WO2021192471A1 - Pemetrexed formulation - Google Patents

Pemetrexed formulation Download PDF

Info

Publication number
WO2021192471A1
WO2021192471A1 PCT/JP2020/048665 JP2020048665W WO2021192471A1 WO 2021192471 A1 WO2021192471 A1 WO 2021192471A1 JP 2020048665 W JP2020048665 W JP 2020048665W WO 2021192471 A1 WO2021192471 A1 WO 2021192471A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
mass
sulfite
thioglycerols
parts
Prior art date
Application number
PCT/JP2020/048665
Other languages
French (fr)
Japanese (ja)
Inventor
萌 大塚
Hiroyuki YAMADA (山田 博之)
Original Assignee
ナガセ医薬品株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ナガセ医薬品株式会社 filed Critical ナガセ医薬品株式会社
Priority to JP2022509275A priority Critical patent/JPWO2021192471A1/ja
Publication of WO2021192471A1 publication Critical patent/WO2021192471A1/en

Links

Classifications

    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a composition (pharmaceutical composition) containing pemetrexed and the like.
  • Pemetrexed is a folic acid metabolism antagonist, and as a pharmaceutical product, "Alimta injection preparation" (100 mg and 500 mg preparations) is commercially available from Eli Lilly Japan K.K. as an anticancer drug. Alimta injectable formulations require a lysis procedure for use, which increases the risk of exposure to anti-cancer agents to healthcare professionals. Therefore, liquidation of pemetrexed is desired.
  • an isotonic physiological saline solution containing pemetrexed forms a related substance derived from pemetrexed by decomposing pemetrexed, which causes a problem that is not pharmaceutically acceptable. Further, in the aqueous solution in which pemetrexed is dissolved, the change in properties due to coloring is also a problem.
  • Patent Document 1 discloses a pharmaceutical composition containing pemetrixto and monothioglycerol.
  • An object of the present invention is to provide a novel pemetrexed composition (pemetrexed preparation).
  • the present inventor can obtain a new composition by combining pemetrexeds with thioglycerols, a sulfite component, and the like, and such a composition. Has found that it can have excellent stability and the like, and has completed further studies to complete the present invention.
  • the present invention relates to the following inventions and the like.
  • a composition containing pemetrexeds, thioglycerols, and a sulfite component [2] The composition according to [1], wherein the sulfite component comprises at least one selected from sulfites, hydrogen sulfites and pyrosulfites. [3] The composition according to [1] or [2], wherein the ratio of thioglycerols is 0.01 mg / mL or more. [4] The composition according to any one of [1] to [3], wherein the ratio of the sulfurous acid component is 0.01 mg / mL or more.
  • the sulfite component comprises at least one selected from sulfite, hydrogen sulfite, pyrosulfite, and salts thereof.
  • the container according to [10] or [11] which is for storage at room temperature or ambient temperature (or non-refrigerated) [container for storage at room temperature or ambient temperature (or non-refrigerated)].
  • a method for improving (or improving) the stability of a composition containing pemetrexeds, wherein the composition contains thioglycerols and a sulfite component [13] A method for improving (or improving) the stability of a composition containing pemetrexeds, wherein the composition contains thioglycerols and a sulfite component. [14] A method for suppressing (or improving) coloring of a composition containing pemetrexeds, wherein the composition contains thioglycerols and a sulfite component. [15] A method for improving (or improving) stability and suppressing (or improving) coloring in a composition containing pemetrexeds, wherein the composition contains thioglycerols and a sulfite component.
  • [16] The method according to any one of [13] to [15], which improves stability and / or suppresses coloring at room temperature or ambient temperature (or under non-refrigerated storage).
  • [17] A method for storing the composition or container according to any one of [1] to [12] at room temperature or ambient temperature.
  • a novel pemetrexed composition (pemetrexed preparation) can be provided.
  • composition of the present invention as described above, excellent stability such as less production (by-product) of related substances and less pH fluctuation can be realized.
  • low coloring property suppression of coloring
  • composition of the present invention both excellent stability and low colorability can be achieved at the same time.
  • composition of the present invention excellent stability and low colorability can be realized under normal temperature (or room temperature or ambient temperature or non-refrigerated storage, for example, 5 to 40 ° C.).
  • normal temperature or room temperature or ambient temperature or non-refrigerated storage, for example, 5 to 40 ° C.
  • Such a composition is useful because it does not require storage at a low temperature or refrigeration (preservation at a low temperature).
  • composition of the present invention a pemetrexed preparation that does not impair the quality and appearance can be efficiently obtained even by long-term storage (particularly long-term storage at room temperature).
  • composition of the present invention contains pemetrexeds, thioglycerols and a sulfite component.
  • Pemetrexeds include pemetrexed, salts of pemetrexed (particularly pharmacologically acceptable salts) and the like.
  • the formula for pemetrexed is as follows.
  • pemetrexed may be in the form in which an acid or a base is liberated.
  • the salt is not particularly limited, and for example, a metal salt [for example, an alkali metal salt (for example, lithium salt, sodium salt, potassium salt, etc.), an alkaline earth metal salt (for example, magnesium salt, calcium salt, etc.), a periodic table.
  • a metal salt for example, an alkali metal salt (for example, lithium salt, sodium salt, potassium salt, etc.), an alkaline earth metal salt (for example, magnesium salt, calcium salt, etc.), a periodic table.
  • Group 13 metal salts eg, aluminum salts
  • transition metal salts eg, salts of zinc, iron, cobalt, copper, etc.
  • ammonium salts amine salts [eg, alkylamine salts (eg, trimethylamine salts, triethylamine) Trialkylamine salts of salts), alkanolamine salts (eg, monoethanolamine salts, triethanolamine salts), cyclic amine salts (eg, pyridine salts, substituted pyridine salts)], amino acid salts (eg, histidine, arginine, etc.) And salt) and so on.
  • the salt may be a single salt or a double salt. It may also form a salt with the same or different acids or bases.
  • Typical pemetrexeds include pemetrexed, alkali metal salts of pemetrexed [sodium salt of pemetrexed (sodium pemetrexed 2 sodium, etc.), potassium salt of pemetrexed] and the like.
  • the pemetrexeds may be contained (blended) in the composition in the form of a hydrate [for example, a hydrate of pemetrexed disodium (2.5 hydrate, hepatohydrate, etc.)].
  • Pemetrexeds may be used alone or in combination of two or more.
  • thioglycerols examples include thioglycerol [for example, monothioglycerol ( ⁇ -monothioglycerol, thioglycerin), etc.].
  • the thioglycerol may form a salt or may be derivatized.
  • thioglycerols thioglycerol (monothioglycerol) can be preferably used.
  • the thioglycerols may be used alone or in combination of two or more.
  • sulfurous acid component examples include sulfites, hydrogen sulfites, pyrosulfites and the like.
  • Specific sulfite components include sulfite, hydrogen sulfite (bisulfite), pyrosulfite (disulfite, metasulfite), and salts thereof (ie, sulfites, hydrogen sulfites, pyrosulfites, especially pharmacologically. Tolerable salt).
  • Examples of the salt include the above-exemplified salt and the like.
  • Typical sulfite components include alkali metal salts of sulfite (for example, sodium sulfite), alkali metal salts of hydrogen sulfite (for example, sodium hydrogen sulfite), alkali metal salts of pyrosulfite (for example, sodium pyrosulfite) and the like. Be done.
  • the sulfurous acid component may be contained (blended) in the composition in the form of a hydrate.
  • the sulfurous acid component may be used alone or in combination of two or more.
  • the composition may contain an isotonic agent.
  • the tonicity agent can be suitably contained in the composition from the viewpoint of adjusting the osmotic pressure and the like.
  • the tonicity agent examples include organic components [eg, sugar alcohols (eg, sorbitol, mannitol (D-mannitol, etc.), xylitol, trehalose, glycerin, etc.), sugars (eg, glucose, lactose, etc.), glycols, etc. (For example, propylene glycol), alcohols (for example, benzyl alcohol), macrogol, etc.], inorganic components [for example, halides of inorganic salts (for example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium bromide, etc.) ) Etc.] etc.
  • organic components eg, sugar alcohols (eg, sorbitol, mannitol (D-mannitol, etc.), xylitol, trehalose, glycerin, etc.), sugars (eg, glucose, lactose, etc.), glycols, etc. (For example, propylene glyco
  • sugar alcohols for example, sugar alcohols, sugars, halides (for example, salts of alkali metals and alkaline earth metals and hydrogen halides) and the like are preferable, and sugar alcohols (especially mannitol) are particularly preferable.
  • halides for example, salts of alkali metals and alkaline earth metals and hydrogen halides
  • sugar alcohols especially mannitol
  • the tonicity agent may be used alone or in combination of two or more.
  • the composition may include a pH regulator.
  • the pH adjuster can be appropriately selected according to the desired pH and is not particularly limited.
  • the pH adjuster may have a buffering action (or function as a buffering agent).
  • pH adjuster examples include inorganic acids (for example, hydrochloric acid, phosphoric acid, boric acid, etc.) and organic acids [for example, carboxylic acids (citrate, tartaric acid, fumaric acid, lactic acid, maleic acid, acetic acid, oxalic acid, adipine).
  • inorganic acids for example, hydrochloric acid, phosphoric acid, boric acid, etc.
  • organic acids for example, carboxylic acids (citrate, tartaric acid, fumaric acid, lactic acid, maleic acid, acetic acid, oxalic acid, adipine).
  • hydroxides eg, alkali hydroxides or alkaline earth metal salts such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide
  • amines eg, alkanolamines (eg, monoethanolamine, triethanolamine, diisopropanolamine, trishydroxy
  • salts examples include the above-exemplified salts.
  • Specific salts include, for example, inorganic salts [eg, phosphates (such as disodium dihydrogen phosphate)] and carboxylates [eg, citrates (eg, trisodium citrate, disodium citrate, etc.). )], Ethylenediamine tetraacetate (for example, disodium ethylenediamine tetraacetate) and the like.
  • these compounds may be hydrates and anhydrides.
  • the pH adjuster may be used alone or in combination of two or more.
  • composition of the present invention may further contain other components [components other than pemetrexeds, thioglycerols, and sulfite components (non-solvent component, solid content)].
  • other components include surfactants, defoamers, solubilizers, solubilizers, dispersants, preservatives, antioxidants and the like.
  • Antioxidants include, for example, amino acids (cysteine, methionine, etc.), thioglycolic acid, lipoic acid, dihydrolipoic acid, chelate-forming compounds (citric acid, ethylenediamine tetraacetic acid). , Lactobionic acid, etc.), thiosulfate, sulfur dioxide, salts thereof (eg, cysteine hydrochloride, sodium citrate, disodium ethylenediamine tetraacetate, thiosulfate, etc.).
  • composition of the present invention can realize excellent stability and suppression of coloring even if it does not contain such an antioxidant (another antioxidant).
  • the composition may usually be a composition (liquid agent) containing a solvent.
  • a solvent usually, an aqueous solvent [for example, water, a solvent which mixes with water (alcohol, etc.), a mixed solvent of these] is mentioned, and the solvent may be water (only water) in particular.
  • the proportion of the solvent may be, for example, 70% by mass or more, preferably 80% by mass or more, and more preferably 90% by mass or more.
  • the composition may or may not contain amino alcohols.
  • Specific amino alcohols include, for example, chain amino alcohols ⁇ for example, alkanolamines [for example, monoethanolamine, diethanolamine, triethanolamine, 2-2-amino-2- (hydroxymethyl) propan-1,3).
  • cyclic amino alcohols for example, cyclic amines having a hydroxy group [eg, 4-4- (2-hydroxyethyl) -morpholin, 1- (2-hydroxyethyl) -pyrrolidin, etc. ] Etc. ⁇ and the like.
  • the ratio (concentration) of pemetrexeds is, for example, 0.1 to 1000 mg / mL (for example, 0.3 to 500 mg / mL), preferably 0.5 to 300 mg / mL (for example, for example). 0.7 to 200 mg / mL), more preferably 1 to 100 mg / mL (for example, 3 to 90 mg / mL), particularly 5 to 80 mg / mL (for example, 7 to 60 mg / mL), and usually It may be about 10 to 50 mg / mL (for example, 15 to 40 mg / mL).
  • the above ratio may be the ratio in terms of pemetrexed (hereinafter, the same applies to the description of the ratio).
  • the ratio (concentration) of thioglycerols is, for example, 0.001 mg / mL or more (for example, 0.001 to 200 mg / mL, 0.005 to 80 mg / mL), preferably 0.
  • 01 mg / mL or more (for example, 0.01 to 50 mg / mL, 0.03 to 40 mg / mL), more preferably 0.05 mg / mL or more (for example, 0.05 to 20 mg / mL, 0.07 to 10 mg / mL) It may be about 0.1 mg / mL or more (for example, 0.1 to 5 mg / mL, 0.2 to 4 mg / mL), and usually 0.3 mg / mL or more (for example, 0.3 to 0.3 to mL). It may be about 3 mg / mL, 0.5 to 1.5 mg / mL).
  • the ratio of thioglycerols is, for example, 0.01 parts by mass or more (for example, 0.01 to 200 parts by mass, 0.02 to 150 parts by mass, 0.05 to 120 parts by mass) with respect to 100 parts by mass of pemetrexeds. ), Preferably 0.1 parts by mass or more (for example, 0.1 to 100 parts by mass, 0.2 to 50 parts by mass), and more preferably 0.3 parts by mass or more (for example, 0.3 to 20 parts by mass). 0.5 to 15 parts by mass), particularly 1 part by mass or more (for example, 1 to 12 parts by mass, 1.5 to 10 parts by mass), and usually 2 parts by mass or more (for example, 2 to 5 parts by mass). Part) may be about.
  • the ratio (concentration) of the sulfite component is, for example, 0.001 mg / mL or more (for example, 0.001 to 100 mg / mL, 0.005 to 80 mg / mL), preferably 0.01 mg.
  • / ML or more (eg 0.01-50 mg / mL, 0.03-40 mg / mL), more preferably 0.05 mg / mL or more (eg 0.05-30 mg / mL, 0.1-25 mg / mL) ), Especially about 0.15 mg / mL or more (for example, 0.15 to 20 mg / mL, 0.2 to 15 mg / mL), and usually 0.25 mg / mL or more (for example, 0.25 to 10 mg).
  • / ML 0.3 to 5 mg / mL, preferably 0.5 to 3 mg / mL).
  • the ratio of the sulfite component is, for example, 0.01 parts by mass or more (for example, 0.01 to 1000 parts by mass, 0.03 to 500 parts by mass), preferably 0.05 parts by mass, with respect to 100 parts by mass of pemetrexeds.
  • 0.05 to 300 parts by mass, 0.07 to 200 parts by mass more preferably 0.1 parts by mass or more (for example, 0.1 to 100 parts by mass, 0.15 to 80 parts by mass).
  • it may be about 0.2 parts by mass or more (for example, 0.2 to 50 parts by mass, 0.5 to 30 parts by mass), and usually 1 part by mass or more (for example, 1 to 20 parts by mass, 2 to 15 parts). It may be about 3 to 10 parts by mass).
  • the ratio of the total amount of the thioglycerols and the sulfite component is preferably 0.01 parts by mass or more (for example, 0.01 to 1000 parts by mass and 0.05 to 500 parts by mass) with respect to 100 parts by mass of pemetrexeds.
  • the proportion (concentration) of the isotonic agent can be selected according to the type, and is, for example, 1 mg / mL or more (for example, 2 to 1000 mg).
  • / ML preferably 3 mg / mL or higher (eg, 4 to 300 mg / mL), more preferably 5 mg / mL or higher (eg, 6 to 100 mg / mL), particularly 8 mg / mL or higher (eg, 8 to 50 mg / mL).
  • the ratio of the isotonic agent is, for example, 0.01 part by mass or more (for example, 0.01 to 0.01 to 100 parts by mass) with respect to 100 parts by mass of pemetrexeds. 10000 parts by mass, 0.1 to 5000 parts by mass), preferably 0.5 parts by mass or more (for example, 0.5 to 2000 parts by mass, 1 to 1500 parts by mass), and more preferably 2 parts by mass or more (for example, 3 parts by mass). It may be about 5 parts by mass or more (for example, 5 to 500 parts by mass, 8 to 300 parts by mass), and usually 10 parts by mass or more (for example, 10 to 200 parts by mass, 20 to 150 parts by mass). It may be about (mass part).
  • the ratio of components other than these components can be appropriately selected according to the intended use, purpose, and the like.
  • the proportion of the pH adjuster can be appropriately selected according to the desired pH.
  • the pH of the composition (liquid agent) containing the solvent can be selected from acidic, neutral and alkaline, and is, for example, 4 to 11 (for example, 5 to 10), preferably 5.5 to 9.5, and further. It may be preferably 6 to 9 (for example, 7.5 to 8.5), or may be neutral to alkaline (for example, pH 7 or higher).
  • the pH may be, for example, a value at room temperature (for example, 25 ° C.).
  • the liquid agent of the present invention can realize excellent stability and anticoloring effect even in the neutral to alkaline region.
  • the osmotic pressure of the composition is, for example, the osmotic pressure ratio to physiological saline of 0.1 to 10 (for example, 0.2 to 5), preferably 0.3 to 3 (for example, 0.5 to 2), and further. It may preferably be 0.6 to 1.4 (eg, 0.7 to 1.3), particularly 0.8 to 1.2 (eg, 0.9 to 1.1), and 1 (about 1). ) May be.
  • the osmotic pressure (osmotic pressure ratio) may be, for example, a value at room temperature (for example, 25 ° C.).
  • the oxygen concentration in the composition (liquid agent) may be a relatively low concentration (for example, 10% by volume or less) from the viewpoint of stability, coloring, etc., for example, 5% by volume or less (for example, 3% by volume or less). ), Preferably 2.5% by volume or less, more preferably 2.0% by volume or less, 1.0% by volume or less (for example, 0.8% by volume or less, preferably 0.7% by volume or less). , More preferably 0.6% by volume or less, particularly 0.5% by volume or less).
  • the oxygen concentration (dissolved oxygen concentration) in the composition can be adjusted (reduced) by a conventional method (such as bubbling with an inert gas).
  • composition (formulation, pemetrexed preparation) of the present invention may be sealed (sealed) in a container.
  • the present invention also includes a container (a container contained therein) containing the composition (pemetrexed preparation).
  • the composition may be usually sealed or hermetically sealed.
  • the composition of the present invention can efficiently realize excellent stability even when sealed (preserved) in such a container.
  • the container can be appropriately selected according to the administration mode and the like, and examples thereof include vials, ampoules, syringes (or syringes, for example, prefilled syringes, etc.), bags, and the like.
  • the material of the container is not particularly limited, and examples thereof include glass, metal, and resin (plastic).
  • the container may be formed by combining two or more kinds of materials.
  • the container (for example, at least the portion of the container that comes into contact with the composition) may be appropriately surface-treated (for example, blast treatment, coating treatment with a surface treatment agent, etc.).
  • the amount of the composition can be appropriately selected according to the type and size of the container, the pemetrexed concentration (desired amount of pemetrexed), etc. For example, 30 mL or less, 25 mL or less, 20 mL or less, 15 mL or less, 10 mL or less, 8 mL or less. , 7 mL or less, 6 mL or less, 5 mL or less.
  • Specific amounts of the composition include 1 mL, 1.5 mL, 2 mL, 2.5 mL, 3 mL, 3.5 mL, 4 mL, 5 mL, 8 mL, 10 mL and the like, and may be typically 4 mL. ..
  • the inside of the container may be composed only of the composition (liquid agent) or may have a void (space). It is particularly preferable that such voids (void portions, headspaces) are filled (or replaced) with an inert gas (nitrogen gas or the like).
  • the oxygen contained in such voids may be relatively small.
  • the oxygen concentration in the voids in the container may be, for example, 10% by volume or less, for example, 5% by volume or less (for example, 3% by volume or less), preferably 2.5% by volume or less, more preferably.
  • the oxygen concentration can be determined by a conventional method, for example, a method of bubbling an inert gas inside the composition and / or the container, a method of degassing the composition and / or the inside of the container, and the void in the container with the inert gas. It can be adjusted by a method of replacement, a method of combining these, and the like.
  • the oxygen concentration in the voids in the container is not strictly (significantly) low, the effect of sufficient stability and color suppression is sufficient. Can be realized.
  • composition of the present invention can be selected according to the administration method, but in particular, it may be in the form of an injection (injection preparation or intravenous drip infusion).
  • Specific administration methods include intravenous injection (intravenous injection), intramuscular injection, subcutaneous injection and the like. More specifically, it may be administered by intravenous infusion into an artery, peritoneum, submeninges, intraventricular, intraurethral, intrasternal, intracranial, or the like, or by intravenous drip infusion.
  • the concentration of each component in the liquid preparation can be selected from the same range as described above, but in particular, when administered by intravenous drip infusion, the composition is mixed with the infusion solution and dissolved to prepare an intravenous drip infusion solution. May be good.
  • the ratio when the composition is mixed with the infusion solution is appropriately selected according to the body surface area, age, gender, application site, degree of medical condition, etc. of the subject such as the patient to whom the intravenous infusion solution is administered. It is not particularly limited.
  • the infusion solution is not particularly limited, and examples thereof include physiological saline solution, sugar aqueous solution (dextrose aqueous solution, fructose aqueous solution, etc.), sugar alcohol aqueous solution (D-sorbitol aqueous solution, xylitol aqueous solution, etc.), amino acid aqueous solution, Ringer solution, and the like.
  • composition of the present invention (or the composition in a container) can realize excellent stability and low colorability even under storage.
  • the composition of the present invention can suppress the formation of related substances even under storage.
  • related substances include related substances A (related substances detected at a relative retention time (RRT) of 0.32 when measured under the conditions of the examples described later) and related substances B (related substances of the examples described later).
  • Relative retention time (RRT) 0.
  • Relative retention time (RRT) 0.
  • Storage may be at low temperature or refrigerated, but in particular, room temperature (or room temperature or ambient temperature, for example, 0 to 50 ° C, 5 to 45 ° C, 10 to 40 ° C, 15 to 35 ° C, 15 to 30). °C etc.) may be lower. According to the composition of the present invention, excellent stability, low colorability and the like can be realized even at room temperature.
  • the oxygen concentration in the gas in the container of each composition (injection solution preparation) was measured by the following measuring device and measuring method.
  • Measuring device Residual oxygen meter (Product name: Packmaster, manufactured by Iijima Electronics Co., Ltd.)
  • Measurement method Diaphragm type galvanized battery type oxygen sensor Measurement method: In a nitrogen atmosphere in a glove box, pierce the sampler needle part of the device into the container of the injection solution preparation and suck the gas in the head space inside the container of the injection solution preparation. Therefore, the oxygen concentration in the gas in the container of each injection solution preparation was measured.
  • compositions injection solution preparation
  • stability test in which it was stored for a predetermined period (3 months or 1 week) under the conditions of 25 ° C. 60% RH or 60 ° C. 60% RH. Then, the stability of pemetrexed from the viewpoint of decomposition (increased related substances) and coloring was evaluated by the method described below.
  • Coloring evaluation The coloration after the stability test was evaluated using an ultraviolet-visible spectrophotometer (UV-2200 manufactured by Shimadzu Corporation). Specifically, the composition (injection solution preparation) after the stability test was performed. The evaluation was performed by determining the absorbance (A430) at a wavelength of 430 nm. Generally, when the evaluation standard is 0.01 or less, it is said that there is no coloring.
  • Detector Ultraviolet absorptiometer (measurement wavelength: 250 nm)
  • Column A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is filled with 3.5 ⁇ m octylsilylated silica gel for liquid chromatography.
  • Column temperature Constant temperature around 35 ° C.
  • Mobile phase A Water in 1.7 mL of acetic acid (100) Add 1000 mL and add 8 mol / L sodium hydroxide TS to adjust the pH to 5.5. Add 30 mL of acetonitrile to 970 mL of this solution.
  • Mobile phase B Add 1000 mL of water to 1.7 mL of acetic acid (100) and add 8 mol / L sodium hydroxide TS to adjust the pH to 5.5. Add 100 mL of acetonitrile to 700 mL of this solution. Flow rate: 1 mL / min
  • the obtained solution was aseptically filtered through a filter having a pore size of 0.22 ⁇ m, then filled in a glass vial with 4 mL, filled with nitrogen, and stoppered in a glove box having an oxygen concentration of 0.8%.
  • the composition (injection solution preparation) enclosed in a container was obtained by winding and sealing with an aluminum cap and used for various measurements.
  • the osmotic pressure ratio (with respect to physiological saline) in the composition was about 1 in all cases except for the composition of Example 7.
  • the oxygen (O 2 ) concentration in the gas in the container at the time of encapsulation was 0.5 to 0.8% by volume.
  • the amount (mg) of each component is the amount occupied in 4 mL of the pharmaceutical product, and the remaining amount is water.
  • the amount of "pemetrexed” (120.8 mg) is the amount of pemetrexed sodium hemipenta hydrate, and the amount of pemetrexed is "100 mg”.
  • the amount of "Na citrate” (40 mg) is the amount of Na citrate hydrate.
  • the unit of the relatives A to C is “%” (area%).
  • “ND” indicates that it was not detected (below the detection limit).
  • the above result is at 25 ° C. (60% RH), and it can be said that the above composition suggests that high stability and the like can be realized when stored at room temperature or room temperature.
  • the accelerated test may not completely reflect the result of the actual temperature (for example, normal temperature), and the stability at a certain temperature [in this case, normal temperature (25 ° C)] is measured at that temperature. This suggests that more accurate results can be obtained.
  • a novel composition (pemetrexed composition) can be obtained.

Abstract

Provided is a novel pemetrexed composition.　This composition contains a pemetrexed, a thioglycerol and a sulfite component (for example, a sulfite component containing at least one compound selected from among a sulfite, a hydrogen sulfite and a pyrosulfite).

Description

ペメトレキセド製剤Pemetrexed preparation
　本発明は、ペメトレキセドを含有する組成物（医薬組成物）等に関する。 The present invention relates to a composition (pharmaceutical composition) containing pemetrexed and the like.
　ペメトレキセドは、葉酸代謝拮抗物質であり、医薬品としては、凍結乾燥製剤として、日本イーライリリー株式会社から、抗癌剤用途等として「アリムタ注射用製剤」（１００ｍｇ及び５００ｍｇ製剤）が市販されている。
　アリムタ注射用製剤は、使用に際して溶解操作を必要とするが、このような溶解操作は、医療従事者への抗癌剤暴露のリスクを高めることとなる。そのため、ペメトレキセドの液剤化が望まれる。 Pemetrexed is a folic acid metabolism antagonist, and as a pharmaceutical product, "Alimta injection preparation" (100 mg and 500 mg preparations) is commercially available from Eli Lilly Japan K.K. as an anticancer drug.
Alimta injectable formulations require a lysis procedure for use, which increases the risk of exposure to anti-cancer agents to healthcare professionals. Therefore, liquidation of pemetrexed is desired.
　しかしながら、ペメトレキセドを含む等張生理食塩水溶液は、ペメトレキセドの分解により、ペメトレキセドに由来する類縁物質を形成するため、医薬的に許容され得ない問題を引き起こすことが問題となっている。また、ペメトレキセドが溶解した水溶液では、着色による性状の変化についても問題となっている。 However, an isotonic physiological saline solution containing pemetrexed forms a related substance derived from pemetrexed by decomposing pemetrexed, which causes a problem that is not pharmaceutically acceptable. Further, in the aqueous solution in which pemetrexed is dissolved, the change in properties due to coloring is also a problem.
　このような中、水溶液中で安定なペメトレキセド製剤の開発が望まれており、いくつかの処方が報告されている。例えば、特表２００３－５２１５１８号公報（特許文献１）には、ペメトレクスト及びモノチオグリセロールを含む医薬組成物等が開示されている。 Under these circumstances, the development of a pemetrexed preparation that is stable in an aqueous solution is desired, and several formulations have been reported. For example, Japanese Patent Application Laid-Open No. 2003-521518 (Patent Document 1) discloses a pharmaceutical composition containing pemetrixto and monothioglycerol.
特表２００３－５２１５１８号公報Special Table 2003-521518
　本発明の目的は、新規なペメトレキセド組成物（ペメトレキセド製剤）を提供することにある。 An object of the present invention is to provide a novel pemetrexed composition (pemetrexed preparation).
　上記の通り、ペメトレキド製剤の安定化処方が検討されているが、本発明者の検討によれば、このような処方では十分な安定性が得られない場合等があった。 As described above, a stabilizing formulation of the pemetrekid preparation is being studied, but according to the study of the present inventor, there are cases where sufficient stability cannot be obtained with such a formulation.
　このような中、本発明者は、鋭意研究を重ねた結果、ペメトレキセド類に対し、チオグリセロール類及び亜硫酸成分等を組み合わせることで、新規な組成物が得られること、また、このような組成物は、優れた安定性を有しうること等を見出し、さらに検討を重ね、本発明を完成させるに至った。 Under these circumstances, as a result of repeated diligent research, the present inventor can obtain a new composition by combining pemetrexeds with thioglycerols, a sulfite component, and the like, and such a composition. Has found that it can have excellent stability and the like, and has completed further studies to complete the present invention.
　すなわち、本発明は、下記の発明等に関する。 That is, the present invention relates to the following inventions and the like.
［１］
　ペメトレキセド類と、チオグリセロール類と、亜硫酸成分とを含む組成物。
［２］
　亜硫酸成分が、亜硫酸類、亜硫酸水素類及びピロ亜硫酸類から選択された少なくとも１種を含む、［１］記載の組成物。
［３］
　チオグリセロール類の割合が０．０１ｍｇ／ｍＬ以上である、［１］又は［２］記載の組成物。
［４］
　亜硫酸成分の割合が０．０１ｍｇ／ｍＬ以上である、［１］～［３］のいずれかに記載の組成物。
［５］
　亜硫酸成分とチオグリセロール類との割合が、前者／後者（質量比）＝１／０．０１～１／５０である、［１］～［４］のいずれかに記載の組成物。
［６］
　ｐＨが５．５～９．５の液剤である［１］～［５］のいずれかに記載の組成物。
［７］
　亜硫酸成分が、亜硫酸、亜硫酸水素、ピロ亜硫酸、及びこれらの塩から選択された少なくとも１種を含み、
　ペメトレキセド類を１～１００ｍｇ／ｍＬ、チオグリセロール類を０．０５ｍｇ／ｍＬ以上、亜硫酸成分を０．０５３０ｍｇ／ｍＬ以上の濃度で含み、
　亜硫酸成分とチオグリセロール類との割合が、前者／後者（質量比）＝１／０．０２～１／３０であり、
　ｐＨが６～９の液剤である、［１］～［６］のいずれかに記載の組成物。
［８］
　さらに、等張化剤を含む、［１］～［７］のいずれかに記載の組成物。
［９］
　常温又は環境温度（又は非冷蔵下）での保存用［常温又は環境温度（又は非冷蔵下）で保存するための組成物］である、［１］～［８］のいずれかに記載の組成物。
［１０］
　［１］～［９］のいずれかに記載の組成物を封入した容器。
［１１］
　容器内の空隙における酸素濃度が２．５体積％以下である［１０］記載の容器。
［１２］
　常温又は環境温度（又は非冷蔵下）での保存用［常温又は環境温度（又は非冷蔵下）で保存するための容器］である、［１０］又は［１１］記載の容器。
［１３］
　ペメトレキセド類を含有する組成物の安定性を向上（又は改善）する方法であって、組成物に、チオグリセロール類及び亜硫酸成分を含有させる方法。
［１４］
　ペメトレキセド類を含有する組成物の着色を抑制（又は改善）する方法であって、組成物に、チオグリセロール類及び亜硫酸成分を含有させる方法。
［１５］
　ペメトレキセド類を含有する組成物において、安定性を向上（又は改善）するとともに、着色を抑制（又は改善）する方法であって、組成物に、チオグリセロール類及び亜硫酸成分を含有させる方法。
［１６］
　常温又は環境温度（又は非冷蔵下）において、安定性を向上及び／又は着色を抑制する、［１３］～［１５］のいずれかに記載の方法。
［１７］
　［１］～［１２］のいずれかに記載の組成物又は容器を、常温又は環境温度で保存する方法。 [1]
A composition containing pemetrexeds, thioglycerols, and a sulfite component.
[2]
The composition according to [1], wherein the sulfite component comprises at least one selected from sulfites, hydrogen sulfites and pyrosulfites.
[3]
The composition according to [1] or [2], wherein the ratio of thioglycerols is 0.01 mg / mL or more.
[4]
The composition according to any one of [1] to [3], wherein the ratio of the sulfurous acid component is 0.01 mg / mL or more.
[5]
The composition according to any one of [1] to [4], wherein the ratio of the sulfurous acid component to the thioglycerols is 1/0.01 to 1/50 of the former / latter (mass ratio).
[6]
The composition according to any one of [1] to [5], which is a liquid preparation having a pH of 5.5 to 9.5.
[7]
The sulfite component comprises at least one selected from sulfite, hydrogen sulfite, pyrosulfite, and salts thereof.
It contains pemetrexeds at a concentration of 1 to 100 mg / mL, thioglycerols at a concentration of 0.05 mg / mL or more, and a sulfite component at a concentration of 0.0530 mg / mL or more.
The ratio of the sulfite component to the thioglycerols is the former / the latter (mass ratio) = 1 / 0.02 to 1/30.
The composition according to any one of [1] to [6], which is a liquid preparation having a pH of 6 to 9.
[8]
The composition according to any one of [1] to [7], further comprising an isotonic agent.
[9]
The composition according to any one of [1] to [8], which is a [composition for storage at room temperature or environmental temperature (or non-refrigerating)] for storage at room temperature or environmental temperature (or non-refrigerated). thing.
[10]
A container containing the composition according to any one of [1] to [9].
[11]
The container according to [10], wherein the oxygen concentration in the void in the container is 2.5% by volume or less.
[12]
The container according to [10] or [11], which is for storage at room temperature or ambient temperature (or non-refrigerated) [container for storage at room temperature or ambient temperature (or non-refrigerated)].
[13]
A method for improving (or improving) the stability of a composition containing pemetrexeds, wherein the composition contains thioglycerols and a sulfite component.
[14]
A method for suppressing (or improving) coloring of a composition containing pemetrexeds, wherein the composition contains thioglycerols and a sulfite component.
[15]
A method for improving (or improving) stability and suppressing (or improving) coloring in a composition containing pemetrexeds, wherein the composition contains thioglycerols and a sulfite component.
[16]
The method according to any one of [13] to [15], which improves stability and / or suppresses coloring at room temperature or ambient temperature (or under non-refrigerated storage).
[17]
A method for storing the composition or container according to any one of [1] to [12] at room temperature or ambient temperature.
　本発明によれば、新規なペメトレキセド組成物（ペメトレキセド製剤）を提供できる。 According to the present invention, a novel pemetrexed composition (pemetrexed preparation) can be provided.
　このような本発明の組成物の一態様では、類縁物質の生成（副生）が少ない、ｐＨ変動が少ない等、優れた安定性を実現しうる。 In one aspect of the composition of the present invention as described above, excellent stability such as less production (by-product) of related substances and less pH fluctuation can be realized.
　また、本発明の組成物の他の態様によれば、長期にわたって、低着色性（着色の抑制）を実現しうる。 Further, according to another aspect of the composition of the present invention, low coloring property (suppression of coloring) can be realized for a long period of time.
　さらに、本発明の組成物の別の態様では、優れた安定性と低着色性とを両立しうる。 Furthermore, in another aspect of the composition of the present invention, both excellent stability and low colorability can be achieved at the same time.
　特に、本発明の組成物では、優れた安定性や低着色性を、常温（又は室温又は環境温度又は非冷蔵下、例えば、５～４０℃等）における保存下において実現しうる。このような組成物では、特段、低温ないし冷蔵下での保存（低温を保持した状態での保存）等を要することがなく、有用である。 In particular, in the composition of the present invention, excellent stability and low colorability can be realized under normal temperature (or room temperature or ambient temperature or non-refrigerated storage, for example, 5 to 40 ° C.). Such a composition is useful because it does not require storage at a low temperature or refrigeration (preservation at a low temperature).
　そのため、本発明の組成物によれば、長期保存（特に長期の常温保存）によっても、品質や外観を損なわないペメトレキセド製剤が効率良く得られうる。 Therefore, according to the composition of the present invention, a pemetrexed preparation that does not impair the quality and appearance can be efficiently obtained even by long-term storage (particularly long-term storage at room temperature).
　本発明の組成物（ペメトレキセド組成物、ペメトレキセド製剤、医薬組成物）は、ペメトレキセド類、チオグリセロール類及び亜硫酸成分を含む。 The composition of the present invention (pemetrexed composition, pemetrexed preparation, pharmaceutical composition) contains pemetrexeds, thioglycerols and a sulfite component.
［ペメトレキセド類］
　ペメトレキセド類としては、ペメトレキセド、ペメトレキセドの塩（特に、薬理学的に許容可能な塩）などが含まれる。
　なお、ペメトレキセドは、下記式 [Pemetrexeds]
Pemetrexeds include pemetrexed, salts of pemetrexed (particularly pharmacologically acceptable salts) and the like.
The formula for pemetrexed is as follows.
Figure JPOXMLDOC01-appb-C000001
 で表される構造を有し、化学名は、Ｎ－｛４－［２－（２－アミノ－４，７－ジヒドロ－４－オキソ－１Ｈ－ピロロ［２，３－ｄ］ピリミジン－５－イル）エチル］ベンゾイル｝－Ｌ－グルタミン酸である。
Figure JPOXMLDOC01-appb-C000001
 It has a structure represented by, and the chemical name is N- {4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-. Il) Ethyl] Benzoyl} -L-glutamic acid.
　また、ペメトレキセドは、酸又は塩基が遊離した形態であってもよい。 Further, pemetrexed may be in the form in which an acid or a base is liberated.
　塩としては、特に限定されず、例えば、金属塩［例えば、アルカリ金属塩（例えば、リチウム塩、ナトリウム塩、カリウム塩など）、アルカリ土類金属塩（例えば、マグネシウム塩、カルシウム塩）、周期表第１３族金属塩（例えば、アルミニウム塩）、遷移金属塩（例えば、亜鉛、鉄、コバルト、銅などの塩）など］、アンモニウム塩、アミン塩［例えば、アルキルアミン塩（例えば、トリメチルアミン塩、トリエチルアミン塩のトリアルキルアミン塩）、アルカノールアミン塩（例えば、モノエタノールアミン塩、トリエタノールアミン塩）、環式アミン塩（例えば、ピリジン塩、置換ピリジン塩）］、アミノ酸塩（例えば、ヒスチジン、アルギニンなどとの塩）などが挙げられる。なお、塩は、単塩であってもよく、複塩であってもよい。また、同一の又は異なる酸又は塩基と塩を形成していてもよい。 The salt is not particularly limited, and for example, a metal salt [for example, an alkali metal salt (for example, lithium salt, sodium salt, potassium salt, etc.), an alkaline earth metal salt (for example, magnesium salt, calcium salt, etc.), a periodic table. Group 13 metal salts (eg, aluminum salts), transition metal salts (eg, salts of zinc, iron, cobalt, copper, etc.), ammonium salts, amine salts [eg, alkylamine salts (eg, trimethylamine salts, triethylamine) Trialkylamine salts of salts), alkanolamine salts (eg, monoethanolamine salts, triethanolamine salts), cyclic amine salts (eg, pyridine salts, substituted pyridine salts)], amino acid salts (eg, histidine, arginine, etc.) And salt) and so on. The salt may be a single salt or a double salt. It may also form a salt with the same or different acids or bases.
　代表的なペメトレキセド類には、ペメトレキセド、ペメトレキセドのアルカリ金属塩［ペメトレキセドのナトリウム塩（ペメトレキセド２ナトリウムなど）、ペメトレキセドのカリウム塩］等が挙げられる。 Typical pemetrexeds include pemetrexed, alkali metal salts of pemetrexed [sodium salt of pemetrexed (sodium pemetrexed 2 sodium, etc.), potassium salt of pemetrexed] and the like.
　なお、ペメトレキセド類は、水和物の形態［例えば、ペメトレキセド２ナトリウムの水和物（２．５水和物、７水和物など）など］で組成物に含有（配合）されてもよい。 The pemetrexeds may be contained (blended) in the composition in the form of a hydrate [for example, a hydrate of pemetrexed disodium (2.5 hydrate, hepatohydrate, etc.)].
　ペメトレキセド類は、単独で又は２種以上組み合わせて使用してもよい。 Pemetrexeds may be used alone or in combination of two or more.
［チオグリセロール類］
　チオグリセロール類としては、例えば、チオグリセロール［例えば、モノチオグリセロール（α－モノチオグリセロール、チオグリセリン）など］が挙げられる。チオグリセロールは、塩を形成していてもよく、誘導体化されていてもよい。
　チオグリセロール類としては、通常、チオグリセロール（モノチオグリセロール）を好適に使用できる。 [Thioglycerols]
Examples of thioglycerols include thioglycerol [for example, monothioglycerol (α-monothioglycerol, thioglycerin), etc.]. The thioglycerol may form a salt or may be derivatized.
As the thioglycerols, thioglycerol (monothioglycerol) can be preferably used.
　チオグリセロール類は、単独で又は２種以上組み合わせて使用してもよい。 The thioglycerols may be used alone or in combination of two or more.
［亜硫酸成分］
　亜硫酸成分としては、例えば、亜硫酸類、亜硫酸水素類、ピロ亜硫酸類等が挙げられる。 [Sulfurous acid component]
Examples of the sulfurous acid component include sulfites, hydrogen sulfites, pyrosulfites and the like.
　具体的な亜硫酸成分としては、亜硫酸、亜硫酸水素（重亜硫酸）、ピロ亜硫酸（二亜硫酸、メタ重亜硫酸）、これらの塩（すなわち、亜硫酸塩、亜硫酸水素塩、ピロ亜硫酸塩、特に、薬理学的に許容可能な塩）が挙げられる。 Specific sulfite components include sulfite, hydrogen sulfite (bisulfite), pyrosulfite (disulfite, metasulfite), and salts thereof (ie, sulfites, hydrogen sulfites, pyrosulfites, especially pharmacologically. Tolerable salt).
　塩としては、前記例示の塩等が挙げられる。 Examples of the salt include the above-exemplified salt and the like.
　代表的な亜硫酸成分には、亜硫酸のアルカリ金属塩（例えば、亜硫酸ナトリウム）、亜硫酸水素のアルカリ金属塩（例えば、亜硫酸水素ナトリウム）、ピロ亜硫酸のアルカリ金属塩（例えば、ピロ亜硫酸ナトリウム）等が挙げられる。 Typical sulfite components include alkali metal salts of sulfite (for example, sodium sulfite), alkali metal salts of hydrogen sulfite (for example, sodium hydrogen sulfite), alkali metal salts of pyrosulfite (for example, sodium pyrosulfite) and the like. Be done.
　なお、亜硫酸成分は、水和物の形態で組成物に含有（配合）されてもよい。 The sulfurous acid component may be contained (blended) in the composition in the form of a hydrate.
　亜硫酸成分は、単独で又は２種以上組み合わせて使用してもよい。 The sulfurous acid component may be used alone or in combination of two or more.
［等張化剤］
　組成物は、等張化剤を含んでいてもよい。
　等張化剤は、浸透圧の調整等の観点から、好適に組成物に含有させうる。 [Isotonic agent]
The composition may contain an isotonic agent.
The tonicity agent can be suitably contained in the composition from the viewpoint of adjusting the osmotic pressure and the like.
　等張化剤としては、例えば、有機成分［例えば、糖アルコール類（例えば、ソルビトール、マンニトール（Ｄ－マンニトール等）、キシリトール、トレハロース、グリセリンなど）、糖類（例えば、ブドウ糖、乳糖など）、グリコール類（例えば、プロピレングリコール）、アルコール類（例えば、ベンジルアルコール）、マクロゴール等］、無機成分［例えば、無機塩（例えば、塩化ナトリウム、塩化カリウム、塩化マグネシウム、塩化カルシウム、臭化ナトリウム等のハロゲン化物）等］等が挙げられる。 Examples of the tonicity agent include organic components [eg, sugar alcohols (eg, sorbitol, mannitol (D-mannitol, etc.), xylitol, trehalose, glycerin, etc.), sugars (eg, glucose, lactose, etc.), glycols, etc. (For example, propylene glycol), alcohols (for example, benzyl alcohol), macrogol, etc.], inorganic components [for example, halides of inorganic salts (for example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium bromide, etc.) ) Etc.] etc.
　これらの中でも、糖アルコール類、糖類、ハロゲン化物（例えば、アルカリ金属やアルカリ土類金属とハロゲン化水素との塩）等が好ましく、特に、糖アルコール類（中でもマンニトール）が好ましい。 Among these, sugar alcohols, sugars, halides (for example, salts of alkali metals and alkaline earth metals and hydrogen halides) and the like are preferable, and sugar alcohols (especially mannitol) are particularly preferable.
　等張化剤は、単独で又は２種以上組み合わせて使用してもよい。 The tonicity agent may be used alone or in combination of two or more.
［ｐＨ調整剤］
　組成物は、ｐＨ調整剤を含んでいてもよい。 [PH regulator]
The composition may include a pH regulator.
　ｐＨ調整剤としては、所望のｐＨに応じて適宜選択でき、特に限定されない。なお、ｐＨ調整剤は、緩衝作用を有して（又は緩衝剤として機能して）いてもよい。 The pH adjuster can be appropriately selected according to the desired pH and is not particularly limited. The pH adjuster may have a buffering action (or function as a buffering agent).
　ｐＨ調整剤としては、例えば、無機酸（例えば、塩酸、リン酸、ホウ酸など）、有機酸［例えば、カルボン酸（クエン酸、酒石酸、フマル酸、乳酸、マレイン酸、酢酸、シュウ酸、アジピン酸、グルコン酸など）、スルホン酸（メタンスルホン酸など）など］、水酸化物（例えば、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、水酸化カルシウムなどの水酸化アルカリ又はアルカリ土類金属塩など）、アミン類［例えば、アルカノールアミン（例えば、モノエタノールアミン、トリエタノールアミン、ジイソプロパノールアミン、トリスヒドロキシメチルアミノメタンなど）］、アミノ酸（例えば、グリシンなど）、キレート剤（例えば、エチレンジアミン四酢酸など）、これらの塩などが挙げられる。 Examples of the pH adjuster include inorganic acids (for example, hydrochloric acid, phosphoric acid, boric acid, etc.) and organic acids [for example, carboxylic acids (citrate, tartaric acid, fumaric acid, lactic acid, maleic acid, acetic acid, oxalic acid, adipine). Acids, gluconic acids, etc.), sulfonic acids (methanesulfonic acids, etc.)], hydroxides (eg, alkali hydroxides or alkaline earth metal salts such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide) Etc.), amines [eg, alkanolamines (eg, monoethanolamine, triethanolamine, diisopropanolamine, trishydroxymethylaminomethane, etc.)], amino acids (eg, glycine, etc.), chelating agents (eg, ethylenediaminetetraacetic acid). Etc.), these salts and the like.
　塩としては、前記例示の塩などが挙げられる。具体的な塩としては、例えば、無機酸塩［例えば、リン酸塩（リン酸二水素二ナトリウムなど）など］、カルボン酸塩［例えば、クエン酸塩（クエン酸三ナトリウム、クエン酸二ナトリウムなど）］、エチレンジアミン四酢酸塩（例えば、エチレンジアミン四酢酸二ナトリウム）などが挙げられる。
　なお、これらの化合物は、水和物や無水物であってもよい。 Examples of the salt include the above-exemplified salts. Specific salts include, for example, inorganic salts [eg, phosphates (such as disodium dihydrogen phosphate)] and carboxylates [eg, citrates (eg, trisodium citrate, disodium citrate, etc.). )], Ethylenediamine tetraacetate (for example, disodium ethylenediamine tetraacetate) and the like.
In addition, these compounds may be hydrates and anhydrides.
　ｐＨ調整剤は、単独で又は２種以上組み合わせて使用してもよい。 The pH adjuster may be used alone or in combination of two or more.
［他の成分］
　本発明の組成物は、必要に応じて、さらに、他の成分［ペメトレキセド類、チオグリセロール類、亜硫酸成分以外の成分（非溶媒成分、固形分）］を含んでいてもよい。
このような他の成分としては、例えば、界面活性剤、消泡剤、溶解剤、溶解補助剤、分散剤、防腐剤、抗酸化剤などが挙げられる。 [Other ingredients]
If necessary, the composition of the present invention may further contain other components [components other than pemetrexeds, thioglycerols, and sulfite components (non-solvent component, solid content)].
Examples of such other components include surfactants, defoamers, solubilizers, solubilizers, dispersants, preservatives, antioxidants and the like.
　抗酸化剤（チオグリセロール類及び亜硫酸成分ではない抗酸化剤）としては、例えば、アミノ酸（システイン、メチオニンなど）、チオグリコール酸、リポ酸、ジヒドロリポ酸、キレート形成性化合物（クエン酸、エチレンジアミン四酢酸、ラクトビオン酸など）、チオ硫酸、二酸化硫黄、これらの塩（例えば、塩酸システイン、クエン酸ナトリウム、エチレンジアミン四酢酸２ナトリウム、チオ硫酸塩など）が含まれる。 Antioxidants (antioxidants that are not thioglycerols and sulfite components) include, for example, amino acids (cysteine, methionine, etc.), thioglycolic acid, lipoic acid, dihydrolipoic acid, chelate-forming compounds (citric acid, ethylenediamine tetraacetic acid). , Lactobionic acid, etc.), thiosulfate, sulfur dioxide, salts thereof (eg, cysteine hydrochloride, sodium citrate, disodium ethylenediamine tetraacetate, thiosulfate, etc.).
　本発明の組成物は、このような抗酸化剤（他の抗酸化剤）を含んでいなくても、優れた安定性や着色の抑制を実現できる。 The composition of the present invention can realize excellent stability and suppression of coloring even if it does not contain such an antioxidant (another antioxidant).
　これらの成分は単独で又は２種以上組み合わせて使用してもよい。 These ingredients may be used alone or in combination of two or more.
［溶媒］
　組成物は、通常、溶媒を含む組成物（液剤）であってもよい。なお、溶媒としては、通常、水性溶媒［例えば、水、水に混和する溶媒（アルコールなど）、これらの混合溶媒］が挙げられ、溶媒は、特に水（水のみ）であってもよい。 [solvent]
The composition may usually be a composition (liquid agent) containing a solvent. In addition, as a solvent, usually, an aqueous solvent [for example, water, a solvent which mixes with water (alcohol, etc.), a mixed solvent of these] is mentioned, and the solvent may be water (only water) in particular.
　液剤において、溶媒（水性溶媒、特に水）の割合は、例えば、７０質量％以上、好ましくは８０質量％以上、さらに好ましくは９０質量％以上であってもよい。
　なお、組成物は、アミノアルコール類を含んでいてもよく、含んでいなくてもよい。
　具体的なアミノアルコール類としては、例えば、鎖状アミノアルコール｛例えば、アルカノールアミン［例えば、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、２－２－アミノ－２－（ヒドロキシメチル）プロパン－１，３－ジオール、グルカミン、メグルミン］等｝、環状アミノアルコール｛例えば、ヒドロキシ基を有する環式アミン［例えば、４－４－（２－ヒドロキシエチル）－モルホリン、１－（２－ヒドロキシエチル）－ピロリジン等］等｝等が挙げられる。 In the liquid preparation, the proportion of the solvent (aqueous solvent, particularly water) may be, for example, 70% by mass or more, preferably 80% by mass or more, and more preferably 90% by mass or more.
The composition may or may not contain amino alcohols.
Specific amino alcohols include, for example, chain amino alcohols {for example, alkanolamines [for example, monoethanolamine, diethanolamine, triethanolamine, 2-2-amino-2- (hydroxymethyl) propan-1,3). -Diol, glucamine, meglumin], etc.}, cyclic amino alcohols {for example, cyclic amines having a hydroxy group [eg, 4-4- (2-hydroxyethyl) -morpholin, 1- (2-hydroxyethyl) -pyrrolidin, etc. ] Etc.} and the like.
［各成分の割合］
　組成物（液剤など）において、ペメトレキセド類の割合（濃度）は、例えば、０．１～１０００ｍｇ／ｍＬ（例えば、０．３～５００ｍｇ／ｍＬ）、好ましくは０．５～３００ｍｇ／ｍＬ（例えば、０．７～２００ｍｇ／ｍＬ）、さらに好ましくは１～１００ｍｇ／ｍＬ（例えば、３～９０ｍｇ／ｍＬ）、特に５～８０ｍｇ／ｍＬ（例えば、７～６０ｍｇ／ｍＬ）程度であってもよく、通常１０～５０ｍｇ／ｍＬ（例えば、１５～４０ｍｇ／ｍＬ）程度であってもよい。 [Ratio of each component]
In the composition (liquid preparation, etc.), the ratio (concentration) of pemetrexeds is, for example, 0.1 to 1000 mg / mL (for example, 0.3 to 500 mg / mL), preferably 0.5 to 300 mg / mL (for example, for example). 0.7 to 200 mg / mL), more preferably 1 to 100 mg / mL (for example, 3 to 90 mg / mL), particularly 5 to 80 mg / mL (for example, 7 to 60 mg / mL), and usually It may be about 10 to 50 mg / mL (for example, 15 to 40 mg / mL).
　なお、ペメトレキセド類が、ペメトレキセドの塩（さらには水和物）である場合、上記割合は、ペメトレキセド換算の割合であってもよい（以下、割合の記載において同じ）。 When the pemetrexeds are salts of pemetrexed (further, hydrates), the above ratio may be the ratio in terms of pemetrexed (hereinafter, the same applies to the description of the ratio).
　組成物（液剤など）において、チオグリセロール類の割合（濃度）は、例えば、０．００１ｍｇ／ｍＬ以上（例えば、０．００１～２００ｍｇ／ｍＬ、０．００５～８０ｍｇ／ｍＬ）、好ましくは０．０１ｍｇ／ｍＬ以上（例えば、０．０１～５０ｍｇ／ｍＬ、０．０３～４０ｍｇ／ｍＬ）、さらに好ましくは０．０５ｍｇ／ｍＬ以上（例えば、０．０５～２０ｍｇ／ｍＬ、０．０７～１０ｍｇ／ｍＬ）、特に０．１ｍｇ／ｍＬ以上（例えば、０．１～５ｍｇ／ｍＬ、０．２～４ｍｇ／ｍＬ）程度であってもよく、通常０．３ｍｇ／ｍＬ以上（例えば、０．３～３ｍｇ／ｍＬ、０．５～１．５ｍｇ／ｍＬ）程度であってもよい。 In the composition (liquid preparation or the like), the ratio (concentration) of thioglycerols is, for example, 0.001 mg / mL or more (for example, 0.001 to 200 mg / mL, 0.005 to 80 mg / mL), preferably 0. 01 mg / mL or more (for example, 0.01 to 50 mg / mL, 0.03 to 40 mg / mL), more preferably 0.05 mg / mL or more (for example, 0.05 to 20 mg / mL, 0.07 to 10 mg / mL) It may be about 0.1 mg / mL or more (for example, 0.1 to 5 mg / mL, 0.2 to 4 mg / mL), and usually 0.3 mg / mL or more (for example, 0.3 to 0.3 to mL). It may be about 3 mg / mL, 0.5 to 1.5 mg / mL).
　チオグリセロール類の割合は、ペメトレキセド類１００質量部に対して、例えば、０．０１質量部以上（例えば、０．０１～２００質量部、０．０２～１５０質量部、０．０５～１２０質量部）、好ましくは０．１質量部以上（例えば、０．１～１００質量部、０．２～５０質量部）、さらに好ましくは０．３質量部以上（例えば、０．３～２０質量部、０．５～１５質量部）、特に１質量部以上（例えば、１～１２質量部、１．５～１０質量部）程度であってもよく、通常２質量部以上（例えば、２～５質量部）程度であってもよい。 The ratio of thioglycerols is, for example, 0.01 parts by mass or more (for example, 0.01 to 200 parts by mass, 0.02 to 150 parts by mass, 0.05 to 120 parts by mass) with respect to 100 parts by mass of pemetrexeds. ), Preferably 0.1 parts by mass or more (for example, 0.1 to 100 parts by mass, 0.2 to 50 parts by mass), and more preferably 0.3 parts by mass or more (for example, 0.3 to 20 parts by mass). 0.5 to 15 parts by mass), particularly 1 part by mass or more (for example, 1 to 12 parts by mass, 1.5 to 10 parts by mass), and usually 2 parts by mass or more (for example, 2 to 5 parts by mass). Part) may be about.
　組成物（液剤など）において、亜硫酸成分の割合（濃度）は、例えば、０．００１ｍｇ／ｍＬ以上（例えば、０．００１～１００ｍｇ／ｍＬ、０．００５～８０ｍｇ／ｍＬ）、好ましくは０．０１ｍｇ／ｍＬ以上（例えば、０．０１～５０ｍｇ／ｍＬ、０．０３～４０ｍｇ／ｍＬ）、さらに好ましくは０．０５ｍｇ／ｍＬ以上（例えば、０．０５～３０ｍｇ／ｍＬ、０．１～２５ｍｇ／ｍＬ）、特に０．１５ｍｇ／ｍＬ以上（例えば、０．１５～２０ｍｇ／ｍＬ、０．２～１５ｍｇ／ｍＬ）程度であってもよく、通常０．２５ｍｇ／ｍＬ以上（例えば、０．２５～１０ｍｇ／ｍＬ、０．３～５ｍｇ／ｍＬ、好ましくは０．５～３ｍｇ／ｍＬ）程度であってもよい。 In the composition (liquid preparation, etc.), the ratio (concentration) of the sulfite component is, for example, 0.001 mg / mL or more (for example, 0.001 to 100 mg / mL, 0.005 to 80 mg / mL), preferably 0.01 mg. / ML or more (eg 0.01-50 mg / mL, 0.03-40 mg / mL), more preferably 0.05 mg / mL or more (eg 0.05-30 mg / mL, 0.1-25 mg / mL) ), Especially about 0.15 mg / mL or more (for example, 0.15 to 20 mg / mL, 0.2 to 15 mg / mL), and usually 0.25 mg / mL or more (for example, 0.25 to 10 mg). / ML, 0.3 to 5 mg / mL, preferably 0.5 to 3 mg / mL).
　亜硫酸成分の割合は、ペメトレキセド類１００質量部に対して、例えば、０．０１質量部以上（例えば、０．０１～１０００質量部、０．０３～５００質量部）、好ましくは０．０５質量部以上（例えば、０．０５～３００質量部、０．０７～２００質量部）、さらに好ましくは０．１質量部以上（例えば、０．１～１００質量部、０．１５～８０質量部）、特に０．２質量部以上（例えば、０．２～５０質量部、０．５～３０質量部）程度であってもよく、通常１質量部以上（例えば、１～２０質量部、２～１５質量部、３～１０質量部）程度であってもよい。 The ratio of the sulfite component is, for example, 0.01 parts by mass or more (for example, 0.01 to 1000 parts by mass, 0.03 to 500 parts by mass), preferably 0.05 parts by mass, with respect to 100 parts by mass of pemetrexeds. Above (for example, 0.05 to 300 parts by mass, 0.07 to 200 parts by mass), more preferably 0.1 parts by mass or more (for example, 0.1 to 100 parts by mass, 0.15 to 80 parts by mass). In particular, it may be about 0.2 parts by mass or more (for example, 0.2 to 50 parts by mass, 0.5 to 30 parts by mass), and usually 1 part by mass or more (for example, 1 to 20 parts by mass, 2 to 15 parts). It may be about 3 to 10 parts by mass).
　チオグリセロール類及び亜硫酸成分の総量の割合は、ペメトレキセド類１００質量部に対して、例えば、０．０１質量部以上（例えば、０．０１～１０００質量部、０．０５～５００質量部）、好ましくは０．１質量部以上（例えば、０．１～３００質量部、０．２～２００質量部）、さらに好ましくは０．３質量部以上（例えば、０．３～１００質量部、０．５～５０質量部）、特に１質量部以上（例えば、１～３０質量部、１．２～２５質量部）程度であってもよく、通常１．５質量部以上（例えば、１．５～２０質量部、２～１５質量部）程度であってもよい。 The ratio of the total amount of the thioglycerols and the sulfite component is preferably 0.01 parts by mass or more (for example, 0.01 to 1000 parts by mass and 0.05 to 500 parts by mass) with respect to 100 parts by mass of pemetrexeds. Is 0.1 parts by mass or more (for example, 0.1 to 300 parts by mass, 0.2 to 200 parts by mass), more preferably 0.3 parts by mass or more (for example, 0.3 to 100 parts by mass, 0.5 parts by mass). It may be about 1 part by mass or more (for example, 1 to 30 parts by mass, 1.2 to 25 parts by mass), and usually 1.5 parts by mass or more (for example, 1.5 to 20 parts by mass). It may be about 2 to 15 parts by mass).
　亜硫酸成分とチオグリセロール類との割合は、前者／後者（質量比）＝１／０．００１～１／１００（例えば、１／０．００５～１／８０）、好ましくは１／０．０１～１／５０（例えば、１／０．０１５～１／４０）、さらに好ましくは１／０．０２～１／３０（例えば、１／０．０３～１／２０）、特に１／０．０５～１／１５（例えば、１／０．１～１／１０）程度であってもよく、通常１／０．２～１／５程度であってもよい。 The ratio of the sulfite component to the thioglycerols is the former / latter (mass ratio) = 1 / 0.001 to 1/100 (for example, 1 / 0.005 to 1/80), preferably 1 / 0.01 to 1. 1/50 (eg 1 / 0.015 to 1/40), more preferably 1 / 0.02 to 1/30 (eg 1 / 0.03 to 1/20), especially 1 / 0.05 to It may be about 1/15 (for example, 1 / 0.1 to 1/10), and usually about 1 / 0.2 to 1/5.
　組成物が、等張化剤（例えば、マンニトール）を含有する場合、等張化剤の割合（濃度）は、その種類に応じて選択できるが、例えば、１ｍｇ／ｍＬ以上（例えば、２～１０００ｍｇ／ｍＬ）、好ましくは３ｍｇ／ｍＬ以上（例えば、４～３００ｍｇ／ｍＬ）、さらに好ましくは５ｍｇ／ｍＬ以上（例えば、６～１００ｍｇ／ｍＬ）、特に８ｍｇ／ｍＬ以上（例えば、８～５０ｍｇ／ｍＬ）、特に好ましくは１０ｍｇ／ｍＬ以上（例えば、１２～４０ｍｇ／ｍＬ）であってもよい。 When the composition contains an isotonic agent (for example, mannitol), the proportion (concentration) of the isotonic agent can be selected according to the type, and is, for example, 1 mg / mL or more (for example, 2 to 1000 mg). / ML), preferably 3 mg / mL or higher (eg, 4 to 300 mg / mL), more preferably 5 mg / mL or higher (eg, 6 to 100 mg / mL), particularly 8 mg / mL or higher (eg, 8 to 50 mg / mL). ), Particularly preferably 10 mg / mL or more (for example, 12-40 mg / mL).
　組成物が、等張化剤（例えば、マンニトール）を含有する場合、等張化剤の割合は、ペメトレキセド類１００質量部に対して、例えば、０．０１質量部以上（例えば、０．０１～１００００質量部、０．１～５０００質量部）、好ましくは０．５質量部以上（例えば、０．５～２０００質量部、１～１５００質量部）、さらに好ましくは２質量部以上（例えば、３～１０００質量部）、特に５質量部以上（例えば、５～５００質量部、８～３００質量部）程度であってもよく、通常１０質量部以上（例えば、１０～２００質量部、２０～１５０質量部）程度であってもよい。 When the composition contains an isotonic agent (for example, mannitol), the ratio of the isotonic agent is, for example, 0.01 part by mass or more (for example, 0.01 to 0.01 to 100 parts by mass) with respect to 100 parts by mass of pemetrexeds. 10000 parts by mass, 0.1 to 5000 parts by mass), preferably 0.5 parts by mass or more (for example, 0.5 to 2000 parts by mass, 1 to 1500 parts by mass), and more preferably 2 parts by mass or more (for example, 3 parts by mass). It may be about 5 parts by mass or more (for example, 5 to 500 parts by mass, 8 to 300 parts by mass), and usually 10 parts by mass or more (for example, 10 to 200 parts by mass, 20 to 150 parts by mass). It may be about (mass part).
　なお、これらの成分以外の成分の割合は、その用途、目的等に応じて適宜選択できる。例えば、組成物がｐＨ調整剤を含む場合、ｐＨ調整剤の割合は、所望のｐＨに応じて適宜選択できる。 The ratio of components other than these components can be appropriately selected according to the intended use, purpose, and the like. For example, when the composition contains a pH adjuster, the proportion of the pH adjuster can be appropriately selected according to the desired pH.
［組成物の態様］
　溶媒を含む組成物（液剤）のｐＨは、酸性、中性及びアルカリ性のいずれからも選択できるが、例えば、４～１１（例えば、５～１０）、好ましくは５．５～９．５、さらに好ましくは６～９（例えば、７．５～８．５）であってもよく、中性ないしアルカリ性（例えば、ｐＨ７以上）であってもよい。
　ｐＨは、例えば、常温（例えば、２５℃等）における値であってもよい。 [Aspects of composition]
The pH of the composition (liquid agent) containing the solvent can be selected from acidic, neutral and alkaline, and is, for example, 4 to 11 (for example, 5 to 10), preferably 5.5 to 9.5, and further. It may be preferably 6 to 9 (for example, 7.5 to 8.5), or may be neutral to alkaline (for example, pH 7 or higher).
The pH may be, for example, a value at room temperature (for example, 25 ° C.).
　本発明の液剤は、中性ないしアルカリ領域においても、優れた安定性や着色抑制効果を実現できる。 The liquid agent of the present invention can realize excellent stability and anticoloring effect even in the neutral to alkaline region.
　組成物の浸透圧は、例えば、生理食塩水に対する浸透圧比で、０．１～１０（例えば、０．２～５）、好ましくは０．３～３（例えば、０．５～２）、さらに好ましくは０．６～１．４（例えば、０．７～１．３）、特に０．８～１．２（例えば、０．９～１．１）であってもよく、１（約１）であってもよい。
　浸透圧（浸透圧比）は、例えば、常温（例えば、２５℃等）における値であってもよい。 The osmotic pressure of the composition is, for example, the osmotic pressure ratio to physiological saline of 0.1 to 10 (for example, 0.2 to 5), preferably 0.3 to 3 (for example, 0.5 to 2), and further. It may preferably be 0.6 to 1.4 (eg, 0.7 to 1.3), particularly 0.8 to 1.2 (eg, 0.9 to 1.1), and 1 (about 1). ) May be.
The osmotic pressure (osmotic pressure ratio) may be, for example, a value at room temperature (for example, 25 ° C.).
　組成物（液剤）における酸素濃度は、安定性や着色等の観点から、比較的低濃度（例えば、１０体積％以下）であってもよく、例えば、５体積％以下（例えば、３体積％以下）、好ましくは２．５体積％以下、さらに好ましくは２．０体積％以下であってもよく、１．０体積％以下（例えば、０．８体積％以下、好ましくは０．７体積％以下、さらに好ましくは０．６体積％以下、特に０．５体積％以下）であってもよい。 The oxygen concentration in the composition (liquid agent) may be a relatively low concentration (for example, 10% by volume or less) from the viewpoint of stability, coloring, etc., for example, 5% by volume or less (for example, 3% by volume or less). ), Preferably 2.5% by volume or less, more preferably 2.0% by volume or less, 1.0% by volume or less (for example, 0.8% by volume or less, preferably 0.7% by volume or less). , More preferably 0.6% by volume or less, particularly 0.5% by volume or less).
　なお、組成物における酸素濃度（溶存酸素濃度）は、慣用の方法（不活性ガスによるバブリングなど）などにより調整（低減）できる。 The oxygen concentration (dissolved oxygen concentration) in the composition can be adjusted (reduced) by a conventional method (such as bubbling with an inert gas).
　本発明の組成物（製剤、ペメトレキセド製剤）は、容器に封入（密閉）されていてもよい。換言すれば、本発明には、組成物（ペメトレキセド製剤）を含む容器（内部に含む容器）も含まれる。 The composition (formulation, pemetrexed preparation) of the present invention may be sealed (sealed) in a container. In other words, the present invention also includes a container (a container contained therein) containing the composition (pemetrexed preparation).
　このような容器には、通常、前記組成物が封入又は密閉されていてもよい。本発明の組成物は、このような容器に封入（保存）されても、効率良く優れた安定性を実現しうる。 In such a container, the composition may be usually sealed or hermetically sealed. The composition of the present invention can efficiently realize excellent stability even when sealed (preserved) in such a container.
　容器としては、投与態様等に応じて適宜選択でき、例えば、バイアル、アンプル、注射器（又はシリンジ、例えば、プレフィルドシリンジ等）、バッグなどが挙げられる。 The container can be appropriately selected according to the administration mode and the like, and examples thereof include vials, ampoules, syringes (or syringes, for example, prefilled syringes, etc.), bags, and the like.
　容器の材質は、特に限定されず、例えば、ガラス、金属、樹脂（プラスチック）等が挙げられる。容器は、２種以上の材質を組み合わせて形成してもよい。 The material of the container is not particularly limited, and examples thereof include glass, metal, and resin (plastic). The container may be formed by combining two or more kinds of materials.
　なお、容器（例えば、容器のうち、少なくとも組成物と接触する部分）は、適宜、表面処理（例えば、ブラスト処理、表面処理剤によるコート処理など）されていてもよい。 The container (for example, at least the portion of the container that comes into contact with the composition) may be appropriately surface-treated (for example, blast treatment, coating treatment with a surface treatment agent, etc.).
　容器において、組成物の量は、容器の種類・サイズ、ペメトレキセド濃度（所望のペメトレセド量）等に応じて適宜選択でき、例えば、３０ｍＬ以下、２５ｍＬ以下、２０ｍＬ以下、１５ｍＬ以下、１０ｍＬ以下、８ｍＬ以下、７ｍＬ以下、６ｍＬ以下、５ｍＬ以下であってもよい。具体的な組成物の量には、１ｍＬ、１．５ｍＬ、２ｍＬ、２．５ｍＬ、３ｍＬ、３．５ｍＬ、４ｍＬ、５ｍＬ、８ｍＬ、１０ｍＬ等が挙げられ、代表的には４ｍＬであってもよい。 In the container, the amount of the composition can be appropriately selected according to the type and size of the container, the pemetrexed concentration (desired amount of pemetrexed), etc. For example, 30 mL or less, 25 mL or less, 20 mL or less, 15 mL or less, 10 mL or less, 8 mL or less. , 7 mL or less, 6 mL or less, 5 mL or less. Specific amounts of the composition include 1 mL, 1.5 mL, 2 mL, 2.5 mL, 3 mL, 3.5 mL, 4 mL, 5 mL, 8 mL, 10 mL and the like, and may be typically 4 mL. ..
　容器の内部は、前記組成物（液剤）のみで構成してもよく、空隙（空間）を有していてもよい。このような空隙（空隙部、ヘッドスペース）は、特に、不活性ガス（窒素ガスなど）で充填されている（又は置換されている）のが好ましい。 The inside of the container may be composed only of the composition (liquid agent) or may have a void (space). It is particularly preferable that such voids (void portions, headspaces) are filled (or replaced) with an inert gas (nitrogen gas or the like).
　さらに、このような空隙に含まれる酸素も、比較的少なくしてもよい。例えば、容器内の空隙中の酸素濃度は、例えば、１０体積％以下であってもよく、例えば、５体積％以下（例えば、３体積％以下）、好ましくは２．５体積％以下、さらに好ましくは２．０体積％以下（例えば、１．５体積％以下）であってもよく、１．０体積％以下（例えば、０．８体積％以下、好ましくは０．７体積％以下、さらに好ましくは０．６体積％以下、特に０．５体積％以下）であってもよい。 Furthermore, the oxygen contained in such voids may be relatively small. For example, the oxygen concentration in the voids in the container may be, for example, 10% by volume or less, for example, 5% by volume or less (for example, 3% by volume or less), preferably 2.5% by volume or less, more preferably. May be 2.0% by volume or less (for example, 1.5% by volume or less), 1.0% by volume or less (for example, 0.8% by volume or less, preferably 0.7% by volume or less, more preferably. May be 0.6% by volume or less, particularly 0.5% by volume or less).
　酸素濃度は、慣用の方法、例えば、前記組成物及び／又は容器内部に不活性ガスをバブリングする方法、前記組成物及び／又は容器内部を脱気する方法、容器内の空隙を不活性ガスで置換する方法、これらを組み合わせた方法などにより調整できる。 The oxygen concentration can be determined by a conventional method, for example, a method of bubbling an inert gas inside the composition and / or the container, a method of degassing the composition and / or the inside of the container, and the void in the container with the inert gas. It can be adjusted by a method of replacement, a method of combining these, and the like.
　なお、本発明の組成物では、このような容器内の空隙の酸素濃度（さらには組成物における酸素濃度）を、厳密に（著しく）低濃度としなくても、十分な安定性や着色抑制効果を実現しうる。 In the composition of the present invention, even if the oxygen concentration in the voids in the container (furthermore, the oxygen concentration in the composition) is not strictly (significantly) low, the effect of sufficient stability and color suppression is sufficient. Can be realized.
　本発明の組成物は、投与方法に応じて選択できるが、特に、注射剤（注射製剤又は点滴静注）の形態であってもよい。具体的な投与方法としては、静注（静脈注射）、筋肉注射、または皮下注射等が挙げられる。さらに具体的には、静注で動脈内、腹膜内、髄膜下、心室内、尿道内、胸骨内、頭蓋内等に投与してもよく、点滴静注により投与してもよい。 The composition of the present invention can be selected according to the administration method, but in particular, it may be in the form of an injection (injection preparation or intravenous drip infusion). Specific administration methods include intravenous injection (intravenous injection), intramuscular injection, subcutaneous injection and the like. More specifically, it may be administered by intravenous infusion into an artery, peritoneum, submeninges, intraventricular, intraurethral, intrasternal, intracranial, or the like, or by intravenous drip infusion.
　なお、液剤における各成分の濃度は、前記と同様の範囲から選択できるが、特に、点滴静注で投与する場合、前記組成物を輸液に混合し溶解させることで点滴静注液を調製してもよい。本態様において、前記組成物を輸液に混合させるときの比率は、該静注液を投与される患者等の対象の体表面積、年齢、性別、適用箇所、病状の程度等に応じて適宜選択してよく、特に限定されない。 The concentration of each component in the liquid preparation can be selected from the same range as described above, but in particular, when administered by intravenous drip infusion, the composition is mixed with the infusion solution and dissolved to prepare an intravenous drip infusion solution. May be good. In this embodiment, the ratio when the composition is mixed with the infusion solution is appropriately selected according to the body surface area, age, gender, application site, degree of medical condition, etc. of the subject such as the patient to whom the intravenous infusion solution is administered. It is not particularly limited.
　輸液としては、特に限定されないが、例えば、生理食塩液、糖水溶液（ブドウ糖水溶液、果糖水溶液など）、糖アルコール水溶液（Ｄ－ソルビトール水溶液、キシリトール水溶液など）、アミノ酸水溶液、リンゲル液などが挙げられる。 The infusion solution is not particularly limited, and examples thereof include physiological saline solution, sugar aqueous solution (dextrose aqueous solution, fructose aqueous solution, etc.), sugar alcohol aqueous solution (D-sorbitol aqueous solution, xylitol aqueous solution, etc.), amino acid aqueous solution, Ringer solution, and the like.
　本発明の組成物（又は容器内の組成物）では、保存下においても、優れた安定性や低着色性を実現しうる。 The composition of the present invention (or the composition in a container) can realize excellent stability and low colorability even under storage.
　例えば、本発明の組成物では、保存下においても、類縁物質の生成を抑制しうる。類縁物質としては、例えば、類縁物質Ａ（後述の実施例の条件にて測定した場合に、相対保持時間（ＲＲＴ）０．３２において検出される類縁物質）、類縁物質Ｂ（後述の実施例の条件にて測定した場合に、相対保持時間（ＲＲＴ）０．６７において検出される類縁物質）、類縁物質Ｃ（後述の実施例の条件にて測定した場合に、相対保持時間（ＲＲＴ）０．７０において検出される類縁物質）等が挙げられる。 For example, the composition of the present invention can suppress the formation of related substances even under storage. Examples of related substances include related substances A (related substances detected at a relative retention time (RRT) of 0.32 when measured under the conditions of the examples described later) and related substances B (related substances of the examples described later). Relative retention time (RRT) 0. Relative retention time (RRT) 0. Related substances detected in 70) and the like.
　保存は、低温ないし冷蔵下などであってもよいが、特に、常温（又は室温又は環境温度、例えば、０～５０℃、５～４５℃、１０～４０℃、１５～３５℃、１５～３０℃等）下であってもよい。本発明の組成物によれば、このような常温下でも優れた安定性や低着色性等を実現しうる。 Storage may be at low temperature or refrigerated, but in particular, room temperature (or room temperature or ambient temperature, for example, 0 to 50 ° C, 5 to 45 ° C, 10 to 40 ° C, 15 to 35 ° C, 15 to 30). ℃ etc.) may be lower. According to the composition of the present invention, excellent stability, low colorability and the like can be realized even at room temperature.
　次に、実施例を挙げて本発明をさらに具体的に説明するが、本発明はこれらの実施例により何ら限定されるものではなく、多くの変形が本発明の技術的思想内で当分野において通常の知識を有する者により可能である。 Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples, and many modifications are made in the art within the technical idea of the present invention. It is possible by a person with ordinary knowledge.
＜容器内の気体中の酸素濃度の測定＞
　各組成物（注射液製剤）の容器内の気体中の酸素濃度は、以下の測定装置及び測定方法により測定した。
　測定装置：残存酸素計（製品名：パックマスター、飯島電子工業（株）製）
　測定方式：隔膜型ガルバニ電池式酸素センサー
　測定方法：グローブボックス内で窒素雰囲気下において、注射液製剤の容器に装置のサンプラー針部分を刺し、注射液製剤の容器内のヘッドスペースの気体を吸引することで、各注射液製剤の容器内の気体中の酸素濃度を測定した。 <Measurement of oxygen concentration in gas in container>
The oxygen concentration in the gas in the container of each composition (injection solution preparation) was measured by the following measuring device and measuring method.
Measuring device: Residual oxygen meter (Product name: Packmaster, manufactured by Iijima Electronics Co., Ltd.)
Measurement method: Diaphragm type galvanized battery type oxygen sensor Measurement method: In a nitrogen atmosphere in a glove box, pierce the sampler needle part of the device into the container of the injection solution preparation and suck the gas in the head space inside the container of the injection solution preparation. Therefore, the oxygen concentration in the gas in the container of each injection solution preparation was measured.
＜ｐＨの測定＞
　日本薬局方ｐＨ測定法に従い、測定した。 <Measurement of pH>
It was measured according to the pH measurement method of the Japanese Pharmacopoeia.
＜浸透圧比＞
　日本薬局方浸透圧測定法に従い、測定した。 <Osmotic pressure ratio>
It was measured according to the Japanese Pharmacopoeia osmotic pressure measurement method.
＜安定性試験＞
　得られた各組成物（注射液製剤）について、２５℃６０％ＲＨ又は６０℃６０％ＲＨの条件下で所定期間（３ヵ月間又は１週間）保存する安定性試験を行った。
　その後、下記に記載の方法にてペメトレキセドの分解（類縁物質増加）及び着色からみた安定性の評価を行った。 <Stability test>
Each of the obtained compositions (injection solution preparation) was subjected to a stability test in which it was stored for a predetermined period (3 months or 1 week) under the conditions of 25 ° C. 60% RH or 60 ° C. 60% RH.
Then, the stability of pemetrexed from the viewpoint of decomposition (increased related substances) and coloring was evaluated by the method described below.
・着色評価（Ａ４３０）
　安定性試験実施後の着色を、紫外可視分光光度計（（島津製作所（株）製ＵＶ－２２００）を用いて評価した。具体的には、安定性試験実施後の組成物（注射液製剤）の波長４３０ｎｍにおける吸光度（Ａ４３０）を求めることで、評価を行った。一般的には、評価基準として０．０１以下であると、着色がないとされている。 ・ Coloring evaluation (A430)
The coloration after the stability test was evaluated using an ultraviolet-visible spectrophotometer (UV-2200 manufactured by Shimadzu Corporation). Specifically, the composition (injection solution preparation) after the stability test was performed. The evaluation was performed by determining the absorbance (A430) at a wavelength of 430 nm. Generally, when the evaluation standard is 0.01 or less, it is said that there is no coloring.
・類縁物質評価
　各類縁物質（類縁Ａ、類縁Ｂ、類縁Ｃ）の量を、以下の測定条件においてＨＰＬＣにより試験を行い、各類縁物質の量をペメトレキセドに由来する全ピーク面積中の各類縁物質のピーク面積の比率（％）から算出した。 -Evaluation of related substances The amount of each related substance (related A, related B, related C) was tested by HPLC under the following measurement conditions, and the amount of each related substance was measured for each related substance in the total peak area derived from pemetrexed. It was calculated from the ratio (%) of the peak area of.
［ＨＰＬＣ試験条件］
　検出器：紫外吸光光度計（測定波長：２５０ｎｍ）
　カラム：内径４．６ｍｍ，長さ１５ｃｍのステンレス管に３．５μｍの液体クロマトグラフィー用オクチルシリル化シリカゲルを充填
　カラム温度：３５℃付近の一定温度
　移動相Ａ：酢酸（１００）１．７ｍＬに水１０００ｍＬを加え、８ｍｏｌ／Ｌ水酸化ナトリウム試液を加えてｐＨ５．５に調整する。この液９７０ｍＬにアセトニトリル３０ｍＬを加える。
　移動相Ｂ：酢酸（１００）１．７ｍＬに水１０００ｍＬを加え、８ｍｏｌ／Ｌ水酸化ナトリウム試液を加えてｐＨ５．５に調整する。この液７００ｍＬにアセトニトリル１００ｍＬを加える。
　流量：毎分１ｍＬ [HPLC test conditions]
Detector: Ultraviolet absorptiometer (measurement wavelength: 250 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is filled with 3.5 μm octylsilylated silica gel for liquid chromatography. Column temperature: Constant temperature around 35 ° C. Mobile phase A: Water in 1.7 mL of acetic acid (100) Add 1000 mL and add 8 mol / L sodium hydroxide TS to adjust the pH to 5.5. Add 30 mL of acetonitrile to 970 mL of this solution.
Mobile phase B: Add 1000 mL of water to 1.7 mL of acetic acid (100) and add 8 mol / L sodium hydroxide TS to adjust the pH to 5.5. Add 100 mL of acetonitrile to 700 mL of this solution.
Flow rate: 1 mL / min
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
（参考例１～７、実施例１～１３）
　ペメトレキセドナトリウムヘミペンタ水和物及び各成分（Ｄ－マンニトール、チオグリセロール、亜硫酸成分等）を注射用水１２０ｍＬに溶解した。完全溶解を確認後、必要に応じて適量のｐＨ調整剤（水酸化ナトリウム及び／又は塩酸）を加え、所定のｐＨに調整し、全量１６０ｍＬとなるように注射用水で定容した。 (Reference Examples 1 to 7, Examples 1 to 13)
Pemetrexed sodium hemipenta hydrate and each component (D-mannitol, thioglycerol, sulfite component, etc.) were dissolved in 120 mL of water for injection. After confirming complete dissolution, an appropriate amount of a pH adjuster (sodium hydroxide and / or hydrochloric acid) was added as needed to adjust the pH to a predetermined pH, and the volume was adjusted with water for injection so that the total volume was 160 mL.
　得られた溶液を孔径０．２２μｍのフィルターで無菌ろ過後、ガラスバイアルに４ｍＬ充填し、窒素を充填し、酸素濃度を０．８％としたグローブボックス内で打栓した。アルミキャップで巻き締めを行い、密封することで、容器に封入した組成物（注射液製剤）を得、各種測定に供した。 The obtained solution was aseptically filtered through a filter having a pore size of 0.22 μm, then filled in a glass vial with 4 mL, filled with nitrogen, and stoppered in a glove box having an oxygen concentration of 0.8%. The composition (injection solution preparation) enclosed in a container was obtained by winding and sealing with an aluminum cap and used for various measurements.
　なお、組成物における浸透圧比（生理食塩水に対する）は、実施例７の組成物を除いて、いずれも、約１であった。
　また、封入時における容器内の気体中の酸素（Ｏ２）濃度は０．５～０．８体積％であった。 The osmotic pressure ratio (with respect to physiological saline) in the composition was about 1 in all cases except for the composition of Example 7.
The oxygen (O 2 ) concentration in the gas in the container at the time of encapsulation was 0.5 to 0.8% by volume.
　結果を下記表に示す。
　なお、表において、各成分の量（ｍｇ）は、製剤４ｍＬ中に占める量であり、残量は水である。
　また、表において、「ペメトレキセド」の量（１２０．８ｍｇ）は、ペメトレキセドナトリウムヘミペンタ水和物の量であり、ペメトレキセドとしては「１００ｍｇ」である。同様に「クエン酸Ｎａ」の量（４０ｍｇ）は、クエン酸Ｎａ水和物の量である。
　さらに、表において、類縁Ａ～Ｃの単位は「％」（面積％）である。
　さらにまた、「Ｎ．Ｄ」とは検出せず（検出限界以下）であったことを示す。 The results are shown in the table below.
In the table, the amount (mg) of each component is the amount occupied in 4 mL of the pharmaceutical product, and the remaining amount is water.
Further, in the table, the amount of "pemetrexed" (120.8 mg) is the amount of pemetrexed sodium hemipenta hydrate, and the amount of pemetrexed is "100 mg". Similarly, the amount of "Na citrate" (40 mg) is the amount of Na citrate hydrate.
Further, in the table, the unit of the relatives A to C is "%" (area%).
Furthermore, "ND" indicates that it was not detected (below the detection limit).
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　上記表の結果から明らかなように、ペメトレキセドに対して、チオグリセロールと亜硫酸成分とを組み合わせることで、高い安定性を有しており（類縁物質Ａ～Ｃの生成が少ない等）、着色（さらにはｐＨ変化）も抑えられていた。 As is clear from the results in the above table, the combination of thioglycerol and the sulfite component has high stability with respect to pemetrexed (the production of related substances A to C is small, etc.) and coloring (further). The pH change) was also suppressed.
　特に、上記結果は、２５℃（６０％ＲＨ）のものであり、上記組成物によれば、常温ないし室温での保存において高い安定性等を実現できることを示唆するものと言える。 In particular, the above result is at 25 ° C. (60% RH), and it can be said that the above composition suggests that high stability and the like can be realized when stored at room temperature or room temperature.
　なお、このような高い安定性等は、２５℃（６０％ＲＨ）のみならず、より高温においても（ひいては苛酷ないし加速試験においても）実現できることを確認している。その結果の一部（実施例の一部、すなわち、実施例２～４）を下記表（表２）に示す。 It has been confirmed that such high stability can be achieved not only at 25 ° C (60% RH) but also at higher temperatures (and even in severe or accelerated tests). A part of the result (a part of Examples, that is, Examples 2 to 4) is shown in the following table (Table 2).
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　上記表２の結果から明らかなように、６０℃６０％ＲＨで１週間保存した場合も、高い安定性等を示した。ただし、２５℃６０％ＲＨで３ヶ月保存した場合とは、一部、安定性（類縁物質Ａの量）の傾向が異なった。 As is clear from the results in Table 2 above, high stability and the like were shown even when stored at 60 ° C. and 60% RH for 1 week. However, the tendency of stability (amount of related substance A) was partially different from that when stored at 25 ° C. and 60% RH for 3 months.
　このことは、加速試験は、実際の温度（例えば、常温）の結果と完全に反映しない場合があり、ある温度［この場合は常温（２５℃）］での安定性等は、その温度において測定することでより確度が高い結果が得られることを示唆するものとなった。 This means that the accelerated test may not completely reflect the result of the actual temperature (for example, normal temperature), and the stability at a certain temperature [in this case, normal temperature (25 ° C)] is measured at that temperature. This suggests that more accurate results can be obtained.
　本発明により、新規な組成物（ペメトレキセド組成物）を得ることができる。 According to the present invention, a novel composition (pemetrexed composition) can be obtained.

Claims (17)

  1. 　ペメトレキセド類と、チオグリセロール類と、亜硫酸成分とを含む組成物。 A composition containing pemetrexeds, thioglycerols, and a sulfite component.
  2. 　亜硫酸成分が、亜硫酸類、亜硫酸水素類及びピロ亜硫酸類から選択された少なくとも１種を含む、請求項１記載の組成物。 The composition according to claim 1, wherein the sulfurous acid component contains at least one selected from sulfites, hydrogen sulfites and pyrosulfites.
  3. 　チオグリセロール類の割合が０．０１ｍｇ／ｍＬ以上である、請求項１又は２記載の組成物。 The composition according to claim 1 or 2, wherein the ratio of thioglycerols is 0.01 mg / mL or more.
  4. 　亜硫酸成分の割合が０．０１ｍｇ／ｍＬ以上である、請求項１～３のいずれかに記載の組成物。 The composition according to any one of claims 1 to 3, wherein the ratio of the sulfurous acid component is 0.01 mg / mL or more.
  5. 　亜硫酸成分とチオグリセロール類との割合が、前者／後者（質量比）＝１／０．０１～１／５０である、請求項１～４のいずれかに記載の組成物。 The composition according to any one of claims 1 to 4, wherein the ratio of the sulfurous acid component to the thioglycerols is 1/0.01 to 1/50 of the former / latter (mass ratio).
  6. 　ｐＨが５．５～９．５の液剤である請求項１～５のいずれかに記載の組成物。 The composition according to any one of claims 1 to 5, which is a liquid preparation having a pH of 5.5 to 9.5.
  7. 　亜硫酸成分が、亜硫酸、亜硫酸水素、ピロ亜硫酸、及びこれらの塩から選択された少なくとも１種を含み、
    　ペメトレキセド類を１～１００ｍｇ／ｍＬ、チオグリセロール類を０．０５ｍｇ／ｍＬ以上、亜硫酸成分を０．０５３０ｍｇ／ｍＬ以上の濃度で含み、
    　亜硫酸成分とチオグリセロール類との割合が、前者／後者（質量比）＝１／０．０２～１／３０であり、
    　ｐＨが６～９の液剤である、請求項１～６のいずれかに記載の組成物。     The sulfite component comprises at least one selected from sulfite, hydrogen sulfite, pyrosulfite, and salts thereof.
    It contains pemetrexeds at a concentration of 1 to 100 mg / mL, thioglycerols at a concentration of 0.05 mg / mL or more, and a sulfite component at a concentration of 0.0530 mg / mL or more.
    The ratio of the sulfite component to the thioglycerols is the former / the latter (mass ratio) = 1 / 0.02 to 1/30.
    The composition according to any one of claims 1 to 6, which is a liquid preparation having a pH of 6 to 9.
  8. 　さらに、等張化剤を含む、請求項１～７のいずれかに記載の組成物。 The composition according to any one of claims 1 to 7, further comprising an isotonic agent.
  9. 　常温又は環境温度での保存用である、請求項１～８のいずれかに記載の組成物。 The composition according to any one of claims 1 to 8, which is for storage at room temperature or ambient temperature.
  10. 　請求項１～９のいずれかに記載の組成物を封入した容器。 A container containing the composition according to any one of claims 1 to 9.
  11. 　容器内の空隙における酸素濃度が２．５体積％以下である請求項１０記載の容器。 The container according to claim 10, wherein the oxygen concentration in the voids in the container is 2.5% by volume or less.
  12. 　常温又は環境温度での保存用である、請求項１０又は１１記載の容器。 The container according to claim 10 or 11, which is used for storage at room temperature or ambient temperature.
  13. 　ペメトレキセド類を含有する組成物の安定性を向上する方法であって、組成物に、チオグリセロール類及び亜硫酸成分を含有させる方法。 A method for improving the stability of a composition containing pemetrexeds, wherein the composition contains thioglycerols and a sulfite component.
  14. 　ペメトレキセド類を含有する組成物の着色を抑制する方法であって、組成物に、チオグリセロール類及び亜硫酸成分を含有させる方法。 A method of suppressing coloration of a composition containing pemetrexeds, which is a method of adding thioglycerols and a sulfite component to the composition.
  15. 　ペメトレキセド類を含有する組成物において、安定性を向上するとともに、着色を抑制する方法であって、組成物に、チオグリセロール類及び亜硫酸成分を含有させる方法。 A method of improving stability and suppressing coloration in a composition containing pemetrexeds, wherein the composition contains thioglycerols and a sulfite component.
  16. 　常温又は環境温度において、安定性を向上及び／又は着色を抑制する、請求項１３～１５のいずれかに記載の方法。 The method according to any one of claims 13 to 15, which improves stability and / or suppresses coloring at room temperature or ambient temperature.
  17. 　請求項１～１２のいずれかに記載の組成物又は容器を、常温又は環境温度で保存する方法。 A method for storing the composition or container according to any one of claims 1 to 12 at room temperature or ambient temperature.
PCT/JP2020/048665 2020-03-24 2020-12-25 Pemetrexed formulation WO2021192471A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2022509275A JPWO2021192471A1 (en) 2020-03-24 2020-12-25

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020-053442 2020-03-24
JP2020053442 2020-03-24

Publications (1)

Publication Number Publication Date
WO2021192471A1 true WO2021192471A1 (en) 2021-09-30

Family

ID=77891253

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2020/048665 WO2021192471A1 (en) 2020-03-24 2020-12-25 Pemetrexed formulation

Country Status (2)

Country Link
JP (1) JPWO2021192471A1 (en)
WO (1) WO2021192471A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014237607A (en) * 2013-06-07 2014-12-18 ニプロ株式会社 Composition for injection comprising pemetrexed
JP2015124215A (en) * 2013-12-27 2015-07-06 富士フイルム株式会社 Injection formulation and production method thereof
JP2016518404A (en) * 2013-05-08 2016-06-23 シージェイ ヘルスケア コーポレイションＣｊ Ｈｅａｌｔｈｃａｒｅ Ｃｏｒｐｏｒａｔｉｏｎ Stabilized pemetrexed formulation
WO2018056336A1 (en) * 2016-09-21 2018-03-29 ナガセ医薬品株式会社 Pemetrexed formulation
JP2019019075A (en) * 2017-07-14 2019-02-07 東和薬品株式会社 Liquid pharmaceutical composition containing pemetrexed

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016518404A (en) * 2013-05-08 2016-06-23 シージェイ ヘルスケア コーポレイションＣｊ Ｈｅａｌｔｈｃａｒｅ Ｃｏｒｐｏｒａｔｉｏｎ Stabilized pemetrexed formulation
JP2014237607A (en) * 2013-06-07 2014-12-18 ニプロ株式会社 Composition for injection comprising pemetrexed
JP2015124215A (en) * 2013-12-27 2015-07-06 富士フイルム株式会社 Injection formulation and production method thereof
WO2018056336A1 (en) * 2016-09-21 2018-03-29 ナガセ医薬品株式会社 Pemetrexed formulation
JP2019019075A (en) * 2017-07-14 2019-02-07 東和薬品株式会社 Liquid pharmaceutical composition containing pemetrexed

Also Published As

Publication number Publication date
JPWO2021192471A1 (en) 2021-09-30

Similar Documents

Publication Publication Date Title
JP4789264B2 (en) Fasudil-containing preparation and method for improving its stability
KR100921199B1 (en) Stable high-concentration injection containing pyrazolone derivative
ES2344697T3 (en) INJECTABLE LIQUID FORMULATION OF PARACETAMOL.
US20100016362A1 (en) Stabilized pharmaceutical composition containing donepezil, process of producing same and method for stabilization
JP4956942B2 (en) Stabilized aqueous solution for injection
JP6501399B2 (en) Injection solution containing pemetrexed
US11382927B2 (en) Liquid medicinal preparation
US20220096414A1 (en) Levothyroxine liquid formulations
US20100249413A1 (en) Stabilized pharmaceutical composition
JP6980665B2 (en) Pemetrexed preparation
KR102138392B1 (en) Stabilized aqueous compositions of neuromuscular blocking agents
WO2021192471A1 (en) Pemetrexed formulation
WO2021192472A1 (en) Pemetrexed formulation
JP2014505081A (en) Paracetamol formulation in aqueous solution with storage stability
US11213480B1 (en) Phenylephrine hydrochloride ready-to-use solution
JP6120766B2 (en) Injection solution preparation and method for producing the same
JP7438802B2 (en) Palonosetron-containing composition
JP6352476B2 (en) Injection solution preparation and method for producing the same
TWI546087B (en) Containing aqueous preparations of acetaminophen and ibuprofen
JP6854710B2 (en) Injectable solution formulation containing pemetrexed
EP1864664A1 (en) Pharmaceutical preparation
JP2017149691A (en) Gemcitabine liquid drug
JP7090845B2 (en) Liquid composition containing palonosetron
WO2021161876A1 (en) Bendamustine liquid preparation
TW202000204A (en) Pemetrexed sodium injection solution formulation and manufacturing method therefor

Legal Events

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

Ref document number: 20926705

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022509275

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20926705

Country of ref document: EP

Kind code of ref document: A1