燥の方法
1.棚温度-60℃でバイアルを冷却し、内容物を凍結した。
2.棚温度-30℃に昇温し、同温度で14時間保持した。
3.棚温度-25℃に昇温し、同温度で25時間保持した。
4.棚温度-20℃に昇温し、同温度で25時間保持した。
5.棚温度-55℃以下に冷却し、同温度で2時間保持した。
6.真空下(50Pa以下)、棚温度40℃に昇温し、同圧力、同温度で50時間保持した。
化合物A73.2gの注射用水1000mL懸濁液にメグルミン91.9gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量1220mLとした。この液200mLにグリシン2.00gを添加し、溶解した後、0.22μmメンブランフィルターで濾過し、調製液(pH7.8)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.03%
凍結乾燥製剤の粉末X線回折のパターンには、実施例3で認められた塩Aの無水物の結晶のピークが認められた。
凍結乾燥の方法:実施例7と同様
化合物A73.2gの注射用水1000mL懸濁液にメグルミン91.9gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量1220mLとした。この液200mLにL-アラニン2.00gを添加し、溶解した後、0.22μmメンブランフィルターで濾過し、調製液(pH7.9)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.03%
凍結乾燥製剤の粉末X線回折のパターンには、実施例3で認められた塩Aの無水物の結晶のピークが認められた。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液35mLにL-ヒスチジン0.35gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
化合物A69.0gの注射用水760mL懸濁液にメグルミン85.8gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量920mLとした。この液240mLにタウリン1.20gを添加し、溶解した後、0.22μmメンブランフィルターで濾過し、調製液(pH7.6)を得た。調製液を8mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液100mLにトレハロース1.00gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.05%
凍結乾燥の方法:実施例7と同様
凍結乾燥製剤の粉末X線回折のパターンには、実施例3で認められた塩Aの無水物の結晶のピークが認められた。
実施例7と同様な方法で製造された調製液160mLにトレハロース3.20gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLにD-マルトース1水和物1.65gを添加し、溶解液(pH8.1)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
化合物A73.2gの注射用水1000mL懸濁液にメグルミン91.9gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量1220mLとした。この液200mLにブドウ糖2.00gを添加し、溶解した後、0.22μmメンブランフィルターで濾過し、調製液(pH8.0)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.04%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLに乳糖1.65gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液(pH8.1)10mLをバイアルに充填し、精製白糖(塩水港精糖社製)を0.30gずつ添加し、溶解した。凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液160mLにD-ソルビトール1.60gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液35mLにキシリトール0.35gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
化合物A69.0gの注射用水760mL懸濁液にメグルミン85.8gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量920mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH7.6)を得た。調製液8mLをバイアルに充填し、イノシトール0.10gを添加し、溶解した。凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液160mLにD-マンニトール1.60gを添加し、溶解液(pH8.1)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLに酢酸ナトリウム3水和物0.55gを添加し、溶解液(pH8.1)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLに乳酸ナトリウム(50%液)1.11gを添加し、溶解液(pH8.1)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLに安息香酸ナトリウム0.55gを添加し、溶解液(pH8.1)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液35mLにクレアチニン0.35gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
化合物A69.0gの注射用水760mL懸濁液にメグルミン85.8gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量920mLとした。この液240mLに尿素1.50gを添加し、溶解した後、0.22μmメンブランフィルターで濾過し、調製液(pH7.7)を得た。調製液を8mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例7と同様
化合物A15.0gの注射用水160mL懸濁液にメグルミン18.6gおよびニコチン酸アミド1.25gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量200mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH7.8)を得た。調製液を8mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法
1.棚温度-60℃でバイアルを冷却し、内容物を凍結した。
2.棚温度-10℃に昇温し、同温度で24時間保持した。
3.棚温度-55℃以下に冷却し、同温度で2時間保持した。
4.真空下(50Pa以下)、棚温度10℃に昇温し、同圧力、同温度で30時間保持した。
5.棚温度20℃に昇温し、同圧力、同温度で2時間保持した。
6.棚温度40℃に昇温し、同圧力、同温度で10時間保持した。
実施例7と同様な方法で製造された調製液55mLにトロメタモール0.55gを添加し、溶解液(pH8.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液210mLにグリシン2.10gおよびトレハロース2.10gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液210mLにL-アラニン2.10gおよびトレハロース2.10gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
含水率:0.05%
凍結乾燥製剤の粉末X線回折のパターンには、実施例3で認められた塩Aの無水物の結晶のピークが認められた。
実施例7と同様な方法で製造された調製液(pH8.1)10mLをバイアルに充填し、グリシン0.10gおよび精製白糖(塩水港精糖社製)0.10gを添加し、溶解した。凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液(pH8.1)10mLをバイアルに充填し、L-アラニン0.10gおよび精製白糖(塩水港精糖社製)0.10gを添加し、溶解した。凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液90mLにグリシン0.90gおよびD-ソルビトール0.90gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液210mLにL-アラニン2.10gおよびD-ソルビトール2.10gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液90mLにグリシン0.90gおよびキシリトール0.90gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液90mLにL-アラニン0.90gおよびキシリトール0.90gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液90mLにグリシン0.90gおよびD-マンニトール0.90gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液210mLにL-アラニン2.10gおよびD-マンニトール2.10gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
凍結乾燥の方法:実施例7と同様
化合物A12.0gの注射用水180mL懸濁液にメグルミン14.9gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量200mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH7.4)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.03%
凍結乾燥の方法:実施例6と同様
化合物A12.0gの注射用水170mL懸濁液にメグルミン15.7gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量200mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH8.5)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例6と同様
実施例41と同様な方法で製造し、調製液(pH7.6)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.01%
凍結乾燥の方法:実施例7と同様
実施例42と同様な方法で製造し、調製液(pH8.5)を得た。調製液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.00%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLにトレハロース1.10gおよびグリシン1.10gを添加し、溶解液(pH7.7)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.12%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLにトレハロース1.10gおよびグリシン1.10gを添加し、溶解液(pH7.8)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.03%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLにD-マンニトール0.28gおよびグリシン0.28gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.07%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLにD-マンニトール1.10gおよびグリシン1.10gを添加し、溶解液(pH7.8)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.04%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLに精製白糖(塩水港精糖社製)1.10gおよびグリシン1.10gを添加し、溶解液(pH7.7)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.14%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLに精製白糖(塩水港精糖社製)1.10gおよびグリシン1.10gを添加し、溶解液(pH7.8)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例7と同様
実施例41と同様な方法で製造された調製液55mLにトレハロース0.55gおよびL-アラニン0.55gを添加し、溶解液(pH7.4)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.03%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLにトレハロース0.28gおよびL-アラニン0.28gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.04%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLにトレハロース0.55gおよびL-アラニン0.55gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.04%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLにトレハロース1.10gおよびL-アラニン1.10gを添加し、溶解液(pH7.8)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.04%
凍結乾燥の方法:実施例6と同様
実施例42と同様な方法で製造された調製液55mLにトレハロース0.55gおよびL-アラニン0.55gを添加し、溶解液(pH8.4)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.03%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLにトレハロース0.28gおよびL-アラニン0.28gを添加し、溶解液(pH8.0)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例7と同様
実施例41と同様な方法で製造された調製液55mLにトレハロース0.55gおよびL-アラニン0.55gを添加し、溶解液(pH7.5)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.01%
凍結乾燥の方法:実施例7と同様
実施例42と同様な方法で製造された調製液55mLにトレハロース0.55gおよびL-アラニン0.55gを添加し、溶解液(pH8.4)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLにトレハロース1.10gおよびL-アラニン1.10gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLにD-ソルビトール0.28gおよびL-アラニン0.28gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.03%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLにD-ソルビトール0.28gおよびL-アラニン0.28gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.04%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLにD-マンニトール1.10gおよびL-アラニン1.10gを添加し、溶解液(pH7.8)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.07%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLにD-マンニトール1.10gおよびL-アラニン1.10gを添加し、溶解液(pH7.8)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.04%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLに精製白糖(塩水港精糖社製)0.28gおよびL-アラニン0.28gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.03%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLに精製白糖(塩水港精糖社製)0.55gおよびL-アラニン0.55gを添加し、溶解液(pH7.8)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLに精製白糖(塩水港精糖社製)1.10gおよびL-アラニン1.10gを添加し、溶解液(pH7.8)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.03%
凍結乾燥の方法:実施例6と同様
実施例7と同様な方法で製造された調製液55mLに精製白糖(塩水港精糖社製)0.28gおよびL-アラニン0.28gを添加し、溶解液(pH7.9)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例7と同様
実施例7と同様な方法で製造された調製液55mLに精製白糖(塩水港精糖社製)1.10gおよびL-アラニン1.10gを添加し、溶解液(pH7.8)を得た。溶解液を10mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例7と同様
化合物A36.0gの注射用水400mL懸濁液にメグルミン46.2gを添加し、撹拌して溶解した。得られた溶解液に注射用水を加え、全量480mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH8.6)を得た。調製液を8mLずつバイアルに充填し、凍結乾燥後、密栓し、結晶の凍結乾燥製剤を得た。
含水率:0.02%
凍結乾燥の方法:実施例6と同様
化合物A13.8gの注射用水50mL懸濁液に1mol/L水酸化ナトリウム水溶液を加え、撹拌して溶解した後、pH8.5となるように1mol/L水酸化ナトリウム水溶液を追加した。注射用水を加え、全量161mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH8.4)を得た。調製液を7mLずつバイアルに充填し、凍結乾燥後、密栓し、非晶質の凍結乾燥製剤を得た。
含水率:2.2%
凍結乾燥の方法
1.棚温度-60℃でバイアルを冷却し、内容物を凍結した。
2.真空下(50Pa以下)、棚温度-10℃に昇温し、同圧力、同温度で37時間保持した。
3.棚温度0℃に昇温し、同圧力、同温度で9時間保持した。
4.棚温度10℃に昇温し、同圧力、同温度で4時間保持した。
5.棚温度20℃に昇温し、同圧力、同温度で4時間保持した。
6.棚温度40℃に昇温し、同圧力、同温度で15時間保持した。
化合物A12.0gの注射用水70mL懸濁液に1mol/L水酸化ナトリウム水溶液を加え、撹拌して溶解した後、pH8.5となるように1mol/L水酸化ナトリウム水溶液を追加した。注射用水を加え、全量160mLとした後、0.22μmメンブランフィルターで濾過し、調製液(pH8.5)を得た。調製液を8mLずつバイアルに充填し、凍結乾燥後、密栓し、非晶質の凍結乾燥製剤を得た。
凍結乾燥の方法
1.棚温度-60℃でバイアルを冷却し、内容物を凍結した。
2.真空下(50Pa以下)、棚温度50℃に昇温し、同圧力、同温度で39時間保持した。
比較例および実施例で得られたバイアルに注射用水10mLを加えて手で振盪し、固体が溶解するまでの時間を測定した。結果を表3に示す。
メグルミン塩の1水和物の結晶の粉砕品(実施例2)の溶解時間は、5秒であった。メグルミン塩の結晶の粉砕品は、ナトリウム塩の非晶質よりも優れた溶解性を示した。
メグルミン塩の非晶質(実施例5)の溶解時間は、5秒であった。メグルミン塩の非晶質は、ナトリウム塩の非晶質よりも優れた溶解性を示した。
アニーリング工程を含む凍結乾燥によって製造された製剤(実施例6~9、41~44)の溶解時間は、10~31秒であった。この製造法で製造された製剤は、粉砕しなくても、ナトリウム塩の非晶質よりも優れた溶解性を示した。
添加物としてアミノ酸類を含有する製剤(実施例10~13)、糖類を含有する製剤(実施例14~19)、糖アルコール類を含有する製剤(実施例20~23)、塩類を含有する製剤(実施例24~26)、クレアチニンを含有する製剤(実施例27)、尿素を含有する製剤(実施例28)、ニコチン酸アミドを含有する製剤(実施例29)およびトロメタモールを含有する製剤(実施例30)の溶解時間は、ナトリウム塩の非晶質よりもはるかに優れた溶解性を示した。
さらに、アミノ酸類および糖類を含有する製剤(実施例31~34、45、46、49~59、64~68)ならびにアミノ酸類および糖アルコール類を含有する製剤(実施例35~40、47、60~63)の溶解時間は、いずれも10秒以内であり、極めて優れた溶解性を示した。
外観を観察した結果、実施例7、8の凍結乾燥製剤には溶融痕が認められず均一な凍結乾燥製剤であった。また、実施例12、15、27、31~33、36、38、51、55および59は溶融痕が認められず均一なケーキであり、表面が滑らかで外観がより良好であった。添加物の配合により、より良好な外観の凍結乾燥製剤が得られた。
実施例7、8、10、11、13、15、20、23、31、32、36、および40の凍結乾燥製剤を40℃で6ヶ月間静置し、外観および化合物Aの残存率を調べた。その結果、外観の変化および化合物Aの含率の低下は、認められなかった。
実施例69および比較例1の凍結乾燥製剤をD65ランプ(FLR20S-D-EDL-D65/M)を用いて照射(120万lx・hr)し、外観を観察した。その結果、実施例69に変化は認められなかった。一方、比較例1は橙黄色に着色した。
Claims (13)
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩またはその水和物。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩またはその水和物の結晶。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩の非晶質。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩またはその水和物を含有する注射用製剤。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩またはその水和物が結晶である、請求項4に記載の注射用製剤。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩またはその水和物が非晶質である、請求項4に記載の注射用製剤。
- さらに、アミノ酸類と糖類、または、アミノ酸類と糖アルコール類を含有する請求項4または5に記載の注射用製剤。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩を含有する凍結乾燥製剤。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩が結晶である、請求項8に記載の凍結乾燥製剤。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドのメグルミン塩が非晶質である、請求項8に記載の凍結乾燥製剤。
- さらに、アミノ酸類と糖類、または、アミノ酸類と糖アルコール類を含有する請求項8または9に記載の凍結乾燥製剤。
- (1)6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドおよびメグルミンを含有する水溶液を冷却して凍結体を製造する工程、(2)凍結体を昇温する工程、(3)凍結体を再度冷却する工程、(4)凍結乾燥を行う工程、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メグルミン塩の結晶を含有する凍結乾燥製剤の製造法。
- 凍結体を昇温する工程における凍結体の到達温度が、-20~-5℃の範囲である、請求項12に記載の製造法。
Priority Applications (16)
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SG2013023353A SG188662A1 (en) | 2010-09-30 | 2011-09-29 | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
JP2012536534A JP5936546B2 (ja) | 2010-09-30 | 2011-09-29 | 6−フルオロ−3−ヒドロキシ−2−ピラジンカルボキサミドのメグルミン塩 |
SI201130754T SI2623497T1 (sl) | 2010-09-30 | 2011-09-29 | Megluminska sol 6-fluoro-3-hidroksi-2-pirazinkarboksamida |
US13/877,037 US20130217708A1 (en) | 2010-09-30 | 2011-09-29 | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
RS20160178A RS54642B1 (en) | 2010-09-30 | 2011-09-29 | MEGLUMIN SO 6-FLUOR-3-HYDROXY-2-PYRAZINE CARBOXAMIDE |
CN201180055096.6A CN103209967B (zh) | 2010-09-30 | 2011-09-29 | 6-氟-3-羟基-2-吡嗪甲酰胺的葡甲胺盐 |
EP11829249.9A EP2623497B1 (en) | 2010-09-30 | 2011-09-29 | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
ES11829249.9T ES2561878T3 (es) | 2010-09-30 | 2011-09-29 | Sal de meglumina de 6-fluoro-3-hidroxi-2-pirazinacarboxamida |
PL11829249T PL2623497T3 (pl) | 2010-09-30 | 2011-09-29 | Sól megluminowa 6-fluoro-3-hydroksy-2-pirazynokarboksamidu |
DK11829249.9T DK2623497T3 (en) | 2010-09-30 | 2011-09-29 | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide |
HK13110206.4A HK1183014A1 (en) | 2010-09-30 | 2013-09-02 | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide 6--3--2- |
US14/508,185 US9090571B2 (en) | 2010-09-30 | 2014-10-07 | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
US14/734,263 US20150266832A1 (en) | 2010-09-30 | 2015-06-09 | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
PH12015501328A PH12015501328A1 (en) | 2010-09-30 | 2015-06-15 | Meglumine salt of 6-flouro-3-hydroxy-2-pyrazine carboxamide |
HRP20160218T HRP20160218T1 (hr) | 2010-09-30 | 2016-03-01 | Megluminska sol 6-fluoro-3-hidroksi-2-pirazin karboksamida |
SM201600184T SMT201600184B (it) | 2010-09-30 | 2016-06-16 | Sale di meglumina di 6-fluoro-3-idrossi-2-pirazincarbossammide |
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JP2010-221620 | 2010-09-30 | ||
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US13/877,037 A-371-Of-International US20130217708A1 (en) | 2010-09-30 | 2011-09-29 | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
US14/508,185 Division US9090571B2 (en) | 2010-09-30 | 2014-10-07 | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
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US (3) | US20130217708A1 (ja) |
EP (1) | EP2623497B1 (ja) |
JP (1) | JP5936546B2 (ja) |
CN (1) | CN103209967B (ja) |
CY (1) | CY1117218T1 (ja) |
DK (1) | DK2623497T3 (ja) |
ES (1) | ES2561878T3 (ja) |
HK (1) | HK1183014A1 (ja) |
HR (1) | HRP20160218T1 (ja) |
HU (1) | HUE026794T2 (ja) |
MY (1) | MY161757A (ja) |
PH (1) | PH12015501328A1 (ja) |
PL (1) | PL2623497T3 (ja) |
RS (1) | RS54642B1 (ja) |
SG (1) | SG188662A1 (ja) |
SI (1) | SI2623497T1 (ja) |
SM (1) | SMT201600184B (ja) |
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WO2018003946A1 (ja) * | 2016-06-30 | 2018-01-04 | 富山化学工業株式会社 | 凍結乾燥製剤の製造方法 |
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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 |
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 |
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WO2022131112A1 (ja) | 2020-12-18 | 2022-06-23 | 富士フイルム富山化学株式会社 | 医薬組成物 |
WO2022131117A1 (ja) | 2020-12-18 | 2022-06-23 | 富士フイルム富山化学株式会社 | 医薬組成物 |
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HRP20160218T1 (hr) | 2016-03-25 |
CN103209967A (zh) | 2013-07-17 |
EP2623497A1 (en) | 2013-08-07 |
DK2623497T3 (en) | 2016-03-21 |
EP2623497A4 (en) | 2014-03-26 |
PH12015501328B1 (en) | 2015-09-21 |
HK1183014A1 (en) | 2013-12-13 |
TWI507397B (zh) | 2015-11-11 |
US9090571B2 (en) | 2015-07-28 |
US20130217708A1 (en) | 2013-08-22 |
JPWO2012043696A1 (ja) | 2014-02-24 |
US20150266832A1 (en) | 2015-09-24 |
CN103209967B (zh) | 2015-04-08 |
PH12015501328A1 (en) | 2015-09-21 |
EP2623497B1 (en) | 2016-01-20 |
US20150031885A1 (en) | 2015-01-29 |
HUE026794T2 (en) | 2016-07-28 |
RS54642B1 (en) | 2016-08-31 |
SG188662A1 (en) | 2013-05-31 |
CY1117218T1 (el) | 2017-04-05 |
SI2623497T1 (sl) | 2016-04-29 |
SMT201600184B (it) | 2016-08-31 |
PL2623497T3 (pl) | 2016-07-29 |
TW201217343A (en) | 2012-05-01 |
ES2561878T3 (es) | 2016-03-01 |
JP5936546B2 (ja) | 2016-06-22 |
MY161757A (en) | 2017-05-15 |
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