WO2021014957A1 - Formulation d'injection de bendamustine - Google Patents

Formulation d'injection de bendamustine Download PDF

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Publication number
WO2021014957A1
WO2021014957A1 PCT/JP2020/026483 JP2020026483W WO2021014957A1 WO 2021014957 A1 WO2021014957 A1 WO 2021014957A1 JP 2020026483 W JP2020026483 W JP 2020026483W WO 2021014957 A1 WO2021014957 A1 WO 2021014957A1
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WIPO (PCT)
Prior art keywords
liquid composition
bendamustine
injection
bendamstin
container
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PCT/JP2020/026483
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English (en)
Japanese (ja)
Inventor
橋本　真一
辻畑　茂朝
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富士フイルム株式会社
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Priority to JP2021533918A priority Critical patent/JPWO2021014957A1/ja
Publication of WO2021014957A1 publication Critical patent/WO2021014957A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K47/20—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
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • This disclosure relates to bendamustine injection preparations.
  • Bendamustine is used for the treatment of cancers such as malignant lymphoma (for example, low-grade B-cell non-Hodgkin's lymphoma, mantle cell lymphoma) and chronic lymphocytic leukemia.
  • malignant lymphoma for example, low-grade B-cell non-Hodgkin's lymphoma, mantle cell lymphoma
  • chronic lymphocytic leukemia for example, low-grade B-cell non-Hodgkin's lymphoma, mantle cell lymphoma
  • propylene glycol or glycerin has been used for the purpose of assisting the dissolution of bendamustine in addition to polyethylene glycol which is the main solvent of bendamustine.
  • Japanese Patent Application Publication No. 1057626472 discloses a bendamustine drug composition containing polyethylene glycol, 1% to 10% glycerin, thioglycerol, and bendamustine hydrochloride.
  • bendamustine analogs are produced in liquid preparations containing bendamustine over time, and various studies have been conducted on methods for suppressing the formation of bendamustine analogs.
  • the problem to be solved by one embodiment of the present invention has been made in view of the above circumstances, and bendamustine appearing in a relative retention time (hereinafter, also referred to as RRT) of 0.67 on a high performance liquid chromatograph (HPLC). It is an object of the present invention to provide a bentamustine injection preparation in which the amount of analog produced over time is suppressed.
  • RRT relative retention time
  • HPLC high performance liquid chromatograph
  • ⁇ 5> One of ⁇ 1> to ⁇ 4>, wherein the content of the antioxidant having a thiol group is 0.1% by mass to 1.0% by mass with respect to the total mass of the liquid composition.
  • the antioxidant having a thiol group is at least one compound selected from the group consisting of cysteine and its salt, thioglycerol, and thioglycolic acid and its salt.
  • ⁇ 7> The bendamustine injection preparation according to any one of ⁇ 1> to ⁇ 6>, wherein the antioxidant having a thiol group is thioglycerol.
  • ⁇ 8> The bendamustine injection preparation according to any one of ⁇ 1> to ⁇ 7>, wherein the total content of propylene glycol and glycerin is less than 1% by mass with respect to the total mass of the liquid composition.
  • ⁇ 9> The bendamustine injection preparation according to any one of ⁇ 1> to ⁇ 8>, which does not contain propylene glycol and glycerin.
  • ⁇ 10> The bendamustine injection preparation according to any one of ⁇ 1> to ⁇ 9>, wherein polyethylene glycol is at least one of polyethylene glycol 300 and polyethylene glycol 400.
  • a bentamustine injection preparation in which the amount of bentamustine analogs produced over time that appear at a relative retention time (RRT) of 0.67 on high performance liquid chromatography (HPLC) is suppressed. Can be done.
  • RRT relative retention time
  • HPLC high performance liquid chromatography
  • the numerical range indicated by using "-" in the present disclosure means a range including the numerical values before and after "-" as the minimum value and the maximum value, respectively.
  • the upper limit value or the lower limit value described in a certain numerical range may be replaced with the upper limit value or the lower limit value of another numerical range described stepwise.
  • the upper limit value or the lower limit value of a certain numerical range may be replaced with the values shown in the examples.
  • a combination of two or more preferred embodiments is a more preferred embodiment.
  • the amount of each component in the bendamustine injection preparation is a plurality of substances existing in the bendamustine injection preparation unless otherwise specified, when a substance corresponding to each component is present in the bendamustine injection preparation. Means the total amount of substances in.
  • process is included in this term not only as an independent process but also as long as the intended purpose of the process is achieved even if it cannot be clearly distinguished from other processes. ..
  • the bendamstin injection solution preparation (hereinafter, also referred to as “injection solution preparation (1)”) according to the first aspect of the present disclosure contains bendamstin or a salt thereof, polyethylene glycol, and an antioxidant having a thiol group, and is propylene.
  • the bendamustine injection solution preparation (hereinafter, also referred to as “injection solution preparation (2)”) according to the second aspect of the present disclosure contains bendamustine or a salt thereof, polyethylene glycol, and an antioxidant having a thiol group, and is propylene.
  • a liquid composition having a total content of glycol and glycerin of 8% by mass or less based on the total mass of the liquid composition and a container for enclosing the liquid composition are provided, and bendamustine or a salt thereof in the bendamustine injection preparation is provided. It is a bendamustine injection preparation having a ratio of the number of oxygen molecules to the number of molecules of 0.1 or less.
  • the present inventors have focused on the bendamustine analogs appearing in RRT 0.67 and conducted research on the bendamustine injection preparation.
  • the present inventors have focused on the bendamustine analogs appearing in RRT 0.67 and conducted research on the bendamustine injection preparation.
  • by controlling the amount of propylene glycol or glycerin decomposition products derived from propylene glycol or glycerin
  • the formation of the bendamustine analog that appears in RRT0.67 is significantly suppressed. I found it.
  • the bendamustine analog appearing in RRT 0.67 is expected to be an oxidant of bendamustine because a correlation with oxygen concentration is observed.
  • polyethylene glycol used in the bendamstin injection preparation has a low oxygen concentration as in the injection preparation (1) or a small number of oxygen molecules as in the injection preparation (2).
  • the peroxide value and water content of polyethylene glycol 400 and polyethylene glycol 300) and propylene glycol were almost the same, for example, by reducing the amount of propylene glycol, the bendamstin analog appearing in RRT 0.67 Suppression of production is an unexpected effect, and the mechanism by which this effect is obtained is unknown.
  • Japanese Patent Application Laid-Open No. 2015-506899, Chinese Patent Application Publication No. 1057264772, and International Publication No. 2017/175098 refer to the oxygen concentration in the injection solution preparation (1) and the injection solution preparation (2). There is no specification regarding the number of oxygen molecules, and details of the oxygen concentration and the number of oxygen molecules cannot be read from the manufacturing method of the preparation or the like. Furthermore, Japanese Patent Application Laid-Open No. 2015-506989, Japanese Patent Application Publication No. 1057264772, and International Publication No. 2017/175098 do not pay attention to the bendamustine analog appearing in RRT0.67 in a low oxygen state. ..
  • the injectable solution preparation (1) and the injectable solution preparation (2) of the present disclosure contain bendamstin or a salt thereof, polyethylene glycol, and an antioxidant having a thiol group, and the total content of propylene glycol and glycerin is the liquid composition.
  • a liquid composition containing 8% by mass or less based on the total mass of the product is provided.
  • Bendamustine is a compound represented by the following structural formula (4- [5- ⁇ bis (2-chloroethyl) amino ⁇ -1-methyl-2-benzimidazolyl] butanoic acid).
  • the salt of bendamstin may be any pharmaceutically acceptable salt, and examples thereof include salts of inorganic acids and salts of organic acids.
  • the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • the organic acid include acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, lactic acid, methylsulfonic acid, p-toluenesulfonic acid and the like.
  • an acid salt prepared from hydrochloric acid, hydrobromic acid, or hydroiodic acid is preferable. Among them, as the salt of bendamustine, bendamustine hydrochloride is preferable from the viewpoint of actual use.
  • the content of bendamstin or a salt thereof is 0.01% by mass to 5% by mass with respect to the total mass of the liquid composition in terms of bendamstin from the viewpoint of solubility and medicinal effect of bendamstin in the liquid composition.
  • 0.05% by mass to 3% by mass is more preferable, 0.1% by mass to 3% by mass is further preferable, and 1% by mass to 3% by mass is particularly preferable.
  • the concentration of bendamstin hydrochloride in the liquid composition is 0.13 mg / mL to 66 mg / from the viewpoint of solubility and medicinal effect of bendamstin hydrochloride in the liquid composition.
  • mL is preferable, 0.66 mg / mL to 40 mg / mL is more preferable, 1.3 mg / mL to 40 mg / mL is further preferable, 13.2 mg / mL to 40 mg / mL is particularly preferable, and 25 mg / mL is most preferable.
  • Polyethylene glycol is an ethylene glycol polymer (specifically, an addition polymer of ethylene oxide and water), and its molecular formula is represented by HOCH 2 (CH 2 OCH 2 ) CH 2 OH (n is an integer). From the viewpoint of application to injection liquid preparations, those in a liquid state at room temperature (for example, temperature 20 ° C.) or higher are preferable.
  • polyethylene glycol polyethylene glycol (so-called macrogol) satisfying the standards listed in the Japanese Pharmacopoeia or the pharmaceutical additive standard is preferable.
  • One type of polyethylene glycol may be used alone, or two or more types may be used in combination.
  • the polyethylene glycol includes polyethylene glycol 200, polyethylene glycol 300 (hereinafter, also referred to as PEG300), polyethylene glycol 400 (hereinafter, also referred to as PEG400), polyethylene glycol 600, and polyethylene glycol 1000 from the viewpoint of solubility of bendamstin or a salt thereof. Is preferable.
  • the polyethylene glycol is preferably at least one of polyethylene glycol 300 and polyethylene glycol 400 from the viewpoint of actual use, and for example, polyethylene glycol 300 and polyethylene glycol 400 may be used in combination.
  • polyethylene glycol has an excellent solubility of bendamstin or a salt thereof, and has a melting point of -10 ° C or lower so that the injection solution preparation does not freeze even in refrigerated storage and is easy to handle.
  • Polyethylene glycol 300 (PEG300) is particularly preferred because of its relatively low viscosity and the ease with which the required amount of the injectable preparation can be withdrawn at the time of administration.
  • the content of polyethylene glycol is preferably 86% by mass to 99.9% by mass, preferably 90% by mass to 99% by mass, based on the total mass of the liquid composition, from the viewpoint of solubility and medicinal effect of bendamstin or a salt thereof. More preferably, 95% by mass to 99% by mass is further preferable, and 95% by mass to 98% by mass is particularly preferable.
  • the antioxidant having a thiol group can be used without particular limitation as long as it has a thiol group (-SH) in the molecule and is pharmacologically acceptable.
  • Antioxidants having a thiol group include cysteine and its salt, thioglycerol, thioglycolic acid and its salt, N-acetylcysteine and its salt, dithioerythol, and 2-mercaptoethane from the viewpoint of antioxidant ability against bendamstin.
  • the salts of cysteine, thioglycolic acid, N-acetylcysteine, 2-mercaptoethanesulfonic acid, and thioapple acid may be any pharmacologically acceptable salt, and may be a salt with an alkali metal; with an alkaline earth metal. Salt; salt with transition metal; salt with basic ammonium; salt of inorganic acid or salt of organic acid; and the like.
  • Specific examples of the salts of cysteine, thioglycolic acid, N-acetylcysteine, 2-mercaptoethanesulfonic acid, and thioannic acid include alkali metal salts with sodium, potassium, and the like; and alkaline earth with calcium, magnesium, and the like.
  • Metal salt Transition metal salt with zinc, iron, cobalt, copper, etc .
  • Basic ammonium salt with ammonium, triethanolamine, L-histidine, L-arginine, L-lysine, etc .
  • Hydrochloride formate, acetate , Maleate, fumarate, tartrate and the like.
  • antioxidant having a thiol group thioglycerol, cysteine, cysteine hydrochloride, N-acetylcysteine, thioglycolic acid, and sodium thioglycolate are preferable from the viewpoint of expressing the antioxidant ability against bendamstin or a salt thereof. .. Further, as the antioxidant having a thiol group, thioglycerol, cysteine, N-acetylcysteine, and thioglycolic acid are more preferable from the viewpoint of solubility in polyethylene glycol.
  • thioglycerol is particularly preferable from the viewpoint of developing antioxidant ability against bendamustine and having high solubility in the liquid composition in the injection solution preparation.
  • the content of the antioxidant having a thiol group is 0. From the viewpoint of expressing the antioxidant capacity and suppressing the production of bendamstin analogs, relative to the total mass of the liquid composition. 05% by mass to 1.5% by mass is preferable, 0.1% by mass to 1.0% by mass is more preferable, 0.1% by mass to 0.8% by mass is further preferable, and 0.1% by mass to 0% by mass. 5% by mass is particularly preferable.
  • the concentration of the antioxidant having a thiol group (preferably thioglycerol) in the liquid composition is 0.6 mg / mL to 18 mg / from the viewpoint of the expression of antioxidant ability and the suppression of the production of bendamstin analogs.
  • mL is preferred, 1.2 mg / mL to 12 mg / mL is more preferred, 1.2 mg / mL to 9.6 mg / mL is even more preferred, 1.2 mg / mL to 6.0 mg / mL is particularly preferred, and 5 mg. / ML is most preferred.
  • the ratio of the content of bendamstin or a salt thereof in the liquid composition to the content of an antioxidant having a thiol group (content of bendamstin or a salt thereof: content of an antioxidant having a thiol group).
  • content of bendamstin or a salt thereof: content of an antioxidant having a thiol group Is preferably 1: 0.004 to 1: 1 on a mass basis, and 1: 0.04 to 1: 0, from the viewpoint of expressing antioxidant capacity and suppressing the production of bendamstin analogs. It is more preferably .5, and even more preferably 1: 0.04 to 1: 0.2.
  • the above-mentioned "content of bendamustine or a salt thereof" means the content in terms of bendamustine.
  • the liquid composition in the present disclosure has a total content of propylene glycol and glycerin of 8% by mass or less based on the total mass of the liquid composition. That is, when the liquid composition contains only propylene glycol, it means that the content of propylene glycol is 8% by mass or less with respect to the total mass of the liquid composition. Similarly, when the liquid composition contains only glycerin, it means that the content of glycerin is 8% by mass or less based on the total mass of the liquid composition.
  • the liquid composition contains both propylene glycol and glycerin, it means that the content of propylene glycol and glycerin is 8% by mass or less based on the total mass of the liquid composition. Further, the lower limit of the total content of propylene glycol and glycerin is 0% by mass (that is, it does not contain propylene glycol and glycerin).
  • the total content of propylene glycol and glycerin in the liquid composition satisfies the above, the formation of bendamustine analogs appearing in RRT 0.67 can be suppressed.
  • the liquid composition in the present disclosure has a total content of propylene glycol and glycerin of less than 1% by mass with respect to the total mass of the liquid composition from the viewpoint of further suppressing the formation of bendamstin analogs appearing in RRT0.67. It is more preferable that it is 0.5% by mass or less, and it is more preferable that it does not contain propylene glycol and glycerin (that is, the total content of propylene glycol and glycerin is 0% by mass).
  • "free of propylene glycol and / or glycerin” means that the amount of propylene glycol and / or glycerin is less than the measurement limit value in the quantification method (for example, gas chromatography).
  • the liquid composition in the present disclosure may contain either propylene glycol or glycerin from the viewpoint of assisting the dissolution of bendamustine.
  • propylene glycol in the present disclosure, from the viewpoint of further suppressing the formation of bendamustine analogs appearing in RRT 0.67, the content of propylene glycol is less than 1% by mass with respect to the total mass of the liquid composition. It is preferably present, and more preferably it does not contain propylene glycol.
  • the content of glycerin is 0.5 mass with respect to the total mass of the liquid composition.
  • % Or less more preferably 0.3% by mass or less, further preferably 0.2% by mass or less, and the content of glycerin is 0.% With respect to the total mass of the liquid composition. It is particularly preferably less than 1% by mass, and most preferably does not contain glycerin.
  • the liquid composition in the present disclosure preferably contains a pH adjuster.
  • the pH adjusting agent is not particularly limited as long as it is pharmacologically acceptable.
  • Specific examples of the pH adjuster include hydrochloric acid, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, phosphoric acid or a salt thereof, citric acid or a salt thereof, tartaric acid or a salt thereof, acetic acid or a salt thereof.
  • Succinic acid or its salt lactic acid or its salt, gluconic acid or its salt, adipic acid or its salt, fumaric acid or its salt, boric acid or its salt, maleic acid or its salt, methanesulfonic acid or its salt, apple Selected from the group consisting of acid or a salt thereof, triethanolamine, monoethanolamine, diisopropanolamine, triisopropanolamine, tromethamole (also known as trishydroxymethylaminomethane, the same applies hereinafter), glycine, meglumin, and disodium edetate.
  • the pH adjuster may be used alone or in combination of two or more.
  • the content of the pH adjuster is not particularly limited, and may be appropriately set according to the type of the pH adjuster and the like.
  • the liquid composition in the present disclosure may contain other pharmacologically acceptable components, if necessary, within the scope of the purposes of the present disclosure.
  • Other ingredients include tonicity agents, stabilizers, solubilizers, surfactants, sustainers, defoamers, colorants, emulsifiers, dispersants, preservatives, preservatives, solubilizers, solvents. Etc., but are not limited to these.
  • the content of other components can be appropriately set within the scope of the object of the present disclosure.
  • the pH of the liquid composition in the present disclosure is preferably 3.3 to 4.0, more preferably 3.3 to 3.8, from the viewpoint of suppressing the decomposition of bendamustine. It is more preferably 3.7.
  • the pH is measured by diluting the liquid composition with uncarbonated water and a saturated aqueous potassium chloride solution and setting the temperature of the diluted liquid to 25 ° C. Specifically, for example, a mixed solution of 100 mg of an injection solution, 2 mL of uncarbonated water, and 6 ⁇ L of a saturated potassium chloride aqueous solution is prepared, and the temperature of the mixed solution is set to 25 ° C. for measurement.
  • the pH is not particularly limited, and a method generally used as a pH measuring method can be used. For example, the pH can be measured with a pH meter (device model number: F-73, manufactured by HORIBA, Ltd., pH electrode: micro Tou pH electrode 9618-10D).
  • the injection solution preparation (1) or (2) of the present disclosure is a container-filled injection solution preparation including a container for enclosing the above-mentioned liquid composition.
  • the container for enclosing the liquid composition include vials, ampoules, syringes (for example, prefilled syringes) and the like.
  • a vial is preferable as a container for enclosing the liquid composition from the viewpoint of handleability in the medical field.
  • a container in which the amount of silicon eluted into water when filled with water and heat-treated at 121 ° C. for 60 minutes is preferably 1.0 ppm or less, preferably 0.5 ppm or less. Is more preferred.
  • an oxygen-blocking film as the packaging of the container for enclosing the liquid composition, the storage stability of bendamustine or a salt thereof contained in the liquid composition can be improved.
  • alumina coated PET polyethylene terephthalate
  • silica coated PET nanocomposite coated PET
  • PET polyvinyl alcohol
  • ethylene-vinyl alcohol copolymer polyvinyl chloride
  • polyvinylidene chloride vinylidene chloride-methyl acrylate.
  • Copolymers taxylylene adipamide 6 nylon, biaxially stretched nylon, unstretched nylon, biaxially stretched polypropylene, high-density polyethylene, unstretched polypropylene, polyvinylidene, polystyrene, low-density polyethylene and the like are used.
  • Oxygen gas permeability of the film from the viewpoint of storage stability, it is preferred that 100cm 3 / m 2 ⁇ 24h ⁇ atm or less, more preferably 10cm 3 / m 2 ⁇ 24h ⁇ atm or less, 2 cm 3 even more preferably less / m 2 ⁇ 24h ⁇ atm.
  • the container for enclosing the liquid composition may be single-packed using an oxygen-blocking film, or may be multiple-packed using a plurality of oxygen-blocking films.
  • an oxygen scavenger is placed in any of the spaces between the container and the outermost space where the container is packaged. It may be loaded.
  • oxygen scavengers iron-based self-sustaining reaction type oxygen scavengers (Ageless ZP, Ageless ZJ-PT, Ageless ZJ-PK, Ageless S manufactured by Mitsubishi Gas Chemical Company, Ltd.), iron-based moisture-dependent oxygen scavengers ( Ageless FX manufactured by Mitsubishi Gas Chemical Company, Inc.), non-ferrous self-sustaining reaction type oxygen scavenger (Ageless GLS, Ageless GL-M, Ageless GT manufactured by Mitsubishi Gas Chemical Company, Inc.) and the like are used.
  • the above "ageless” is a registered trademark.
  • the oxygen concentration in the gas in the container containing the liquid composition is 5% by volume or less.
  • the oxygen concentration in the gas in the container containing the liquid composition exceeds 5% by volume, it is represented by RRT 0.67 due to the decomposition of bendamustine during storage (particularly, the decomposition of bendamustine). It becomes difficult to suppress the formation of bentamustine analogs.
  • the oxygen concentration in the gas in the container containing the liquid composition is preferably 4% by volume or less from the viewpoint of further suppressing the decomposition of bendamustine during storage. It is more preferably 3% by volume or less, further preferably 2% by volume or less, and particularly preferably 1% by volume or less.
  • the oxygen concentration in the gas in the container in the present disclosure is a measurement of the oxygen concentration in the gas sealed in the container during the production of the injection solution preparation, and the oxygen concentration in the gas in the container immediately after the production of the injection solution preparation. It includes both those measured and those in which the oxygen concentration in the gas in the container is measured after the injection solution preparation is stored for a certain period of time.
  • the gas in the container that encloses the liquid composition is preferably replaced with an inert gas.
  • Nitrogen is preferable as the inert gas. According to the inert gas (particularly nitrogen), the oxygen concentration in the gas in the container containing the liquid composition can be easily adjusted.
  • the method for measuring the oxygen concentration in the gas in the container is not particularly limited, and a method generally used as a method for measuring the oxygen concentration in the gas can be used.
  • the oxygen concentration in the gas in the container is measured by an oxygen concentration meter based on a fluorescence time disappearance type.
  • a needle type oxygen densitometer product name: Microx TX3, manufactured by PreSens, measuring method: fluorescence time disappearance type
  • the following method can be used.
  • a method of measuring the oxygen concentration in the gas in the ampoule for example, it is a method of nondestructively measuring the oxygen concentration in the head space in the container by using the absorption of near-infrared laser light by oxygen. May be.
  • a head space oxygen analyzer FMS-760 manufactured by Lighthouse Co., Ltd. can be used as a method for non-destructively measuring the oxygen concentration in the head space in the container.
  • Specific examples of the method for measuring the oxygen concentration in the gas in the container include the following two methods. (1) Insert the sampler needle portion of the oxygen concentration meter into the container of the Bendamstin injection solution preparation, suck the gas in the head space in the container, and measure the oxygen concentration in the gas (minimum resolution: 0.01%). (2) When it is necessary to non-destructively measure the oxygen concentration in the gas in the container The oxygen concentration in the head space in the container (for example, ampoule) of the Bendamstin injection solution preparation is non-destructively measured. In the case of the method (1), it is preferable to perform the measurement in a nitrogen atmosphere (gas oxygen concentration less than 0.1 v / v%) in order to prevent oxygen from being mixed outside the container during the measurement.
  • the injectable solution preparation (1) of the present disclosure it is dissolved in the liquid composition from the viewpoint of suppressing the decomposition of bendamustine during storage (particularly, the formation of the bendamustine analog represented by RRT0.67 due to the decomposition of bendamustine).
  • the oxygen concentration is preferably 9 ppm or less, more preferably 7 ppm or less, further preferably 3 ppm or less, particularly preferably 0.5 ppm or less, and most preferably 0.1 ppm or less. preferable.
  • the method for measuring the dissolved oxygen concentration in the liquid composition is not particularly limited, and a method generally used as a method for measuring the dissolved oxygen concentration in the solution can be used.
  • the dissolved oxygen concentration in the liquid composition can be measured using an oxygen concentration measuring device.
  • the oxygen concentration measuring device for example, a product name: organic solvent compatible DO meter B-506S, manufactured by Iijima Denshi Kogyo Co., Ltd. is used.
  • the electrode of the oxygen concentration measuring device is applied to the liquid composition in a nitrogen atmosphere (oxygen concentration is 0.1% by volume or less) in a glove box.
  • a method of measuring the dissolved oxygen concentration in the liquid composition by contacting the liquid, or piercing the sampler needle part of the oxygen concentration measuring device into the container of the injection solution preparation and sucking the liquid composition in the container.
  • a method of measuring the dissolved oxygen concentration in the liquid composition can be mentioned.
  • the oxygen concentration in the liquid composition can be calculated by measuring the oxygen concentration in the gas in the container from Henry's law.
  • the ratio of the number of oxygen molecules to the number of molecules of bendamstin or a salt thereof (that is, the number of oxygen molecules / the number of bendamstin molecules) in the bendamstin injection solution preparation is 0.1 or less.
  • the ratio of the number of oxygen molecules to the number of bendamustine molecules in the injectable preparation exceeds 0.1, the decomposition of bendamustine during storage (particularly, RRT 0.67 due to the decomposition of bendamustine) It becomes difficult to suppress the formation of the represented bendamustine analog.
  • the ratio of the number of oxygen molecules to the number of bendamstin molecules is 0.08 or less from the viewpoint of further suppressing the decomposition of bendamstin during storage. It is preferably 0.06 or less, more preferably 0.04 or less, and particularly preferably 0.02 or less.
  • the ratio of the number of oxygen molecules to the number of bendamstin molecules in the injection solution preparation is the oxygen concentration in the gas in the container when the liquid composition is sealed in the container. It is calculated based on the total number of oxygen molecules calculated by multiplying the dissolved oxygen concentration in the liquid composition by the respective volumes.
  • the ratio of the number of oxygen molecules to the number of bendamstin molecules in the injection solution preparation is a gas when the liquid composition is not sealed in the container or when the liquid composition is sealed in the container. When is not present (for example, a prefilled syringe, etc.), it is calculated based on the dissolved oxygen concentration in the liquid composition.
  • the ratio of the number of oxygen molecules to the number of bendamustine molecules is measured and calculated at the time of manufacturing the bendamustine injection preparation, measured immediately after the production of the bendamustine injection preparation, or after storage of the bendamustine injection preparation for a certain period of time. Any of the measured and calculated ones is included.
  • the number of bendamustine molecules in the bendamustine injection preparation and the number of oxygen molecules in the bendamustine injection preparation are calculated according to the following methods, respectively.
  • an injection solution preparation is prepared while controlling the injection amount of nitrogen and oxygen so that the method of measuring the oxygen concentration in the gas in the container reaches the target oxygen concentration in the glove box.
  • the method of reading the display value of the oxygen monitor with a built-in sensor in the glove box it means the temperature when sealed.
  • the method of measuring the oxygen concentration in the gas in the container is to pierce the sampler needle part of the oxygen concentration measuring device into the container of the injection solution preparation, suck the gas in the head space in the container of the injection solution preparation, and gas.
  • the temperature in the formula 3 means the temperature at the time of measurement.
  • the method for producing the injectable solution preparation (1) or (2) of the present disclosure contains bendamstin or a salt thereof, polyethylene glycol, and an antioxidant having a thiol group, and the total content of propylene glycol and glycerin is the liquid composition.
  • To prepare a liquid composition of 8% by mass or less based on the total mass of the product (hereinafter, also referred to as “liquid composition preparation step”), and to fill the container with the liquid composition in an inert gas atmosphere.
  • filling step or after filling the container with the liquid composition, the gas in the container is replaced with an inert gas (hereinafter, also referred to as “replacement step”).
  • replacement step an inert gas
  • This manufacturing method may include other steps, if necessary.
  • the production method will be described, but the description will be omitted with respect to matters common to the above-described injection solution preparations of the present disclosure, for example, the components contained in the liquid composition, their amounts, containers, and the like.
  • liquid composition preparation process In the liquid composition preparation step, a liquid composition is prepared using each component contained in the liquid composition.
  • the method for preparing the liquid composition is not particularly limited, and examples thereof include the following methods. First, polyethylene glycol and, if necessary, at least one of propylene glycol and glycerin are mixed, and bendamustine or a salt thereof and an antioxidant having a thiol group are gradually added to the obtained solution. There is a way to do it.
  • the temperature conditions for dissolving bendamustine or a salt thereof in the above-mentioned solution are not particularly limited, and can be appropriately set according to the composition (type and content) of the solution. Usually, the temperature of the solution is set to 25 ° C. to 80 ° C., and bendamustine or a salt thereof, an antioxidant having a thiol group, and, if necessary, a pH adjuster, other components, etc. are added. Can be dissolved.
  • the liquid composition is filled in a container under an inert gas atmosphere.
  • the method of filling the container with the liquid composition under the atmosphere of an inert gas is not particularly limited, and a known method can be adopted. Nitrogen is preferable as the inert gas.
  • the oxygen concentration in the gas in the container in which the liquid composition is enclosed is set to 5% by volume or less, and the liquid composition is filled in the container in an inert gas atmosphere to obtain an injection solution preparation (1).
  • the ratio of the number of oxygen molecules to the number of bendamstin molecules in the injection solution preparation is set to 0.1 or less, and the liquid composition is filled in the container in an inert gas atmosphere. As a result, the injection solution preparation (2) can be obtained.
  • the replacement step after the liquid composition is filled in the container, the gas in the container is replaced with the inert gas.
  • the method of substituting the gas in the container filled with the liquid composition with the inert gas is not particularly limited, and a known method can be adopted.
  • the inert gas nitrogen or argon is preferable.
  • the oxygen concentration in the gas in the container containing the liquid composition is set to 5% by volume or less, the liquid composition is filled in the container, and then the gas in the container is replaced with an inert gas for injection.
  • a liquid preparation (1) can be obtained.
  • the ratio of the number of oxygen molecules to the number of bendamstin molecules in the injection solution preparation is set to 0.1 or less, the liquid composition is filled in the container, and then the gas in the container is filled.
  • the device used in the replacement step is not particularly limited, and is, for example, a glove box, a tapping machine having a function of tapping under an inert gas stream, a vacuum tapping machine, or a sealed state.
  • a chamber having the function of plugging can be used.
  • a replacement method specifically, a vial and a rubber stopper filled with a liquid composition are placed in a glove box, an inert gas is blown into the glove box to obtain a desired oxygen concentration, and then the glove.
  • An example is a method of replacing the gas in the container with an inert gas by sealing the box with a rubber stopper.
  • the vial filled with the liquid composition is covered with a chamber part to shut off the vial from the outside air, and vacuuming and blowing an inert gas are repeated to eliminate the gas in the container.
  • a method of substituting with an active gas can be mentioned.
  • a semi-plugged vial is installed in a chamber that has a function of tapping in a sealed state, an inert gas is blown into the chamber so that the desired oxygen concentration is obtained, and the vial is sealed in the chamber.
  • a method of replacing the gas in the chamber with an inert gas can be mentioned.
  • the production method of the present disclosure may include steps other than the above-mentioned liquid composition preparation step, filling step, and substitution step.
  • Other steps include, for example, a pH adjusting step of adjusting the pH of the liquid composition obtained in the liquid composition preparing step.
  • the method for adjusting the pH of the liquid composition is not particularly limited, and for example, it can be adjusted by using the above-mentioned pH adjuster or the like.
  • JP-A-2003-521518 For a general method for producing an injectable solution preparation, for example, the description in JP-A-2003-521518 can be referred to.
  • the present disclosure also includes a method for treating cancer using the injectable solution preparation (1) or (2) of the present disclosure described above.
  • the present disclosure is a patient who is a target for cancer treatment with a liquid composition containing bendamustine or a salt thereof as an active ingredient in the above-mentioned injection solution preparation (1) or (2) of the present disclosure. It also includes methods of treating cancer, including administration in an amount effective for the treatment of cancer.
  • the cancer applied to the above-mentioned treatment method include malignant lymphoma (for example, low-grade B-cell non-Hodgkin's lymphoma, mantle cell lymphoma), chronic lymphocytic leukemia, multiple myeloma and the like.
  • Example 1 Preparation of injection solution preparation (C-1)> In a clean 20 mL vial containing a stir bar, weigh 37.6 mg of thioglycerol, 16.58 g of polyethylene glycol 400, and 41.5 mg of a 1 mol / L sodium hydroxide aqueous solution (denoted as "1N NaOH” in Table 2). After covering and lightly mixing to obtain a uniform solution, 374.9 mg of bendamstin hydrochloride was weighed, stirred at room temperature for 10 minutes, and then stirred at 80 ° C. for 10 minutes to obtain a liquid composition.
  • the obtained liquid composition was placed in a glove box and stirred at room temperature for 30 minutes in a nitrogen atmosphere to replace the gas in the liquid composition with nitrogen, and the dissolved oxygen concentration of the liquid composition was set to 0 ppm. Then, in a nitrogen atmosphere (oxygen concentration: 2% by volume, temperature: 25 ° C.), 1.8 mL was filled in a vial (Vial bottle CS-2 manufactured by Fuji Glass Co., Ltd.). The volume of gas in the container at this time was 2.5 mL.
  • Example 2 to 4 Preparation of bendamustine injection preparations (C-2) to (C-4)>
  • the target bentamustine injection preparations (C-2) to (C-4) were obtained in the same manner as in Example 1 except that the composition of the liquid composition was changed as shown in Table 2 below.
  • Examples 5 to 6 Preparation of bendamustine injection preparations (C-5) to (C-6)> The composition of the liquid composition was changed as shown in Table 2 below, and the conditions for sterilization filtration of the obtained liquid composition were changed from an oxygen concentration of 2% by volume and a temperature of 25 ° C. to a nitrogen atmosphere.
  • the target Bendamstin injection liquid preparations (C-5) to (C-6) were obtained in the same manner as in Example 1 except that the temperature was changed to 1% by volume and the temperature was changed to 25 ° C. in a nitrogen atmosphere.
  • Examples 7 to 8 Preparation of bendamustine injection preparations (C-7) to (C-8)> The composition of the liquid composition was changed as shown in Table 2 below, and the conditions for sterilization filtration of the obtained liquid composition were changed from an oxygen concentration of 2% by volume and a temperature of 25 ° C. to a nitrogen atmosphere.
  • the target Bendamstin injection preparations (C-7) to (C-8) were obtained in the same manner as in Example 1 except that the temperature was changed to 0% by volume and the temperature was changed to 25 ° C. in a nitrogen atmosphere.
  • Example 9 Preparation of bentamustine injection preparation (C-9)>
  • the composition of the liquid composition was changed as shown in Table 2 below, and the conditions for sterilization filtration of the obtained liquid composition were changed from an oxygen concentration of 2% by volume and a temperature of 25 ° C. to a nitrogen atmosphere.
  • the target Bendamstin injection solution preparation (C-9) was obtained in the same manner as in Example 1 except that the temperature was changed to 0% by volume and the temperature was changed to 25 ° C. in a nitrogen atmosphere.
  • the amount of bendamustine [area%] was calculated from the total amount [area%] of the analogs of bendamustine obtained under the following measurement conditions.
  • the total amount of bendamustine analogs is the sum of the bendamustine analogs detected at relative retention times of 0.67, 1.03, and 1.04 and the bendamustine analogs detected at other relative retention times. Is.
  • the bendamustine injection preparations of Examples 1 to 9 have a smaller amount of RRT0.67 analogs than the bendamustine injection preparations of Comparative Examples 1 to 14. That is, the oxygen concentration in the gas in the container is 5% by volume or less, or the oxygen molecule number / bendamustine molecule number in the bendamustine injection preparation is 0.1 or less, and bendamustine or a salt thereof, polyethylene glycol and thio
  • the bentamustine injection formulation comprising a liquid composition containing glycerol has a low RRT 0.67 analog content. Further, since the bendamustine injection preparations of Examples 1 to 9 have a larger amount of bendamustine than the bendamustine injection preparations of Comparative Examples 1 to 14, it can be seen that the stability of bendamustine over time is excellent.
  • the formation of the RRT0.67 analog is not suppressed when the liquid composition does not contain an antioxidant having a thiol group (Comparative Examples 4 to 5 and Comparative Examples 9 to 10). Further, when the oxygen concentration in the gas in the container is 21% by volume (when the number of oxygen molecules / the number of bendamstin molecules in the bendamstin injection preparation is 0.18), the antioxidant having a thiol group in the liquid composition.
  • Comparative Examples 11 to 14 had a high oxygen concentration (a large value of oxygen molecule number / bendamustine molecule number) even though the liquid composition did not contain propylene glycol and glycerin. It can be seen that the formation of 67 analogs is not suppressed.
  • the pH values of the liquid compositions in each of the injectable preparations of Examples 1 to 8 are the pH values of the liquid compositions of each of the injectable preparations of Comparative Examples 1 to 13 (3.53 to 3. It can be seen that it is within the range of 67). From this, it is presumed that the suppression of the formation of RRT0.67 analogs after storage at 60 ° C. for 1 week in each of the injection solution preparations of Examples 1 to 8 is not due to the influence of the pH of the liquid composition. ..
  • 0.5 mL of saturated potassium iodide (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the admixture and shaken for exactly 1 minute to obtain a potassium iodide solution.
  • 0.5 g of starch (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and 5 mL of cold water are suspended by hand stirring, and the solution is poured into 100 mL of boiling water, stirred until the solution becomes translucent, and then the stirring is stopped to reach room temperature.
  • a starch test solution was prepared by slow cooling. 5 mL of the supernatant of this starch test solution was placed in the above potassium iodide solution and shaken vigorously for 30 seconds.
  • Moisture measuring device CA-200 / KF-200 (Mitsubishi Chemical Analytical Co., Ltd.) for the three components used in Examples and Comparative Examples, that is, polyethylene glycol 400 (PEG400), polyethylene glycol 300 (PEG300), and propylene glycol.
  • the water content was measured by the coulometric titration method.
  • a Karl Fischer reagent (Aquamicron (registered trademark) AX, manufactured by Mitsubishi Chemical Analytical Co., Ltd.) was used for the anode solution tank. The measured values are shown in Table 4.

Abstract

La formulation d'injection de bendamustine comprend une composition liquide comprenant de la bendamustine ou un sel de celle-ci, du polyéthylène glycol et un antioxydant ayant un groupe thiol, la teneur totale en propylène glycol et en glycérol étant de 8 % en masse ou moins par rapport à la masse totale de la composition liquide, et un récipient renfermant la composition liquide. La concentration en oxygène dans l'air à l'intérieur du récipient renfermant la composition liquide est de 5 % en volume ou moins ou le rapport du nombre d'atomes d'oxygène au nombre de molécules de bendamustine ou de sel de celle-ci dans la formulation d'injection de bendamustine est de 0,1 ou moins.
PCT/JP2020/026483 2019-07-22 2020-07-06 Formulation d'injection de bendamustine WO2021014957A1 (fr)

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WO2015050230A1 (fr) * 2013-10-03 2015-04-09 富士フイルム株式会社 Préparation pharmaceutique d'injection, et procédé de fabrication de celle-ci
JP2016523232A (ja) * 2013-06-04 2016-08-08 ビョーメ バイオサイエンシズ ピーブイティー．リミテッド コーティングされた粒子およびそれを含む組成物
JP2018197248A (ja) * 2012-03-20 2018-12-13 イーグル・ファーマシューティカルズ・インコーポレーテッド 低減された投与容量を必要とする患者におけるベンダムスチン応答性症状の治療方法
JP2019099557A (ja) * 2017-11-28 2019-06-24 日本化薬株式会社 ベンダムスチンを含有する溶液製剤
JP2020090481A (ja) * 2018-11-27 2020-06-11 日本化薬株式会社 ベンダムスチンを含有する溶液製剤
JP2020109066A (ja) * 2019-01-07 2020-07-16 コーアイセイ株式会社 ベンダムスチンの液体製剤

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Publication number Priority date Publication date Assignee Title
US10905677B2 (en) * 2016-08-31 2021-02-02 Navinta, Llc Bendamustine solution formulations

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018197248A (ja) * 2012-03-20 2018-12-13 イーグル・ファーマシューティカルズ・インコーポレーテッド 低減された投与容量を必要とする患者におけるベンダムスチン応答性症状の治療方法
JP2016523232A (ja) * 2013-06-04 2016-08-08 ビョーメ バイオサイエンシズ ピーブイティー．リミテッド コーティングされた粒子およびそれを含む組成物
WO2015050230A1 (fr) * 2013-10-03 2015-04-09 富士フイルム株式会社 Préparation pharmaceutique d'injection, et procédé de fabrication de celle-ci
JP2019099557A (ja) * 2017-11-28 2019-06-24 日本化薬株式会社 ベンダムスチンを含有する溶液製剤
JP2020090481A (ja) * 2018-11-27 2020-06-11 日本化薬株式会社 ベンダムスチンを含有する溶液製剤
JP2020109066A (ja) * 2019-01-07 2020-07-16 コーアイセイ株式会社 ベンダムスチンの液体製剤

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