WO2021192472A1 - Préparation pharmaceutique de pémétrexed - Google Patents

Préparation pharmaceutique de pémétrexed Download PDF

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Publication number
WO2021192472A1
WO2021192472A1 PCT/JP2020/048666 JP2020048666W WO2021192472A1 WO 2021192472 A1 WO2021192472 A1 WO 2021192472A1 JP 2020048666 W JP2020048666 W JP 2020048666W WO 2021192472 A1 WO2021192472 A1 WO 2021192472A1
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Prior art keywords
composition
mass
parts
thioglycerols
container
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PCT/JP2020/048666
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English (en)
Japanese (ja)
Inventor
萌 大塚
Hiroyuki YAMADA (山田 博之)
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ナガセ医薬品株式会社
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Priority to JP2022509276A priority Critical patent/JPWO2021192472A1/ja
Publication of WO2021192472A1 publication Critical patent/WO2021192472A1/fr

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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
    • A61K31/505—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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—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 invention relates to the following inventions and the like.
  • a composition containing pemetrexeds and aminoalcohols [2] The composition according to [1], wherein the amino alcohols contain amino sugars. [3] The composition according to [1] or [2], wherein the ratio of amino alcohols is 0.01 mg / mL or more. [4] The composition according to any one of [1] to [3], further containing an antioxidant. [5] The composition according to any one of [1] to [4], further containing an antioxidant containing at least one selected from thioglycerols and a sulfite component. [6] The composition according to any one of [1] to [5], further containing thioglycerols and a sulfite component.
  • composition according to any one of. [8] The composition according to any one of [5] to [8], wherein the sulfite component comprises at least one selected from sulfites, hydrogen sulfites and pyrosulfites. [9] The composition according to any one of [1] to [8], which is a liquid preparation having a pH of 5.5 to 9.5.
  • Amino alcohols contain meglumine, It contains pemetrexeds at a concentration of 1 to 100 mg / mL and aminoalcohols at a concentration of 0.5 mg / mL or more. In addition, it contains an antioxidant containing at least one selected from thioglycerols and sulfite components.
  • the container according to [13] or [14] 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)].
  • [16] A method for improving (or improving) the stability of a composition containing pemetrexeds, wherein the composition contains aminoalcohols.
  • [17] A method for suppressing (or improving) coloring of a composition containing pemetrexeds, wherein the composition contains aminoalcohols.
  • [18] A method for improving (or improving) stability and suppressing (or improving) coloring in a composition containing pemetrexeds, wherein the composition contains aminoalcohols and antioxidants.
  • the antioxidant comprises at least one selected from thioglycerols and nitrite components.
  • 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 storage at room temperature (or room temperature or ambient temperature, for example, 5 to 40 ° C.).
  • room temperature or room temperature or ambient temperature, 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 at least pemetrexeds and aminoalcohols.
  • 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.
  • the amino alcohols may be any component having an amino group and a hydroxy group (alcohols having an amino group, amines having a hydroxy group), and may be an amino sugar.
  • Amino alcohols may be chain-like (linear or branched-chain) or cyclic.
  • 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.
  • 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-hydroxy
  • amino sugars eg, glucamine, meglumine
  • meglumine amino sugars
  • meglumine amino sugars
  • Amino alcohols may be used alone or in combination of two or more.
  • the composition may include an antioxidant.
  • the combination of aminoalcohols and antioxidants may be more advantageous in improving stability and coloration, and in such cases, these can be preferably combined.
  • antioxidants include thioglycerols, sulfite components, amino acids (cysteine, methionine, etc.), thioglycolic acid, lipoic acid, dihydrolipoic acid, chelate-forming compounds (citric acid, ethylenediamine tetraacetic acid, lactobionic acid, etc.), Thiosulfate, sulfite, sulfurous acid, salts thereof (eg, cysteine hydrochloride, sodium citrate, disodium ethylenediamine tetraacetate, sulfite, thiosulfate, etc.) are included.
  • Antioxidants may be used alone or in combination of two or more.
  • thioglycerols, sulfite components and the like are preferable, and in particular, these may be used in combination.
  • the composition is preferably at least one selected from thioglycerols and sulfite components [particularly, at least thioglycerols (for example, thioglycerols, thioglycerols, and the like). Sulfurous acid component, etc.)] may be included.
  • thioglycerols and sulfite components particularly, at least thioglycerols (for example, thioglycerols, thioglycerols, and the like). Sulfurous acid component, etc.)] may be included.
  • these antioxidants will be described in detail.
  • 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.
  • composition may contain an isotonic agent 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 [pemetrexeds, aminoalcohols, components other than antioxidants (non-solvent component, solid content)], if necessary.
  • other components include surfactants, defoamers, solubilizers, solubilizers, dispersants, preservatives and the like.
  • 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 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 aminoalcohols is, for example, 0.1 mg / mL or more (for example, 0.2 to 1000 mg / mL, 0.3 to 800 mg / mL), preferably 0.5 mg.
  • / ML or more (for example, 0.6 to 700 mg / mL, 0.8 to 600 mg / mL), more preferably 1 mg / mL or more (for example, 1.2 to 500 mg / mL, 1.5 to 400 mg / mL), In particular, it may be about 2 mg / mL or more (for example, 2.2 to 300 mg / mL, 2.5 to 200 mg / mL), and usually 3 mg / mL or more (for example, 4 to 150 mg / mL, 5 to 100 mg / mL). ) May be the case.
  • the ratio of amino alcohols is, for example, 0.1 parts by mass or more (for example, 0.2 to 10000 parts by mass, 0.3 to 8000 parts by mass, 0.5 to 6000 parts by mass) with respect to 100 parts by mass of pemetrexeds. ), preferably 1 part by mass or more (for example, 2 to 5000 parts by mass, 3 to 3000 parts by mass), more preferably 5 parts by mass or more (for example, 6 to 2000 parts by mass, 8 to 1000 parts by mass), particularly 10 parts by mass. It may be about 20 parts by mass or more (for example, 12 to 800 parts by mass, 15 to 500 parts by mass), and usually about 20 parts by mass or more (for example, 22 to 300 parts by mass).
  • the ratio thereof can be appropriately selected depending on the type of the antioxidant and the like, and is, for example, 0.001 mg / mL or more (for example, 0.001 to 1000 mg /). mL, 0.005-800 mg / mL), preferably 0.01 mg / mL or higher (eg, 0.01-500 mg / mL, 0.03-400 mg / mL), more preferably 0.05 mg / mL or higher (eg, 0.01-500 mg / mL). , 0.05 to 300 mg / mL, 0.1 to 250 mg / mL).
  • the ratio of the antioxidant is, for example, 0.01 part by mass or more (for example, 0.01 to 1000 parts by mass) with respect to 100 parts by mass of pemetrexeds.
  • 0.05 to 500 parts by mass preferably 0.1 parts by mass or more (for example, 0.1 to 300 parts by mass, 0.2 to 200 parts by mass), and more preferably 0.3 parts by mass or more (for example, 0).
  • the ratio of the antioxidant is, for example, 0.01 part by mass or more (for example, 0.01 to 1000 parts by mass) with respect to 100 parts by mass of amino alcohols. , 0.05 to 500 parts by mass), preferably 0.1 parts by mass or more (for example, 0.1 to 300 parts by mass, 0.2 to 200 parts by mass), and more preferably 0.3 parts by mass or more (for example, It may be about 0.3 to 150 parts by mass, 0.5 to 120 parts by mass), particularly 1 part by mass or more (for example, 1 to 100 parts by mass, 1.2 to 80 parts by mass), and usually 1.5. It may be about a mass part or more (for example, 1.5 to 50 parts by mass, 2 to 40 parts by mass).
  • the proportion (concentration) of the thioglycerols in the composition is, for example, 0.001 mg / mL or more (for example, 0.001 to 200 mg / mL, 0.005). -80 mg / mL), preferably 0.01 mg / mL or higher (eg, 0.01-50 mg / mL, 0.03-40 mg / mL), more preferably 0.05 mg / mL or higher (eg, 0.05-0.05).
  • 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 proportion (concentration) of the sulfite component in the composition 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 (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 30 mg / mL).
  • It may be 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. It may be about the above (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 thioglycerols and sulfite components is, for example, 0.01 parts by mass or more (for example, 0) with respect to 100 parts by mass of pemetrexeds. 0.01 to 1000 parts by mass, 0.05 to 500 parts by mass), preferably 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. Even if it is about 1 part by mass or more (for example, 0.3 to 100 parts by mass, 0.5 to 50 parts by mass), particularly 1 part by mass or more (for example, 1 to 30 parts by mass, 1.2 to 25 parts by mass). It may be usually about 1.5 parts by mass or more (for example, 1.5 to 20 parts by mass and 2 to 15 parts by mass).
  • the ratio (ratio of total amount) of thioglycerols and sulfite components is, for example, 0.01 parts by mass with respect to 100 parts by mass of aminoalcohols.
  • the ratio (ratio of total amount) of thioglycerols and sulfite components is, for example, 0.01 parts by mass with respect to 100 parts by mass of aminoalcohols.
  • 0.01 to 1000 parts by mass, 0.05 to 500 parts by mass preferably 0.1 parts by mass or more (for example, 0.1 to 300 parts by mass, 0.2 to 200 parts by mass), and further.
  • 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).
  • it may be about 1 / 0.03 to 1/20), particularly 1 / 0.05 to 1/15 (for example, 1 / 0.1 to 1/10), and usually 1 / 0.2 to 1 / 0.2 to 1/10. It may be about 1/5.
  • 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, 6 months) under the condition of 25 ° C. and 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.
  • the oxygen (O 2 ) concentration in the gas in the container at the time of encapsulation was 0.5 to 0.8% by volume.
  • Example 14 to 23 The compositions were obtained and subjected to various measurements in the same manner as in Reference Example 1 and Examples 1 to 13, except that the oxygen (O 2 ) concentration in the gas in the container at the time of encapsulation was 0.5% by volume. ..
  • Examples 24-28 In the same formulation, Reference Example 1 and Except that the oxygen (O 2 ) concentration in the gas in the container at the time of encapsulation was changed by 0, 0.2, 0.6, 0.8, 1.0% by volume. The compositions were obtained and subjected to various measurements in the same manner as in Examples 1 to 13.
  • 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.
  • a novel composition (pemetrexed composition) can be obtained.

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Abstract

L'invention concerne une nouvelle composition de pémétrexed.　Plus spécifiquement, cette composition contient des pémétrexeds et des amino-alcools.
PCT/JP2020/048666 2020-03-24 2020-12-25 Préparation pharmaceutique de pémétrexed WO2021192472A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150111905A1 (en) * 2012-05-30 2015-04-23 Fresenius Kabi Oncology Limited Pharmaceutical compositions of pemetrexed
JP2015124215A (ja) * 2013-12-27 2015-07-06 富士フイルム株式会社 注射液製剤及びその製造方法
JP2016521731A (ja) * 2013-06-14 2016-07-25 シントン・ベスローテン・フェンノートシャップ 抗がん剤を含む安定な水溶性医薬組成物
WO2016207443A1 (fr) * 2015-06-25 2016-12-29 Actavis Group Ptc Ehf Composition pharmaceutique comprenant du pemetrexed
WO2018056336A1 (fr) * 2016-09-21 2018-03-29 ナガセ医薬品株式会社 Formulation de pemetrexed
JP2019019075A (ja) * 2017-07-14 2019-02-07 東和薬品株式会社 ペメトレキセド含有液状医薬組成物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150111905A1 (en) * 2012-05-30 2015-04-23 Fresenius Kabi Oncology Limited Pharmaceutical compositions of pemetrexed
JP2016521731A (ja) * 2013-06-14 2016-07-25 シントン・ベスローテン・フェンノートシャップ 抗がん剤を含む安定な水溶性医薬組成物
JP2015124215A (ja) * 2013-12-27 2015-07-06 富士フイルム株式会社 注射液製剤及びその製造方法
WO2016207443A1 (fr) * 2015-06-25 2016-12-29 Actavis Group Ptc Ehf Composition pharmaceutique comprenant du pemetrexed
WO2018056336A1 (fr) * 2016-09-21 2018-03-29 ナガセ医薬品株式会社 Formulation de pemetrexed
JP2019019075A (ja) * 2017-07-14 2019-02-07 東和薬品株式会社 ペメトレキセド含有液状医薬組成物

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