WO2022075408A1 - Agent de solution aqueuse pour une injection de fosaprépitant - Google Patents

Agent de solution aqueuse pour une injection de fosaprépitant Download PDF

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WO2022075408A1
WO2022075408A1 PCT/JP2021/037143 JP2021037143W WO2022075408A1 WO 2022075408 A1 WO2022075408 A1 WO 2022075408A1 JP 2021037143 W JP2021037143 W JP 2021037143W WO 2022075408 A1 WO2022075408 A1 WO 2022075408A1
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fosaprepitant
aqueous solution
injection
production
mass
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PCT/JP2021/037143
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English (en)
Japanese (ja)
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達也 舩井
麻以 野村
敬亮 神保
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丸石製薬株式会社
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Publication of WO2022075408A1 publication Critical patent/WO2022075408A1/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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an aqueous solution for injecting fosaprepitant.
  • Fosaprepitant is a prodrug of aprepitant, a selective neurokinin 1 (NK1) receptor antagonist antiemetic.
  • NK1 receptor antagonist antiemetic a selective neurokinin 1 receptor antagonist antiemetic.
  • pharmaceutical preparations containing dimeglumine salt of fosaprepitant as an active ingredient are sold in Japan as lyophilized products, and after dissolving 150 mg of fosaprepitant in 5 mL of physiological saline, the final volume is 100 to 250 mL (final concentration). It is used to prevent nausea and vomiting and alleviate the symptoms associated with the administration of antineoplastic agents by intravenous drip infusion of a diluted solution of physiological saline to a concentration of 0.6 to 1.5 mg / mL. ..
  • Non-Patent Document 1 It has been reported that fosaprepitant is rapidly hydrolyzed to aprepitant and other related substances in an aqueous environment, and that hydrolysis to aprepitant further progresses particularly when the pH is 7 or less. .. Therefore, commercially available pharmaceutical preparations are freeze-dried in consideration of stability and stored in a cold place (2 to 8 ° C.) (Non-Patent Document 2).
  • An object of the present invention is to provide an aqueous solution for injecting fosaprepitant in which the production of a fosaprepitant-related substance is suppressed.
  • the present invention provides the following [1] to [15].
  • the dosage form is an aqueous solution that can be administered as it is, or an aqueous solution that is diluted and administered immediately before use and is a concentrated aqueous solution.
  • Aqueous solution for injection of fosaprepitant according to.
  • a method for producing an aqueous solution for fosaprepitant injection which comprises a step of mixing with diethylenetriamine pentaacetic acid.
  • the aqueous solution for injecting fosaprepitant of the present invention has sufficiently enhanced stability of fosaprepitant in an aqueous environment, and thus can suppress the production of fosaprepitant-related substances. Therefore, since the aqueous solution for injecting fosaprepitant of the present invention can safely and fully enjoy the effects of fosaprepitant, it is useful for preventing nausea and vomiting and alleviating symptoms associated with administration of an antineoplastic agent.
  • FIG. It is a figure which shows the chromatogram obtained by HPLC analysis of the aqueous solution for fosaprepitant injection of Example 1.
  • FIG. It is a figure which shows the chromatogram obtained by HPLC analysis of the aqueous solution for fosaprepitant injection of Comparative Example 1.
  • aqueous solution for injecting fosaprepitant may be an aqueous solution whose dosage form can be administered as it is, or a concentrated aqueous solution which is diluted and administered immediately before use. good.
  • the aqueous solution of the present invention contains fosaprepitant.
  • fosaprepitant is a concept that includes fosaprepitant and a pharmacologically acceptable salt thereof.
  • the pharmacologically acceptable salt is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and examples thereof include acid addition salts and base salts. ..
  • the acid addition salt may be an inorganic acid salt or an organic acid salt.
  • inorganic acid salts such as hydrochloride, phosphate, heavy sulfate, hydrobromide, hydroiodide, persulfate, acetate, adipate, benzoate, etc.
  • Organic acid salts can be mentioned.
  • Examples of the basic salt include ammonium salt; alkali metal salt such as sodium salt, lithium salt and potassium salt; alkaline earth metal salt such as calcium salt and magnesium salt; N-methyl-D-glucamine (meglumin) and dicyclohexylamine.
  • Examples thereof include salts with organic amines such as salts and salts with amino acids such as arginine, lysine and ornithine.
  • a dimeglumine salt of fosaprepitant is preferable.
  • the content of fosaprepitant in the aqueous solution of the present invention is not particularly limited as long as it is a therapeutically effective amount, but is preferably 0.15 to 20 mg / mL, more preferably 0.15 to 20 mg / mL in the aqueous solution as the final administration form. It is 0.3 to 5 mg / mL, more preferably 0.5 to 2 mg / mL.
  • the content of the fosaprepitant shall be a value converted into the amount of fosaprepitant. In the following description of the quantity ratio, if fosaprepitant is in the form of a salt, it shall be converted in the same manner.
  • the aqueous solution agent of the present invention contains diethylenetriamine pentaacetic acid as a chelating agent.
  • Diethylenetriamine pentaacetic acid enhances the stability of fosaprepitant in an aqueous environment and functions as an inhibitor of the production of fosaprepitant-related substances.
  • the term "fosaprepitant-related substance" as used herein refers to when a fosaprepitant injectable aqueous solution is analyzed by a high-speed liquid chromatograph (hereinafter, also referred to as "HPLC") according to the analysis conditions shown below.
  • HPLC high-speed liquid chromatograph
  • the aqueous solution for injecting fosaprepitant shall be analyzed by adjusting the concentration of fosaprepitant suitable for HPLC analysis. Specifically, if dilution is required, it is diluted with an appropriate solvent, and if concentration is required, it is concentrated by an appropriate method, and the fosaprepitant concentration is adjusted to be within the concentration range suitable for HPLC analysis. It is subjected to HPLC analysis. If pretreatment is required due to precipitation or the like, the concentration is adjusted after performing an appropriate pretreatment. Further, if the same result as this analysis condition can be obtained, HPLC analysis may be performed under other analysis conditions.
  • the amount of substance related to fosaprepitant is calculated from the peak area of the chromatogram based on the following formula. That is, the fosaprepitant analogs, fosaprepitant, and relative retention time (RRT) 1.41 ⁇ 1 detected at relative retention time (RRT) 0.95 ⁇ 0.1 in the chromatogram obtained by HPLC analysis. The amount of fosaprepitant-related substances is calculated using each peak area of aprepitant detected in 0.4.
  • Amount of substance related to fosaprepitant (%) x / (x + y + z) x 100
  • x indicates the peak area of a substance related to fosaprepitant
  • y indicates the peak area of fosaprepitant
  • z indicates the peak area of aprepitant.
  • Analytical conditions / analyzer High performance liquid chromatograph (Waters Allinace 2996) -Column: Octadecylsilylated silica gel with a column size of 4.6 x 250 mm and a particle size of 5 ⁇ m (L-volume2 ODS, Chemicals Evaluation and Research Institute) -Column temperature: constant temperature around 30 ° C.
  • -Mobile phase A 0.1% phosphoric acid (V / V%)
  • Mobile phase B Acetonitrile-Analysis conditions: Gradient analysis time (minutes) Mobile phase A (volume%) Mobile phase B (volume%) 0.01 65 35 5 65 35 20 30 70 40 5 95 42 65 35 50 65 35 ⁇
  • Sample injection amount 20 ⁇ L ⁇
  • Liquid delivery volume 1.0 mL / min -Detector wavelength: 263 nm
  • the aqueous solution of the present invention was stored at 50 ° C. for 7 days and then analyzed by HPLC under the same conditions as above, the relative retention time (RRT) 0.95 using the retention time (RT) of fosaprepitant as an index.
  • the content of the related substance of ⁇ 0.1 can be usually 0.2% or less, preferably 0.1% or less.
  • the content of diethylenetriamine pentaacetic acid in the aqueous solution of the present invention is preferably 0.005 to 0.08 parts by mass, preferably 0.005 parts by mass, based on 1 part by mass of fosaprepitant, from the viewpoint of suppressing the production of fosaprepitant-related substances. -0.075 parts by mass is more preferable, and 0.005 to 0.07 parts by mass is further preferable.
  • the aqueous solution of the present invention preferably further contains sodium hydrogen carbonate.
  • sodium hydrogen carbonate in combination with diethylenetriamine pentaacetic acid, the effect of suppressing the production of fosaprepitant-related substances can be exhibited at a higher level.
  • the content of sodium hydrogen carbonate in the aqueous solution of the present invention is preferably 0.05 to 1.5 parts by mass, preferably 0.05 to 1 part by mass with respect to 1 part by mass of fosaprepitant, from the viewpoint of suppressing the production of fosaprepitant-related substances.
  • ⁇ 1.3 parts by mass is more preferable, and 0.05 to 1.2 parts by mass is further preferable.
  • the mass ratio [(B) / (A)] of (A) diethylenetriamine pentaacetic acid and (B) sodium hydrogen carbonate is preferably 0.4 to 300 from the viewpoint of suppressing the production of fosaprepitant-related substances, and is 0. .5-250 is more preferable, and 0.625-200 is even more preferable.
  • the aqueous solution agent of the present invention preferably contains a pH adjuster from the viewpoint of suppressing the production of fosaprepitant-related substances.
  • the pH adjuster can contain 1 or 2 or more.
  • Examples of the pH adjuster include acid agents and alkaline agents.
  • Examples of the acid agent include inorganic acids such as hydrochloric acid, phosphoric acid, boric acid and carbonic acid; and organic acids such as ascorbic acid, acetic acid, citric acid, succinic acid and tartrate acid, which may contain 1 or 2 or more. ..
  • alkaline agent examples include inorganic or organic bases such as ammonia, monoethanolamine, diethanolamine, triethanolamine, triethylamine and trishydroxymethylaminomethane (tromethamole); sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • an acid agent and an alkaline agent may be used in combination.
  • the content of the pH adjuster can be appropriately set so as to have a desired pH according to the type of the pH adjuster.
  • the pH of the aqueous solution as the final administration form is preferably 8.0 to 10, more preferably 8.0 to 9.5, still more preferably 8.5 to 9.5, and 8.8 to 9. 2 is particularly preferable.
  • the pH shall be measured using a pH meter.
  • the aqueous solution agent of the present invention can contain a surfactant.
  • the surfactant may be contained in an amount of 1 or 2 or more.
  • a nonionic surfactant is preferable, and examples thereof include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polyoxyethylene hydroxy fatty acid ester.
  • polyoxyethylene sorbitan C 10-20 fatty acid ester is preferable.
  • polyoxyethylene (20) sorbitan monolauric acid ester polyoxyethylene (20) sorbitan monopalmitic acid ester
  • polyoxyethylene (20) sorbitan monostearic acid ester polyoxyethylene (20) sorbitantry.
  • examples thereof include stearic acid ester and polyoxyethylene (20) sorbitan monooleic acid ester.
  • the values in parentheses are the average number of moles of ethylene oxide added, and the same applies to the following.
  • the polyoxyethylene hydrogenated castor oil is preferably added with 5 to 200 mol of ethylene oxide, more preferably 10 to 150 mol, and further preferably 20 to 120 mol.
  • polyoxyethylene (25) hardened castor oil polyoxyethylene (40) hardened castor oil, polyoxyethylene (50) hardened castor oil, polyoxyethylene (60) hardened castor oil, polyoxyethylene. (100) Hardened castor oil can be mentioned.
  • the polyoxyethylene castor oil include polyoxyethylene (35) castor oil.
  • polyoxyethylene hydroxy fatty acid ester polyoxyethylene hydroxy C 10-20 fatty acid ester is preferable, and polyoxyethylene (15) hydroxystearic acid ester is more preferable.
  • polyoxyethylene sorbitan fatty acid ester 1 or 2 or more selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene cured castor oil, polyoxyethylene castor oil and polyoxyethylene hydroxy fatty acid ester is preferable.
  • the content of the surfactant is preferably 0.1 to 70 parts by mass, more preferably 0.2 to 50 parts by mass, still more preferably 0.3 to 27 parts by mass, and 0. 4 to 18 parts by mass is particularly preferable.
  • the aqueous solution of the present invention may further contain other components, if desired.
  • other components include stabilizers, buffers, preservatives, and tonicity agents, but excipients such as lactose and cyclodextrin are not always required to be contained.
  • the stabilizer include sodium sulfite and sodium meta sulfite.
  • the buffer include borate buffer, phosphate buffer, carbon dioxide buffer, citrate buffer, acetate buffer, glycine buffer, glycylglycine buffer, tris buffer, aspartic acid, and aspartate. , Epsilon-aminocaproic acid.
  • Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.
  • Examples of the tonicity agent include sodium chloride, glucose, sorbitol, mannitol, xylitol and the like. Of these, sodium chloride and glucose are preferable. The content of these additives can be appropriately set within a range that does not impair the object of the present invention.
  • the aqueous solution of the present invention can be filled in a container.
  • the container can be appropriately selected depending on the intended use, and examples thereof include a container having a specified capacity such as a vial, an ampoule, a bag, and a syringe, and a container having a large capacity such as a bottle.
  • Examples of the material of the container include glass and plastic.
  • the surface inside the container may be subjected to silica coating treatment, silicone coating treatment, sulfur treatment, various low alkali treatments and the like.
  • the material of the gasket of the prefilled syringe or the stopper of the prefilled syringe or vial is not particularly limited, and for example, various rubbers such as natural rubber, butyl rubber, chlorobutyl rubber, isoprene rubber, butadiene rubber, styrene-butadiene rubber, and silicone rubber.
  • materials Various thermoplastic elastomers such as polyurethane-based, polyester-based, polyamide-based, olefin-based, and styrene-based; or elastic materials such as mixtures thereof.
  • the aqueous solution of the present invention can be prepared by an appropriate method.
  • the dosage form when the dosage form is an aqueous solution that can be administered as it is, it can be produced by dissolving fosaprepitant and diethylenetriaminepentaacetic acid, and if necessary, other components in an aqueous medium.
  • the dosage form is a concentrated aqueous solution, adjust the amount of the aqueous medium used and prepare it so that it can be an aqueous solution containing an effective amount of fosaprepitant when diluted at a predetermined ratio. Just do it.
  • a concentrated aqueous solution may be obtained by concentrating the aqueous solution that can be administered as it is by a known method.
  • aqueous medium for example, one or two or more selected from physiological saline, 5% glucose, distilled water for injection, xylitol solution and infusion solution can be used.
  • the infusion solution include electrolyte solution (Ringer's solution, etc.), nutritional infusion solution, protein amino acid injection solution, vitamin injection solution, etc., substitute blood combined with electrolytic solution and nutritional infusion solution (sugar solution, etc.), and fat emulsion emulsified with fat.
  • the concentrated aqueous solution can be diluted at the time of use, for example, by using one or more of the aqueous mediums described above so that the concentration of fosaprepitant in the aqueous solution as the final administration form is within the above range. good.
  • the aqueous solution of the present invention has an osmotic pressure ratio of preferably 0.5 to 3.0, more preferably 0.7 to 2.5, and further, in the aqueous solution as the final administration form. It is preferably 0.9 to 2.0.
  • the dilution ratio is not particularly limited as long as the osmotic pressure ratio with respect to the physiological saline is within the above range, but is usually 3 to 100 times, preferably 5 to 100. It is double, more preferably 10 to 100 times.
  • the osmotic pressure can be measured using an automatic osmotic pressure analyzer.
  • Examples of the administration route of the aqueous solution include subcutaneous administration, intramuscular administration, and intravenous administration. Of these, intravenous administration is preferable. Examples of the intravenous administration include intravenous injection and intravenous drip. Intravenous injection may be a single injection or multiple injections. Intravenous drip can be administered in the form of gravity drip drip, pump injection via a drip tube pump, or drip syringe driver.
  • the related substance production inhibitor and the related substance production suppressing method of the present invention suppress the production of fosaprepitant related substances in an aqueous environment.
  • the production inhibitor of the present invention is a production inhibitor of a fosaprepitant-related substance in an aqueous solution for injecting fosaprepitant, and contains diethylenetriamine pentaacetic acid as an active ingredient.
  • the method for suppressing the production of fosaprepitant is a method for suppressing the production of fosaprepitant-related substances in an aqueous solution for injecting fosaprepitant, in which fosaprepitant is allowed to coexist with diethylenetriamine pentaacetic acid.
  • Fosaprepitant and diethylenetriaminepentaacetic acid may be in a state of finally coexisting in the aqueous solution for injection of fosaprepitant, and the timing and order of coexistence are not particularly limited.
  • the method for producing an aqueous solution for injecting fosaprepitant of the present invention includes a step of mixing with diethylenetriamine pentaacetic acid.
  • the diethylenetriamine pentaacetic acid may be in a state of coexisting with fosaprepitant in any one of the production steps of the aqueous solution for injecting fosaprepitant, and the timing and order of mixing are not particularly limited.
  • the specific configurations of the aqueous solution for injecting fosaprepitant, fosaprepitant and diethylenetriaminepentaacetic acid are as described above.
  • sodium hydrogen carbonate may be further contained as an active ingredient.
  • the blending amount of diethylenetriamine pentaacetic acid and sodium hydrogencarbonate with respect to fosaprepitant and the mass ratio of diethylenetriaminepentacetic acid and sodium hydrogencarbonate are as described above.
  • [4A] The aqueous solution for fosaprepitant injection according to any one of the above [1A] to [3A], which further contains a surfactant.
  • [5A] The aqueous solution for fosaprepitant injection according to [3A] above, wherein the surfactant is a nonionic surfactant.
  • [6A] The aqueous solution for fosaprepitant injection according to the above [5A], wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester.
  • [7A] The aqueous solution for fosaprepitant injection according to any one of [4A] to [6A] above, wherein the content of the surfactant is 0.4 to 18 parts by mass with respect to 1 part by mass of fosaprepitant.
  • [8A] The aqueous solution for fosaprepitant injection according to any one of [1A] to [7A] above, which does not contain any excipient or cyclodextrin.
  • Aqueous solution for injection of fosaprepitant according to.
  • [13A] The aqueous solution for fosaprepitant injection according to any one of [1A] to [12A] above, wherein the content of fosaprepitant is 0.5 to 2 mg / mL in the aqueous solution as the final administration form.
  • [14A] When the aqueous solution stored at 50 ° C. for 7 days was analyzed by HPLC by the method described in the present specification, the relative retention time (RRT) 0. The aqueous solution for fosaprepitant injection according to any one of [1A] to [13A] above, wherein the content of 95 ⁇ 0.1 related substances is 0.2% or less.
  • [15A] The aqueous solution for fosaprepitant injection according to any one of the above [2A] to [14A], wherein the content of sodium hydrogen carbonate is 0.05 to 1.2 parts by mass with respect to 1 part by mass of fosaprepitant.
  • Agent. Any one of the above [2A] to [15A], wherein the mass ratio [(B) / (A)] of (A) diethylenetriamine pentaacetic acid and (B) sodium hydrogen carbonate is 0.625 to 200.
  • the aqueous solution for injecting fosaprepitant according to.
  • [1B] A method for producing an aqueous solution for fosaprepitant injection, which comprises a step of mixing with diethylenetriamine pentaacetic acid.
  • [2B] A method for producing an aqueous solution for injecting fosaprepitant, which comprises a step of mixing with diethylenetriamine pentaacetic acid and allowing it to coexist with fosaprepitant.
  • [3B] The production method according to the above [1B] or [2B], which is further mixed with sodium hydrogen carbonate.
  • [4B] The production method according to any one of [1B] to [3B] above, which is not mixed with an excipient and cyclodextrin.
  • [5B] The production method according to any one of [1B] to [4B] above, wherein the blending amount of diethylenetriamine pentaacetic acid is 0.005 to 0.07 parts by mass with respect to 1 part by mass of fosaprepitant.
  • [6B] The production method according to any one of [3B] to [5B] above, wherein the blending amount of sodium hydrogen carbonate is 0.05 to 1.2 parts by mass with respect to 1 part by mass of fosaprepitant.
  • the ratio of (A) diethylenetriamine pentaacetic acid to (B) sodium hydrogen carbonate is 0.625 to 200 as a mass ratio [(B) / (A)].
  • [8B] The production method according to any one of [1B] to [7B] above, wherein the content of fosaprepitant is 0.5 to 2 mg / mL in the aqueous solution as the final administration form.
  • [4C] The production inhibitor according to the above [2C] or [3C], which contains 0.05 to 1.2 parts by mass of sodium hydrogen carbonate with respect to 1 part by mass of fosaprepitant.
  • [5C] In the above [2C] to [4C], the ratio of (A) diethylenetriamine pentaacetic acid to (B) sodium hydrogen carbonate is 0.625 to 200 as a mass ratio [(B) / (A)].
  • the production inhibitor according to any one.
  • [6C] When the aqueous solution for injecting fosaprepitant stored at 50 ° C.
  • [1D] A method for suppressing the production of a fosaprepitant-related substance in an aqueous solution for injecting fosaprepitant, in which fosaprepitant is allowed to coexist with diethylenetriamine pentaacetic acid.
  • [2D] A method for suppressing the production of fosaprepitant-related substances in an aqueous solution for injecting fosaprepitant, in which fosaprepitant is allowed to coexist with diethylenetriaminepentaacetic acid and sodium hydrogencarbonate.
  • [3D] The method for suppressing production according to the above [1D] or [2D], wherein 0.005 to 0.07 parts by mass of diethylenetriamine pentaacetic acid coexists with 1 part by mass of fosaprepitant.
  • [4D] The method for suppressing production according to the above [2D] or [3D], wherein 0.05 to 1.2 parts by mass of sodium hydrogen carbonate coexists with 1 part by mass of fosaprepitant.
  • [5D] In the above [2D] to [4D], the ratio of (A) diethylenetriamine pentaacetic acid to (B) sodium hydrogen carbonate is 0.625 to 200 as a mass ratio [(B) / (A)].
  • the production suppression method according to any one.
  • [1E] Use of diethylenetriamine pentaacetic acid to suppress the production of fosaprepitant-related substances in an aqueous solution for injection of fosaprepitant.
  • [2E] Use of diethylenetriamine pentaacetic acid and sodium hydrogencarbonate to suppress the production of fosaprepitant-related substances in an aqueous solution for injecting fosaprepitant.
  • [3E] The use according to the above [1E] or [2E], wherein 0.005 to 0.07 parts by mass of diethylenetriamine pentaacetic acid is used with respect to 1 part by mass of fosaprepitant.
  • a sample was prepared by diluting a filtrate obtained by filtering a fosaprepitant injectable aqueous solution with a 0.45 ⁇ m membrane filter with water so that the fosaprepitant concentration was suitable for HPLC analysis.
  • this sample was subjected to a high performance liquid chromatograph (model Alliance 2996, manufactured by Waters) equipped with a column (octadecylsilylated silica gel, L-column2 ODS, Chemicals Evaluation and Research Institute), and the column temperature was 30. It was analyzed by the gradient method at ° C.
  • Amount of substance related to fosaprepitant (%) x / (x + y + z) x 100
  • x indicates the peak area of a substance related to fosaprepitant
  • y indicates the peak area of fosaprepitant
  • z indicates the peak area of aprepitant.
  • Example 1 Dissolve diethylenetriamine pentaacetic acid and polysolvate 80 in physiological saline to adjust the pH to 8.5 with sodium hydroxide so that the prepared concentration becomes the concentration shown in Example 1 of Table 1, and then use a physiological saline solution to prepare the scalpel. It was used as a solvent for preparing the preparation.
  • fosaprepitant tomeglumin is dissolved in a solvent for preparing the preparation so that the prepared concentration becomes the concentration shown in Table 1, the pH is adjusted to 8.5 with sodium hydroxide, and then the preparation is made up with the solvent for preparing the preparation.
  • the aqueous solution for fosaprepitant injection shown in Table 1 was produced (the aqueous solution for fosaprepitant injection, which was prepared by the same production method and then diluted 20-fold with a physiological saline solution, had an osmotic pressure ratio with respect to the physiological saline solution. It was 1.00). Then, this aqueous solution for injecting fosaprepitant was stored at 50 ° C. for 7 days. The relative retention time (RRT) of the aqueous solution for injection of fosaprepitant after storage was 0.95 ⁇ 0. The related substances detected in 1 were analyzed. The results are shown in FIG. In addition, the amount of related substances was calculated from the peak area of the chromatogram obtained by HPLC analysis based on the above formula. As a result, the related substance was not detected (Table 2).
  • Comparative Example 1 An aqueous solution for fosaprepitant injection was produced by the same procedure as in Example 1 except that diethylenetriamine pentaacetic acid was changed to equimolar sodium edetate hydrate (Table 1, Comparative Example 1). Then, the aqueous solution for injecting fosaprepitant was stored at 50 ° C. for 7 days. The aqueous solution for injecting fosaprepitant after storage was diluted 20-fold with water in the same manner as in Example 1, and then the fosaprepitant-related substances were analyzed by HPLC. The results are shown in FIG. In addition, the amount of related substances was calculated from the peak area of the chromatogram obtained by HPLC analysis based on the above formula. The results are shown in Table 2.
  • the fosaprepitant injectable aqueous solution containing diethylenetriaminepentacetic acid did not detect a fosaprepitant-related substance (Table 2, Example 1), whereas it contained sodium edetate hydrate instead of diethylenetriaminepentaacetic acid. Since the fosaprepitant-related substance was detected in the fosaprepitant injectable aqueous solution (Table 2, Comparative Example 1), the production of the fosaprepitant-related substance was suppressed in the coexistence of fosaprepitant and diethylenetriaminepentaacetic acid. It can be seen that such an effect is not observed with the same chelating agent, sodium edetate hydrate.
  • Example 2 Diethylenetriamine pentaacetic acid, polysolvate 80 and sodium hydrogencarbonate were dissolved in physiological saline, the pH was adjusted to 9.0 with sodium hydroxide, and then physiological so that the prepared concentration was the concentration shown in Example 2 of Table 3. It was prepared with a saline solution and used as a solvent for preparing the preparation. Next, fosaprepitant tomeglumin was dissolved in a solvent for preparing the preparation so that the prepared concentration would be the concentration shown in Example 2 in Table 3, the pH was adjusted to 9.0 with sodium hydroxide, and then the preparation was made. An aqueous solution for fosaprepitant injection was produced by messing up with a solvent. It was 1.00).
  • the aqueous solution for injecting fosaprepitant was stored at 50 ° C. for 7 days.
  • the aqueous solution for injecting fosaprepitant after storage was diluted 20-fold with water in the same manner as in Example 1, and then the fosaprepitant-related substances were analyzed by HPLC. As a result, the related substance was not detected.
  • aqueous solution for fosaprepitant injection was produced by the same operation as in Example 2 except that diethylenetriamine pentaacetic acid was changed to equimolar sodium edetate. Then, the aqueous solution for injecting fosaprepitant was stored at 50 ° C. for 7 days. The aqueous solution for injecting fosaprepitant after storage was diluted 20-fold with water in the same manner as in Example 1, and then the fosaprepitant-related substances were analyzed by HPLC. The amount of substance was calculated. The results are shown in Table 4.
  • Example 3 An aqueous solution for fosaprepitant injection was produced by the same operation as in Example 2 except that sodium hydrogen carbonate was not added (Table 3, Example 3) (after preparation by the same production method, physiological saline was prepared. The aqueous solution for injecting fosaprepitant diluted 20-fold with the solution had an osmotic pressure ratio of 1.00 to the physiological saline solution). Then, the aqueous solution for injecting fosaprepitant was stored at 50 ° C. for 7 days. The aqueous solution for injecting fosaprepitant after storage was diluted 20-fold with water by HPLC in the same manner as in Example 1, and then the fosaprepitant-related substances were analyzed. The amount of substance was calculated. The results are shown in Table 4.

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Abstract

L'invention concerne un agent de solution aqueuse pour une injection de fosaprépitant, la solution aqueuse contenant un fosaprépitant et un acide diéthylènetriamine pentaacétique.
PCT/JP2021/037143 2020-10-08 2021-10-07 Agent de solution aqueuse pour une injection de fosaprépitant WO2022075408A1 (fr)

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JP2020170581A JP2023169446A (ja) 2020-10-08 2020-10-08 ホスアプレピタント注射用水溶液剤

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017021880A1 (fr) * 2015-08-03 2017-02-09 Leiutis Pharmaceuticals Pvt Ltd Formulations liquides de fosaprépitant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017021880A1 (fr) * 2015-08-03 2017-02-09 Leiutis Pharmaceuticals Pvt Ltd Formulations liquides de fosaprépitant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AKERS M J: "EXCIPIENT-DRUG INTERACTIONS IN PARENTERAL FORMULATIONS", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 91, no. 11, 1 November 2002 (2002-11-01), US , pages 2283 - 2300, XP001130297, ISSN: 0022-3549, DOI: 10.1002/jps.10154 *
MASANORI FURUKAWA: "Application of Aminopolycarboxylic Acid Chelating Agents", JAPAN TAPPI JOURNAL, vol. 54, no. 2, 1 February 2000 (2000-02-01), pages 184 - 197, XP055920037, ISSN: 0022-815X, DOI: 10.2524/jtappij.54.184 *

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