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WO2018142514A1 - Composition pharmaceutique liquide contenant de la darbépoétine - Google Patents

Composition pharmaceutique liquide contenant de la darbépoétine Download PDF

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Publication number
WO2018142514A1
WO2018142514A1 PCT/JP2017/003634 JP2017003634W WO2018142514A1 WO 2018142514 A1 WO2018142514 A1 WO 2018142514A1 JP 2017003634 W JP2017003634 W JP 2017003634W WO 2018142514 A1 WO2018142514 A1 WO 2018142514A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
liquid pharmaceutical
darbepoetin
sugar
composition according
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2017/003634
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English (en)
Japanese (ja)
Inventor
恭子 山内
拓弥 徳田
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Kyowa Kirin Co Ltd
Original Assignee
Kyowa Hakko Kirin Co Ltd
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Filing date
Publication date
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Priority to PCT/JP2017/003634 priority Critical patent/WO2018142514A1/fr
Priority to JP2017509058A priority patent/JP6172880B1/ja
Publication of WO2018142514A1 publication Critical patent/WO2018142514A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to a liquid pharmaceutical composition containing darbepoetin.
  • EPO erythropoietin
  • G-CSF granulocyte colony stimulating factor
  • interferon alpha, beta, gamma, consensus
  • TNFbp tumor necrosis factor binding protein
  • IL-1ra interleukin-1 receptor Antagonist
  • BDNF brain-derived neurotrophic factor
  • KGF keratinocyte growth factor
  • SCF stem cell factor
  • MDF megakaryocyte growth differentiation factor
  • OPG osteoprotegilein
  • GDNF glial cell line Origin neurotrophic factor
  • OB protein obesity protein
  • Darbepoetin is a hyperglycosylated erythropoietin analog with five changes in the amino acid sequence of human erythropoietin (HuEPO), two at the 30th and 88th amino acid residues with the numbering corresponding to the amino acid sequence of HuEPO. Contains additional N-linked carbohydrate chains (Patent Document 1).
  • Darbepoetin is also biochemically distinguished from EPO and has a longer serum half-life and higher in vivo biological activity.
  • ESA erythropoiesis-stimulating factor preparations
  • an injection solution containing darbepoetin, polysorbate 80 and L-methionine is known.
  • ESA erythropoiesis-stimulating factor preparations
  • an injection solution containing epoetin beta pegol, sodium sulfate, L-methionine and polyoxyethylene (160) polyoxypropylene (30) glycol is known.
  • Patent Document 2 describes a liquid pharmaceutical composition of erythropoietin protein containing sodium sulfate as a polyvalent charged inorganic anion.
  • Liquid pharmaceutical compositions containing darbepoetin currently on the market are unstable at temperatures above refrigeration, usually between 2-8 ° C.
  • the liquid pharmaceutical composition containing darbepoetin currently on the market is in a form filled in a syringe or the like, and its aqueous solution stability is examined. It has become.
  • preparations containing epoetin beta pegol are also protected from light and stored at 2-8 ° C.
  • the problem to be solved by the present invention is to provide a liquid pharmaceutical composition comprising darbepoetin with improved stability.
  • a liquid pharmaceutical composition containing darbepoetin contains a sugar or a sugar alcohol and a block copolymer of polyethylene oxide and polypropylene oxide, thereby improving stability.
  • the present inventors have found that a liquid pharmaceutical composition can be provided that has improved the above, and has completed the present invention.
  • the present invention is as follows.
  • a liquid pharmaceutical composition comprising darbepoetin, a sugar or sugar alcohol, and a block copolymer of polyethylene oxide and polypropylene oxide.
  • the block copolymer of polyethylene oxide and polypropylene oxide is selected from the group consisting of Pluronic F68, Pluronic F87, Pluronic F108, Pluronic F127, Poloxamer 188, Poloxamer 237, Poloxamer 338 and Poloxamer 407, preferably from Pluronic F68 and Pluronic F127
  • wenty one) Contains 1 ⁇ g / mL to 5000 ⁇ g / mL darbepoetin, 1 mM to 300 mM mannitol or sorbitol, and 0.001% (w / v) to 1% (w / v) polyoxyethylene polyoxypropylene glycol, and has a pH of The liquid pharmaceutical composition according to any one of (1) to (17), which is 5 to 7 and does not contain sodium sulfate.
  • a liquid pharmaceutical composition containing darbepoetin with improved stability can be provided.
  • the liquid pharmaceutical composition of the present invention comprises darbepoetin, a sugar or sugar alcohol, and a block copolymer of polyethylene oxide and polypropylene oxide.
  • the liquid pharmaceutical composition of the present invention can improve the stability of darbepoetin in the liquid pharmaceutical composition by containing a sugar or sugar alcohol and a block copolymer of polyethylene oxide and polypropylene oxide.
  • Darbepoetin used in the liquid pharmaceutical composition of the present invention is a hyperglycosylated EPO analog comprising an additional carbohydrate chain attached to each of the two additional glycosylation sites of HuEPO.
  • Darbepoetin can usually be expressed in mammalian host cells by known gene recombination methods. Specifically, darbepoetin can be produced, for example, by the method described in WO95 / 05365. Specifically, darbepoetin has 165 amino acid residues (C 800 ) produced by introducing a cDNA mutated to change amino acid residues at 5 positions of erythropoietin derived from human hepatocytes into Chinese hamster ovary cells.
  • darbepoetin examples include a protein having the structure shown in FIG.
  • darbepoetin includes, for example, darbepoetin alfa or darbepoetin alfa (genetical recombination), or biosuccessors thereof.
  • novel erythropoiesis stimulating protein, NESP (registered trademark) or ARANESP (registered trademark) disclosed in International Publication No. 2003/020299, or their biosimilar products are also included in the darbepoetin of the present invention.
  • the content of darbepoetin is not particularly limited, but taking into account the amount of treatment, the weight ratio of darbepoetin to the volume of the liquid pharmaceutical composition, mL to 5000 ⁇ g / mL, more preferably 10 ⁇ g / mL to 1000 ⁇ g / mL, and still more preferably 10 ⁇ g / mL to 500 ⁇ g / mL.
  • the liquid pharmaceutical composition contains a sugar or a sugar alcohol.
  • a sugar is a compound containing a polyhydric alcohol compound having a reducing end classified as ketose or aldose as a structural unit.
  • the sugar is not particularly limited, and examples thereof include monosaccharides such as glucose, fructose, lactose and maltose, and disaccharides such as trehalose. Among them, a disaccharide having no reducing end is preferable, and trehalose is preferably used.
  • sugar alcohol is a linear sugar-derived compound in which an aldehyde group of aldose is reduced to a hydroxymethyl group, and is also referred to as alditol.
  • the sugar alcohol is not particularly limited, and examples thereof include glycerol, erythritol, xylitol, mannitol, sorbitol, maltitol, reduced starch saccharified product, xylitol, and reduced palatinose.
  • the sugar alcohol is preferably glycerol, sorbitol, and mannitol, more preferably mannitol and sorbitol, and further preferably mannitol.
  • the sugar or sugar alcohol is not particularly limited in the mixing ratio of the D-form and the L-form, and the D-form may be used, the L-form may be used, or a DL mixture of any ratio may be used. It is preferable to use a naturally occurring optically active substance.
  • the content of sugar or sugar alcohol is not particularly limited, but it can also be used as an osmotic pressure adjusting agent (isotonic agent) for adapting sugar or sugar alcohol for injection. Since it may be intended, the concentration of sugar or sugar alcohol in the liquid pharmaceutical composition is preferably 1 to 300 ⁇ m, more preferably 100 to 300 ⁇ m.
  • the liquid pharmaceutical composition contains a block copolymer of polyethylene oxide and polypropylene oxide.
  • the block copolymer of polyethylene oxide and polypropylene oxide is a block copolymer having ethylene oxide and propylene oxide as monomer units, respectively, and is also called poloxamer, collifol, pluronic or lutrol.
  • the block copolymer of polyethylene oxide and polypropylene oxide is not particularly limited. Poloxamer 338, poloxamer 407 and the like.
  • the block copolymer of polyethylene oxide and polypropylene oxide is preferably Pluronic F68 and Pluronic F127.
  • the content of the block copolymer of polyethylene oxide and polypropylene oxide is not particularly limited, but from the viewpoint of the stability of darbepoetin in the liquid pharmaceutical composition, the liquid pharmaceutical composition As a percentage of the weight of the block copolymer of polyethylene oxide and polypropylene oxide with respect to the capacity of, preferably 1% (w / v) or less, more preferably 0.1% (w / v) or less, more preferably 0.05% (w / v) or less.
  • the content is preferably 0.001% (w / v) or more, more preferably 0.005% (w / v) or more.
  • the content of the block copolymer of polyethylene oxide and polypropylene oxide is preferably 0.001% (w / v) to 1% (w / v), and is suitable within the range. Upper and lower limits can be taken.
  • a liquid pharmaceutical composition containing darbepoetin includes darbepoetin with improved stability by containing a sugar or sugar alcohol, a block copolymer of polyethylene oxide and polypropylene oxide.
  • darbepoetin is stored refrigerated (2-8 ° C.) and not at room temperature.
  • Darbepoetin degrades by storage at room temperature, for example 25 ° C., for long periods of time, for example several months or more than six months.
  • darbepoetin is decomposed to darbepoetin with respect to light stress, and is thus commercialized under storage conditions under light shielding.
  • Degradation of darbepoetin means a physical change (eg aggregation) and / or a chemical change (eg oxidation) of a protein molecule. Degradation of darbepoetin may reduce the effectiveness of the drug and induce adverse side effects after injection into humans.
  • the liquid pharmaceutical composition of the present invention is a composition in which the stability of darbepoetin is improved in a storage environment.
  • “Improved stability” in the liquid pharmaceutical composition of the present invention means that darbepoetin can be more stably present in the liquid pharmaceutical composition, and means that the degradation of darbepoetin is suppressed.
  • the storage stability of darbepoetin is improved at a temperature exceeding the refrigeration temperature (2 to 8 ° C.), for example, room temperature or 40 ° C., and light stress is applied.
  • the storage stability of darbepoetin is improved under certain conditions, for example, under white light scattering.
  • a method for preserving darbepoetin by using a liquid pharmaceutical composition comprising darbepoetin, a sugar or sugar alcohol, and a block copolymer of polyethylene oxide and polypropylene oxide.
  • a method for stabilizing darbepoetin in a liquid pharmaceutical composition by using a liquid pharmaceutical composition comprising darbepoetin, a sugar or a sugar alcohol, and a block copolymer of polyethylene oxide and polypropylene oxide. Also provide.
  • the present invention relates to a method for preserving a liquid pharmaceutical composition containing darbepoetin, which comprises darbepoetin, a sugar or sugar alcohol, and a block copolymer of polyethylene oxide and polypropylene oxide, or a block copolymer of sugar alcohol, polyethylene oxide and polypropylene oxide. It also relates to a method for stabilizing a liquid pharmaceutical composition comprising darbepoetin by comprising a polymer.
  • the liquid pharmaceutical composition of the present invention preferably exhibits improved thermal stability and improved light stability. More preferably, the liquid pharmaceutical composition of the present invention exhibits both improved thermal stability and improved light stability.
  • the method for preserving the liquid pharmaceutical composition, and the method for stabilizing the liquid pharmaceutical composition can be used without using a refrigerator, light-shielding condition, light-shielding container or light-shielding packaging. Can be stored for a long time without significant degradation.
  • the dosing frequency with the liquid pharmaceutical composition of the present invention is less than 3 times per week.
  • the dosing frequency may be twice per week, once per week, or less than once per week, eg once every other week, once per month or once every two months.
  • the liquid pharmaceutical composition of the present invention can be used to treat all symptoms of red blood cell loss such as reduced or lost renal function, chronic renal failure, myelosuppressive treatment, cancer, viral infection, chronic disease, and excessive during surgery. Can be used in blood loss.
  • the pH of the liquid pharmaceutical composition of the present invention is preferably 5-7.
  • the pH of the liquid pharmaceutical composition is preferably 5.5 to 6.4, and more preferably 6.0 to 6.4.
  • the pH of the liquid pharmaceutical composition of the present invention is not particularly limited, and is measured according to, for example, the Japanese Pharmacopoeia pH measurement method.
  • a commercially available pH meter can be used for pH measurement, for example, HM-60G (Toa Denpa Kogyo) is used.
  • the liquid pharmaceutical composition of the present invention may further comprise a pH adjusting agent and / or a pH buffering agent in order to maintain the pH of the solution within a desired range.
  • the pH adjuster is not particularly limited as long as it is used for the purpose of adjusting the pH described above, and examples thereof include hydrochloric acid, sodium hydroxide, succinic acid, and salts thereof.
  • the pH buffer is not particularly limited, and a known pharmaceutically acceptable pH buffer can be used. For example, sodium phosphate or potassium phosphate or a monohydrogen salt or a dihydrogen salt thereof. Etc., sodium citrate, citric acid, sodium succinate, succinic acid and the like.
  • the content of the pH buffer is not particularly limited, but the concentration in the liquid pharmaceutical composition is preferably 1 mM. ⁇ 100 mM, more preferably 10 mM to 50 mM.
  • Two or more pH adjusters may be used as pH adjusters and pH buffer agents, or two or more pH buffer agents may be used, and one or more pH adjusters and pH buffer agents are used in combination. May be.
  • the pH buffer is phosphate buffer or phosphate / citrate buffer, more preferably 10 mM to 50 mM phosphate buffer or 10 mM to 50 mM phosphate / citrate buffer. It contains an agent.
  • the citric acid contained in the pH buffer is preferably 10 mM or less, more preferably 5 mM or less.
  • the liquid pharmaceutical composition of the present invention may contain known pharmaceutically acceptable additives.
  • the isotonic agent include inorganic salts such as sodium chloride and potassium chloride, dextran, propylene glycol, polyethylene glycol, and nicotinic acid amide.
  • soothing agents include inositol, chlorobutanol, propylene glycol, benzyl alcohol, lidocaine, and magnesium sulfate.
  • Preservatives include, for example, parabens such as methyl paraoxybenzoate and ethyl paraoxybenzoate, benzoic acid, ethanol, tetrasodium edetate, salicylic acid, sorbitol, sorbic acid, glycerin, chlorobutanol, phenol, propylene glycol, and benzyl Alcohol etc. are mentioned.
  • the thickener include cellulose alkyl ethers such as hydroxypropylcellulose and hydroxypropylmethylcellulose, sodium alginate, xanthan gum, gelatin, dextran, dextrin, polyethylene glycol, and polyvinyl alcohol.
  • the antioxidant examples include cysteine, methionine, acetylcysteine, and ascorbic acid, and methionine is preferable.
  • examples of the stabilizer include inorganic salts such as sodium sulfate.
  • the liquid pharmaceutical composition of the present invention may contain a known pharmaceutically acceptable additive, but contains sodium sulfate by containing sugar or sugar alcohol and a block copolymer of polyethylene oxide and polypropylene oxide. It can be a composition free of sodium sulfate and sodium chloride or a composition free of sodium sulfate, sodium chloride and methionine.
  • the liquid pharmaceutical composition of the present invention contains a known pharmaceutically acceptable solvent. Although it does not specifically limit as a solvent, For example, water, alcohol, etc. are mentioned, Preferably it is water, such as water for injection.
  • the liquid pharmaceutical composition of the present invention comprises a darbepoetin, a sugar or sugar alcohol, a block copolymer of polyethylene oxide and polypropylene oxide, and a liquid composition which preferably exists as a solution by containing a solvent. is there.
  • the liquid pharmaceutical composition of the present invention is sterilized by a general technique such as aseptic filtration, and then used as an injection by enclosing it in an injection container such as an ampoule, vial or syringe in an aseptic environment. Can do.
  • an injection container such as an ampoule, vial or syringe in an aseptic environment.
  • Can do When encapsulating in the injection container, the container space may be replaced with an inert gas such as nitrogen or argon.
  • the liquid pharmaceutical composition of the present invention preferably contains, as an aqueous solution, 10 ⁇ g to 500 ⁇ g darbepoetin per mL, 100 to 300 mM mannitol and 0.1% (w / v) or less pluronic F68, if desired, Contains 10 mM to 50 mM phosphate buffer (pH 6.0 to 6.4) or 10 mM to 50 mM phosphate / citrate buffer (pH 6.0 to 6.4).
  • the liquid pharmaceutical composition of the present invention may be a liquid pharmaceutical composition containing 0.5 mM to 50 mM methionine. In that case, the liquid pharmaceutical composition may not contain sodium sulfate or may contain neither sodium sulfate nor sodium chloride. Good.
  • each component is appropriately selected within the preferable content range described above.
  • a nitrogen overlay may be performed in order to suppress methionine oxidation.
  • the nitrogen overlay can be introduced into the top space of the vial or prefilled syringe by scavenging with nitrogen during the filling process.
  • the liquid pharmaceutical composition of the present invention can be produced by sequentially mixing darbepoetin, sugar or sugar alcohol, and a block copolymer of polyethylene oxide and polypropylene oxide in a pharmaceutically acceptable solvent. The order of mixing including other components such as additives and the pH can be adjusted as appropriate.
  • a liquid pharmaceutical composition is provided.
  • the liquid pharmaceutical composition can also be distributed as a lyophilized product obtained by lyophilizing the liquid pharmaceutical composition, and a pharmaceutically acceptable solvent is added to the lyophilized formulation. It can also be set as a liquid pharmaceutical composition.
  • compositions (chemical solutions) of Formula 1 to Formula 3 were prepared.
  • Formula 1 40 ⁇ g / mL darbepoetin alfa (Kyowa Hakko Kirin), 20 mM sodium dihydrogen phosphate (Wako Pure Chemical), 5 mM citric acid (Wako Pure Chemical), 1 mM L-methionine (Sigma Aldrich), 245 mM D-mannitol (Mitsubishi Foodtech), 0.01% (w / v) Pluronic F68 (Sigma Aldrich), pH 6.2
  • Formula 2 40 ⁇ g / mL darbepoetin alfa, 20 mM sodium dihydrogen phosphate, 1 mM L-methionine, 245 mM D-mannitol, 0.005% (w / v) Polysorbate 80 (Nippon Oil), pH 6.2 Formula 3: 40 ⁇ g / mL darbepoetin alfa, 20 mM sodium dihydr
  • the obtained chemical solution is filtered through a 0.2 ⁇ m pore size filter (material polyethersulfone, Merck Millipore), then filled into a glass vial (Daiwa Special Glass, Type 1), and a rubber plug made of butyl rubber (Daikyo Seiko, D713) And sealed.
  • a 0.2 ⁇ m pore size filter material polyethersulfone, Merck Millipore
  • the drug solution filled in the vial was stored at 60 ° C. for 1 week.
  • the aggregate composition ratio was measured by size exclusion chromatography (equipment used: “LC-10Avp” manufactured by Shimadzu Corporation, measurement wavelength: 210 nm), and the oxidant composition ratio was measured by reverse phase chromatography ( Equipment used: “LC-20A” manufactured by Shimadzu Corporation, measurement wavelength: 210 nm).
  • LC-10Avp size exclusion chromatography
  • oxidant composition ratio was measured by reverse phase chromatography
  • LC-20A manufactured by Shimadzu Corporation, measurement wavelength: 210 nm
  • Table 1 shows the measurement results of the aggregate composition ratio and the oxidant composition ratio in the chemical solution after storage.
  • compositions (chemical solutions) of Formula 4 and Formula 5 were prepared in the same manner as Formula 1 using Pluronic F127 (Sigma Aldrich) and Trehalose (Tokyo Chemical Industry).
  • Formula 4 40 ⁇ g / mL darbepoetin alfa, 20 mM sodium dihydrogen phosphate, 5 mM citric acid, 1 mM L-methionine, 245 mM D-mannitol, 0.01% (w / v) Pluronic F127, pH 6.2
  • Formula 5 40 ⁇ g / mL darbepoetin alfa, 10 mM sodium dihydrogen phosphate, 5 mM citric acid, 1 mM L-methionine, 280 mM trehalose, 0.01% (w / v) Pluronic F68, pH 6.2
  • the drug solution filled in the vial was stored at 40 ° C. for 2 and 3 months, and the oxidant composition ratio was measured in the same manner as in Formula 1.
  • Table 2 shows the measurement results of the oxidant composition ratio in the chemical solution after storage.
  • compositions (chemical solutions) of Formula 6 to Formula 13 were prepared in the same manner as Formula 1.
  • Formula 6 40 ⁇ g / mL darbepoetin alfa, 20 mM sodium dihydrogen phosphate, 245 mM D-mannitol, 0.005% (w / v) polysorbate 80, pH 6.2
  • Formula 7 40 ⁇ g / mL darbepoetin alfa, 20 mM sodium dihydrogen phosphate, 245 mM D-mannitol, 0.01% (w / v) polysorbate 80, pH 6.2
  • Formula 8 40 ⁇ g / mL darbepoetin alfa, 20 mM sodium dihydrogen phosphate, 245 mM D-mannitol, 0.1% (w / v) polysorbate 80, pH 6.2 Formula 9: 40 ⁇ g / mL darbepoetin alfa, 20 mM sodium dihydrogen phosphate, 2
  • the drug solution filled in the vial was stored at 40 ° C. for 1 month and 2 months, and the oxidant composition ratio was measured in the same manner as in Formula 1.
  • Table 3 shows the measurement results of the oxidant composition ratio in the chemical solution after storage.
  • the chemical solution filled in the vial was stored at a white fluorescent lamp total illumination of 1,200,000 lx ⁇ h, and the aggregate composition ratio and the oxidant composition ratio were measured in the same manner as in Formula 1.
  • Table 4 shows the measurement results of the aggregate composition ratio and the oxidant composition ratio in the chemical solution after storage.
  • compositions (medical solutions) of Formula 14 to Formula 16 were prepared.
  • Formula 14 40 ⁇ g / mL darbepoetin alfa, 20 mM sodium dihydrogen phosphate, 165 mM D-mannitol, 0.01% (w / v) Pluronic F68, pH 6.2
  • Formula 15 40 ⁇ g / mL darbepoetin alfa, 20 mM sodium dihydrogen phosphate, 40 mM sodium sulfate, 165 mM D-mannitol, 0.01% (w / v) Pluronic F68, pH 6.2
  • Formula 16 40 ⁇ g / mL darbepoetin alfa, 10 mM sodium dihydrogen phosphate, 40 mM sodium sulfate, 10 mM L-methionine, 165 mM D-mannitol,
  • the drug solution filled in the vial was stored at 60 ° C. for 1 week, or at 60 ° C. for 8 days and at 40 ° C. for 3 months, and the aggregate composition ratio and the oxidant composition ratio were measured in the same manner as in Formula 1.
  • Tables 5 and 6 show the measurement results of the aggregate composition ratio and the oxidant composition ratio in the chemical solution after storage.

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Abstract

La présente invention a pour objet une composition pharmaceutique liquide contenant de la darbépoétine ayant une stabilité améliorée. À cet effet, la présente invention concerne une composition pharmaceutique liquide contenant de la darbépoétine, un sucre ou un alcool de sucre, et un copolymère bloc de poly(oxyde d'éthylène) et de poly(oxyde de propylène).
PCT/JP2017/003634 2017-02-01 2017-02-01 Composition pharmaceutique liquide contenant de la darbépoétine Ceased WO2018142514A1 (fr)

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PCT/JP2017/003634 WO2018142514A1 (fr) 2017-02-01 2017-02-01 Composition pharmaceutique liquide contenant de la darbépoétine
JP2017509058A JP6172880B1 (ja) 2017-02-01 2017-02-01 ダルベポエチンを含む液体医薬組成物

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Citations (9)

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JP2004091469A (ja) * 2002-07-11 2004-03-25 Asahi Kasei Pharma Kk 光に安定なカルシトニン水溶液
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