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WO2010134556A1 - Solution pour injection aqueuse contenant un dérivé de l'acide 5-méthyl-2-(1-pipérazinyl)benzènesulfonique - Google Patents

Solution pour injection aqueuse contenant un dérivé de l'acide 5-méthyl-2-(1-pipérazinyl)benzènesulfonique Download PDF

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WO2010134556A1
WO2010134556A1 PCT/JP2010/058471 JP2010058471W WO2010134556A1 WO 2010134556 A1 WO2010134556 A1 WO 2010134556A1 JP 2010058471 W JP2010058471 W JP 2010058471W WO 2010134556 A1 WO2010134556 A1 WO 2010134556A1
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injection
group
aqueous solution
liquid chromatography
general formula
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Japanese (ja)
Inventor
敬則 齋藤
博 吉田
千佳 大野
勝芳 吉澤
和彦 尾崎
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Mitsubishi Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is the following general formula (I)
  • R 1 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 4 halogenated alkyl group, a halogen atom, or a C 6 -C 12
  • R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, or a cyano group, a nitro group, a C 1 -C 6 alkoxy group, a halogen atom, a C 1 -C 6 alkyl group, and amino A C 7 -C 12 aralkyl group which may have one or more substituents selected from the group consisting of groups; n represents an integer of 1 to 4)
  • an aqueous solution for injection containing a 5-methyl-2- (1-piperazinyl) benzenesulfonic acid derivative, a salt thereof, or a hydrate or solvate thereof.
  • the aminobenzenesulfonic acid derivative represented by the above general formula (I) has an action of suppressing excessive accumulation of intracellular calcium ions, and these compounds are various cardiovascular diseases such as angina pectoris, myocardial infarction, It has been revealed that it is useful for the prevention and treatment of hypertension, heart failure or arrhythmia (Patent Documents 1 to 4 etc.). Furthermore, these patent documents also describe general additives for producing an aqueous solution for injection. Although it is possible to produce an injectable aqueous solution using these additives, in order to provide an injectable aqueous solution that can actually be used in the medical field, a preparation with a guaranteed storage stability for a certain period of time must be used. There is a need to. However, the above patent document does not disclose the kind and amount of additives for obtaining a stable aqueous solution for injection.
  • the measurement of the decomposition product formation state is generally called a stability test.
  • the data on stability includes the results of long-term storage tests, severe tests and accelerated tests (Appendix 1 of the same issue).
  • the long-term storage test is a test in which the preparation is stored at 25 ° C. for 36 months
  • the severe test is a test in which the preparation is stored at 60 ° C. for one month
  • the accelerated test is for example stored at 40 ° C. for three months or six months. Test to do.
  • the active ingredient of the present application is gradually hydrolyzed in water or physiological saline solution to generate decomposition impurities. Therefore, there is a problem in storage stability. Further, it has been found that the active ingredient of the present application accelerates the generation of decomposition products by light, heat, pH, and the like. Therefore, considerable difficulty was anticipated in the development of an aqueous solution for injection containing the active ingredient of the present application and excellent in stability.
  • R 1 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 4 halogenated alkyl group, a halogen atom, or a C 6 -C 12
  • R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, or a cyano group, a nitro group, a C 1 -C 6 alkoxy group, a halogen atom, a C 1 -C 6 alkyl group, and amino A C 7 -C 12 aralkyl group which may have one or more substituents selected from the group consisting of groups; n represents an integer of 1 to 4)
  • An aqueous solution for injection containing an aminobenzenesulfonic acid derivative represented by the formula (1) or a salt thereof, or a hydrate or solvate thereof, and containing trometamol.
  • the concentration of the aminobenzenesulfonic acid derivative represented by the general formula (I) or a salt thereof, or a hydrate or solvate thereof is from 1 mg / ml to 20 mg / ml, The aqueous solution for injection according to any one of 3).
  • the amount of the main degradation product detected at a relative retention time of 1.2 detected under the high performance liquid chromatography measurement conditions described in (5) above is 0.1% (Calculated from the peak area value of the main decomposition product of high performance liquid chromatography)
  • the aminobenzenesulfonic acid derivative represented by the general formula (I) or a salt thereof, or a hydrate or solvate thereof is contained below.
  • Aqueous solution for injection. (7) After storage at 40 ° C. for 6 months, the production amount of the main decomposition product detected at a relative retention time of 1.2 detected under the high performance liquid chromatography measurement conditions described in (5) above is 0.2%.
  • the aminobenzenesulfonic acid derivative represented by the general formula (I) or a salt thereof, or a hydrate or solvate thereof is contained below.
  • Aqueous solution for injection. After storage at 60 ° C. for 1 month, the amount of main decomposition products detected at a relative retention time of 1.2 detected under the high performance liquid chromatography measurement conditions described in (5) above is 0.1% (Calculated from the peak area value of the main decomposition product of high performance liquid chromatography)
  • the aminobenzenesulfonic acid derivative represented by the general formula (I) or a salt thereof, or a hydrate or solvate thereof is contained below.
  • the compounds represented by the general formula (I) are 5-methyl-2- (1-piperazinyl) benzenesulfonic acid or a salt thereof, or a hydrate or solvate thereof (1) to (8) The aqueous solution for injection according to any one of (1).
  • (11) The injectable aqueous solution according to the above (9), wherein the compound represented by the general formula (I) is 5-methyl-2- (1-piperazinyl) benzenesulfonic acid monohydrate.
  • the trometamol concentration is 10 mM to 20 mM, the pH is 6.5 to 7.5, and the compound represented by the general formula (I) is contained at a concentration of 5 mg / ml to 15 mg / ml.
  • An injection comprising a container filled with the aqueous solution for injection according to any one of (1) to (12).
  • the injection according to (13), wherein the container is a sealed container.
  • the injection according to (14) above, wherein the gas phase portion of the sealed container is substituted with an inert gas.
  • the injection according to (15) above, wherein the inert gas is nitrogen.
  • R 1 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 4 halogenated alkyl group, a halogen atom, or a C 6 -C 12
  • R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, or a cyano group, a nitro group, a C 1 -C 6 alkoxy group, a halogen atom, a C 1 -C 6 alkyl group, and amino A C 7 -C 12 aralkyl group which may have one or more substituents selected from the group consisting of groups; n represents an integer of 1 to 4)
  • the production amount of the main degradation product detected at a relative retention time of 1.2 detected under the high performance liquid chromatography measurement conditions described in (21) above is 0.1% (Calculated from the peak area value of the main decomposition product of high performance liquid chromatography)
  • the stabilization method according to any one of (17) to (20) above is 0.2% (Calculated from the peak area value of the main decomposition product of high performance liquid chromatography)
  • the amount of the main degradation product detected at a relative retention time of 1.2 detected under the measurement conditions for high performance liquid chromatography described in (21) above is 0.1% (Calculated from the peak area value of the main decomposition product of high performance liquid chromatography)
  • the compounds represented by the general formula (I) are 5-methyl-2- (1-piperazinyl) benzenesulfonic acid or a salt thereof, or a hydrate or solvate thereof (17) to (24 The stabilization method according to any one of (1).
  • the amount of decomposition products of compound (I) can be suppressed to a very low level even when an aqueous solution for injection of compound (I) is stored for a long period of time. For example, after 36 months storage at 25 ° C., the amount of main degradation products detected at a relative retention time of 1.2 detected under certain high performance liquid chromatography measurement conditions is 0.2% (the main performance of high performance liquid chromatography is Calculated from the peak area value of the decomposition product) or less.
  • Examples of the active ingredient of the aqueous solution for injection of the present invention include aminobenzenesulfonic acid derivatives represented by the above general formula (I) or salts thereof, or hydrates or solvates thereof.
  • examples of the C 1 -C 6 alkyl group defined by R 1 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, Examples thereof include a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, and an isohexyl group.
  • Examples of the C 3 -C 7 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • Examples of the C 1 -C 4 halogenated alkyl group include a trifluoromethyl group, a trifluoroethyl group, a pentafluoroethyl group, and the like.
  • a halogen atom a fluorine atom, a chlorine atom, a bromine atom, etc. are mentioned, for example.
  • Examples of the C 6 -C 12 aryl group include a phenyl group and a naphthyl group.
  • R 1 examples include a hydrogen atom, a C 1 -C 6 alkyl group, a C 5 -C 6 cycloalkyl group (eg, cyclopentyl group, cyclohexyl group), trifluoromethyl group, halogen atom or phenyl group.
  • R 1 is a C 1 -C 3 alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group), cyclohexyl group, trifluoromethyl group, chlorine atom, bromine atom or phenyl group
  • a methyl group or a propyl group is preferable.
  • the alkyl group of C 1 -C 6 defined by R 2 for example, an alkyl group of C 1 -C 6 as defined above R 1 can be mentioned.
  • Examples of the C 7 -C 12 aralkyl group include a benzyl group, a phenethyl group, and a naphthylmethyl group.
  • This aralkyl group is a cyano group; a nitro group; a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a tert-pentyloxy group, selected from group consisting of an alkyl group and an amino group of C 1 -C 6 as defined above R 1; the halogen atom as defined R 1; alkoxy C 1 -C 6 such as a hexyloxy group You may have 1 or 2 or more substituents.
  • R 2 include a hydrogen atom, a C 1 -C 3 alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group), and a C 1 -C 3 alkyl group (eg, methyl group).
  • Ethyl group, propyl group, isopropyl group C 1 -C 3 alkoxy group (eg, methoxy group, ethoxy group, propoxy group, isopropoxy group) and halogen atom (eg, fluorine atom, chlorine atom, bromine atom)
  • a C 7 -C 12 aralkyl group optionally having 1 or 2 or more substituents selected from: More preferable examples include R 2 being a hydrogen atom or 1 or 2 or more C 1 -C Examples thereof include C 7 -C 12 aralkyl groups which may be substituted with 3 alkoxy groups, and particularly preferably a hydrogen atom.
  • n is preferably 2.
  • compounds in which the substitution position of R 1 is at the 5-position are preferable, and more preferable compounds include the following compounds.
  • salts of the compounds listed above are also included in the scope of the present invention.
  • the salt of the above compound include alkali metal salts or alkaline earth metal salts such as sodium salt, potassium salt, magnesium salt, calcium salt and aluminum salt; lower alkylamine salts such as ammonium salt and triethylamine salt; 2-hydroxy Hydroxy lower alkylamine salts such as ethylamine salts, bis- (2-hydroxyethyl) amine salts, tris (hydroxymethyl) aminomethane salts, N-methyl-D-glucamine salts, cycloalkylamine salts such as dicyclohexylamine salts, N , N-dibenzylethylenediamine salt and other benzylamine salts, dibenzylamine salt and other amine salts; hydrochlorides, hydrobromides, sulfates, phosphates and other inorganic acid salts; Organic acid salts such as acid salts, oxalate salts,
  • any hydrate or solvate thereof may be used as an active ingredient of the aqueous solution for injection of the present invention.
  • the solvent that can form a solvate of the above compound include methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, methylene chloride, and the like.
  • 5-methyl-2- (1-piperazinyl) benzenesulfonic acid anhydride and 5-methyl-2- (1-piperazinyl) benzenesulfonic acid monohydrate are most preferable. Can be mentioned.
  • aminobenzenesulfonic acid derivatives represented by the above general formula (I) are known compounds, such as JP-A-3-7263 and JP-A-9-212479, European Patent Application Publication Nos. 390654 and 799283, In addition, the compound can be easily synthesized by a method described in US Pat. Nos. 5,053,409 and 5,990,113, and can be easily obtained by those skilled in the art.
  • the concentration of the active ingredient of the present application is preferably 1 mg / ml or more and 20 mg / ml or less, more preferably 5 mg / ml or more and 15 mg / ml or less, from the viewpoint of improving the stability of the aqueous solution for injection. It is.
  • the amount is less than 1 mg / ml, there is a tendency that related substances such as degradation products tend to increase, and the administration volume increases, which may be undesirable, especially for patients with heart disease. If it is more than 20 mg / ml, there is a possibility of precipitation.
  • the concentration of trometamol used in the present invention is desirably 2 mM or more and 50 mM or less. More desirably, it is 5 mM or more and 50 mM or less, more desirably 5 mM or more and less than 50 mM, further desirably 5 mM or more and 40 mM or less, further desirably 5 mM or more and 30 mM or less, and most desirably 10 mM or more. 20 mM or less. If it is less than 2 mM or more than 50 mM, the stabilization effect of trometamol on the aqueous solution for injection of the present invention may not be sufficiently exhibited.
  • the pH of the aqueous solution for injection of the present invention is preferably 6.0 or more and 8.0 or less, more preferably 6.0 or more and 7.5 or less, and most preferably 6.5 or more and 7.5 or less (7 ⁇ 0.5).
  • a pH adjusting agent can be added as necessary.
  • the pH adjuster used in the injectable aqueous solution of the present invention is not particularly limited as long as it is a pharmaceutically acceptable buffer having a pH buffering ability in the vicinity of the above range.
  • the aqueous solution for injection of the present invention is preferably made isotonic with 0.9% physiological saline for reasons such as ease of hemolysis and pain when administered to the human body.
  • To be isotonic with 0.9% physiological saline means that the osmotic pressure ratio of 0.9% physiological saline to the injection goods of the present invention is between 0.8 and 1.2, preferably 0.9 to Means between 1.1.
  • the substance used for isotonicity is not particularly limited as long as it is pharmaceutically acceptable, and sodium chloride is preferable.
  • additives such as pH adjusters and tonicity agents
  • additives such as soothing agents and preservatives can be added to the aqueous solution for injection of the present invention as necessary.
  • the aqueous solution for injection of the present invention can be stored and used by filling a container.
  • the container is preferably a sealed container.
  • Examples of the form of the sealed container include an ampoule, a vial, and a bag.
  • Examples of the material of the container include glass and plastic.
  • the injectable aqueous solution of the present invention it is highly desirable that no decomposition product of the compound (I) contained is generated, that is, the peak of the decomposition product is not formed in high performance liquid chromatography, or it is below the detection limit.
  • the decomposition product of compound (I) may be produced depending on the storage temperature and storage period. Even if a decomposition product of compound (I) is generated and a peak of the main decomposition product is formed, the amount of the product generated after storage of the aqueous solution for injection of the present invention at 25 ° C. for 36 months is 1.0% (high performance liquid chromatography). Or less, desirably 0.5% or less, and more desirably 0.2% or less. When stored at 40 ° C.
  • the amount produced is 1.0% or less (calculated from the peak area value of the main decomposition product of high performance liquid chromatography), preferably 0.5% or less, more preferably 0.2 % Or less, most preferably 0.1% or less.
  • the amount produced is 1.0% (calculated from the peak area value of the main decomposition product of high performance liquid chromatography) or less, preferably 0.5% or less, more preferably 0.2 % Or less.
  • the amount produced is 1.0% or less (calculated from the peak area value of the main decomposition product of high performance liquid chromatography), preferably 0.5% or less, more preferably 0.2%.
  • the content be 0.1% or less.
  • the amount of the main decomposition product of compound (I) produced after storage at 25 ° C. for 36 months is 0.2% or less.
  • the main decomposition product of compound (I) include a substance having a peak detected at a relative retention time of 1.2 detected under measurement conditions of high performance liquid chromatography.
  • the measurement conditions of high performance liquid chromatography are as follows.
  • Measurement condition (Mobile phase composition) Dissolved sodium dihydrogen phosphate dihydrate (7.8 g) in 1000 ml of a water / acetonitrile mixture (6/1) (column used) A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm filled with 5 ⁇ m octylsilylated silica gel for liquid chromatography (column temperature) Constant temperature around 40 ° C (flow rate) 7ml / min (detector) Ultraviolet absorptiometer (measurement wavelength 248nm)
  • Examples of the main decomposition product of compound (I) include a compound represented by the following general formula (II).
  • the amount of main decomposition product generated can be calculated by determining the peak area value of the main decomposition product of high performance liquid chromatography. Specifically, it can be calculated as the ratio of the peak area value of the main decomposition product detected at a relative retention time of 1.2 under the above measurement conditions to the peak area value of the compound (I) in high performance liquid chromatography. Alternatively, it can also be calculated as the ratio of the peak area value of the main degradation product to the total area value of all peaks when the aqueous solution for injection of Compound (I) is measured under the measurement conditions.
  • the aqueous solution for injection of the present invention is preferably administered continuously or intermittently in a daily dose range of 0.01 mg / kg body weight to 100 mg / kg body weight as the amount of the active ingredient of the present application. It is more preferable to increase or decrease appropriately depending on the presence or absence.
  • the active ingredient of the present application used in the following Examples and Comparative Examples is 5-methyl-2- (1-piperazinyl) benzenesulfonic acid monohydrate produced according to the method described in JP-A-9-212479. .
  • the compound is also referred to as the present compound.
  • Example 1 A 0.1 M to 1 M hydrochloric acid aqueous solution was added to a 0.1 M trometamol aqueous solution to prepare a trometamol aqueous solution having a pH of 7.8 to 8.0. To this trometamol aqueous solution, 5.4 mg / mL of this compound and 0.1 M to 1 M hydrochloric acid aqueous solution were added to adjust the pH to around 7.5, and sodium chloride that was isotonic in the final amount was added thereto. . Finally, the total amount was adjusted with distilled water for injection so that the trometamol concentration was 50 mM. This solution was filled in a 10 mL vial, sealed with a rubber stopper and an aluminum cap, and subjected to steam sterilization to obtain an injection.
  • Example 2 An injection was obtained in the same manner as in Example 1 except that the sodium chloride of Example 1 was not added.
  • Example 3 An injection having a pH of around 7 was obtained in the same manner as in Example 1.
  • Example 4 A 0.1 M to 1 M hydrochloric acid aqueous solution was added to a 0.1 M trometamol aqueous solution to prepare a trometamol aqueous solution having a pH of 6.3 to 6.5. To this trometamol aqueous solution, 5.4 mg / mL of this compound and 0.1 M to 1 M hydrochloric acid aqueous solution were added to adjust the pH to 6.0, and sodium chloride that is isotonic in the final amount was added thereto. Thereafter, an injection was obtained in the same manner as in Example 1.
  • Example 5 A 0.1 M to 1 M hydrochloric acid aqueous solution was added to a 0.1 M trometamol aqueous solution to prepare a trometamol aqueous solution having a pH of around 8.5. To this trometamol aqueous solution, 10.7 mg / mL of this compound and 0.1 M to 1 M hydrochloric acid aqueous solution were added to adjust the pH to 6.0, and sodium chloride that is isotonic in the final amount was added thereto. Thereafter, an injection was obtained in the same manner as in Example 1.
  • Example 6 An injection having a pH of 6.5 was obtained in the same manner as in Example 5.
  • Example 7 An injection having a pH of 7.0 was obtained in the same manner as in Example 5.
  • Example 8 An injection having a pH of 7.5 was obtained in the same manner as in Example 5.
  • Example 9 An injection having a pH of 8.0 was obtained in the same manner as in Example 5.
  • Example 10 A 0.1 M to 1 M hydrochloric acid aqueous solution was added to a 0.1 M trometamol aqueous solution to prepare a trometamol aqueous solution having a pH of around 7.2. To this trometamol aqueous solution, 10.7 mg / mL of this compound and 0.1 M to 1 M hydrochloric acid aqueous solution were added to adjust the pH to 7.0, and sodium chloride that was isotonic in the final amount was added thereto. Finally, the total amount was adjusted with distilled water for injection so that the trometamol concentration was 2 mM. Thereafter, an injection was obtained in the same manner as in Example 1.
  • Example 11 An injection having a trometamol concentration of 5 mM was obtained in the same manner as in Example 10.
  • Example 12 An injection with a trometamol concentration of 10 mM was obtained in the same manner as in Example 10.
  • Example 13 An injection having a trometamol concentration of 20 mM was obtained in the same manner as in Example 10.
  • Example 14 A solution prepared by the same method as in Example 13 was filled into a 10 mL vial, the gas phase portion was purged with nitrogen, sealed with a rubber stopper and an aluminum cap, and subjected to steam sterilization to obtain an injection.
  • Comparative Example 2 A solution having a pH of 4 was obtained in the same manner as in Comparative Example 1.
  • Comparative Example 8 An injection was obtained in the same manner as in Comparative Example 7 except that physiological saline was used instead of the distilled water for injection in Comparative Example 7.
  • Comparative Example 9 An injection was obtained in the same manner as in Comparative Example 7 except that 10 mM NaCl aqueous solution was used instead of distilled water for injection in Comparative Example 7.
  • Test Example 1 Effect of Solution pH on Degradation Product Formation of the Compound
  • the aqueous solutions for injection obtained in Comparative Examples 1 to 6 were stored in a constant temperature bath at 80 ° C. for 14 days, and were detected under the following HPLC conditions.
  • R. The time-dependent change of the main decomposition product production amount (* 1) detected at T (relative retention time) of about 1.2 was measured. The results are as shown in the following table, and it was found that the decomposition of the present compound was suppressed in a solution having a pH of 5 or higher.
  • HPLC conditions (The conditions in the following test examples are also the same.) (Mobile phase composition) Dissolved sodium dihydrogen phosphate dihydrate (7.8 g) in 1000 mL of water / acetonitrile mixture (6/1) (column used) A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm filled with 5 ⁇ m octylsilylated silica gel for liquid chromatography (column temperature) Constant temperature around 40 ° C (flow rate) About 0.7mL / min (detector) Ultraviolet absorptiometer (measurement wavelength 248nm)
  • Test Example 2 Effects of various pH adjusting agents at pH 6 on the decomposition product generation of this compound Example 4 and Comparative Examples 11 to 13
  • the injections obtained were stored in a constant temperature bath at 60 ° C., and the main decomposition product generation amount (* 1)
  • the change with time was measured by the HPLC method.
  • the results are as shown in the following table, and it was confirmed that the injection of the present invention significantly contributed to the inhibition of decomposition of the present compound by using trometamol as a pH adjuster.
  • Example 3 Effect of phosphate and trometamol at pH 7.0 on formation of decomposition product of this compound
  • the injections obtained in Example 3 and Comparative Example 10 were stored in a 60 ° C. constant temperature bath, and the main decomposition product generation amount (* 1 ) was measured by the HPLC method.
  • the results are shown in the following table, and it was confirmed that the injection of the present invention improves the stability of the present compound by using trometamol as a pH adjuster.
  • the stabilizing effect of trometamol on the present compound was significant regardless of the ionic strength (here, sodium chloride).
  • Test Example 4 Stabilizing effect by trometamol
  • the injections obtained in Examples 1 and 2 and Comparative Examples 7 to 9 were stored in a thermostatic bath at 60 ° C., and the time-dependent change in the amount of main decomposition products (* 1) was measured by the HPLC method. .
  • the change with time of pH was also described. The results are shown in the following table. It was confirmed that the injection of the present invention had no change in pH with time and the production of main degradation products was suppressed. Although the influence of ionic strength (here, sodium chloride) on the inhibition of decomposition of the present compound was confirmed, it was revealed that trometamol significantly contributes to stabilization of the present compound regardless of the ionic strength.
  • ionic strength here, sodium chloride
  • Test Example 6 Stabilizing effect by trometamol
  • the injections obtained in Examples 3, 10 to 13 and Comparative Example 14 were stored in a constant temperature bath at 80 ° C., and the change over time in the amount of main decomposition product (* 1) was measured by the HPLC method. .
  • the results are shown in the following table.
  • the injection of the present invention was found to improve the stability of the present compound by using trometamol as a pH adjuster.
  • the improvement in stability was remarkable when the trometamol concentration was 5 mM or more.
  • the stabilization effect of trometamol on the present compound was significant regardless of the ionic strength (here, sodium chloride).
  • Test Example 7 Effect of stabilizing nitrogen in the gas phase portion
  • the injections obtained in Examples 13 and 14 were stored in a constant temperature bath at 60 ° C., and the change over time in the amount of main decomposition product (* 1) was measured by the HPLC method. The results are shown in the following table.
  • the injection of the present invention was found to improve the stability of this compound by filling the vial gas phase with nitrogen.
  • Example 15 This compound, trometamol, and sodium chloride were dissolved in distilled water for injection to give final concentrations of 5 mg / mL, 50 mM, and 110 mM, respectively.
  • a 1M hydrochloric acid aqueous solution was added to this solution to adjust the pH to 7.0, and the total amount was adjusted with distilled water for injection to obtain a final solution.
  • the solution was filtered through a 0.2 ⁇ m filter, filled into a 25 mL vial, the gas phase portion was purged with nitrogen, sealed with a rubber stopper and an aluminum cap, and steam sterilized to give an injection.
  • Example 16 This compound, trometamol, and sodium chloride were dissolved in distilled water for injection so that the final concentrations were 10 mg / mL, 20 mM, and 120 mM, respectively.
  • a 1M hydrochloric acid aqueous solution was added to this solution to adjust the pH to 7.0, and the total amount was adjusted with distilled water for injection to obtain a final solution.
  • the solution was filtered through a 0.2 ⁇ m filter, filled into a 25 mL vial, the gas phase portion was purged with nitrogen, sealed with a rubber stopper and an aluminum cap, and steam sterilized to give an injection.
  • Example 8 25 ° C., 36 month stability test
  • the injections obtained in Example 15 and Example 16 were stored in a constant temperature bath at 25 ° C. for 36 months, and R.D. detected under the same HPLC conditions as in Test Example 1.
  • R. T. T. Relative retention time
  • the change with time of 3, 6, 9, 12, 18, 24, 30 and 36 months after the main decomposition product production amount (* 1) detected at about 1.2 was measured.
  • the results are as shown in Table 10.
  • the degradation of the compound is still less than 0.01% after 36 months. found.
  • Example 15 in the injection of Example 15 containing 50 mM trometamol and adjusting the pH of the solution to 7.5, the degradation of this compound showed a low value of 0.13% after 24 months.
  • the production amount of the main degradation product after 24 months storage at 25 ° C. was suppressed to a low level.
  • trometamol was highly effective in suppressing the production of the main degradation product in the injection of this compound.
  • the amount of main degradation product produced after 36 months was lower in Example 16, suggesting that the addition amount of 20 mM of trometamol is more suitable for the main degradation product inhibiting effect.
  • Test Example 9 40 ° C. 3 Month and 6 Month Stability Test
  • the injections obtained in Examples 15 and 16 were stored in a constant temperature bath at 40 ° C. for 6 months and detected under the same HPLC conditions as in Test Example 1.
  • R. T. T. Relative retention time
  • the change with time of 1, 3 and 6 months after the main degradation product production (* 1) detected at about 1.2 was measured.
  • the results are as shown in Table 11.
  • the degradation of this compound was less than 0.01% after 3 and 6 months. It turned out to be.
  • Example 15 In addition, in the injection of Example 15 containing 50 mM trometamol and adjusting the pH of the solution to 7.5, the decomposition of this compound was less than 0.01% after 1 month, and was also reduced to 0. The low value of less than 0.1% was 06%.
  • trometamol In the injection of this compound, trometamol was found to have a high effect of suppressing the formation of the main degradation product, and the effect was particularly high in Example 16, and thus was found to be higher at 20 mM of trometamol.
  • Test Example 10 Compound (II) Confirmation Test R.D. detected under the same HPLC conditions as in Test Example 1 R. T. T. (Relative retention time)
  • a 1 H-NMR spectrum of the main decomposition product detected at about 1.2 was measured at 30 ° C. in deuterated dimethyl sulfoxide using tetramethylsilane as an internal reference substance. The spectrum is shown in FIG. 1, and the assignment of each signal is shown in Table 12.
  • AVANCE500 manufactured by Bruker was used as a pulse Fourier transform NMR spectrum measuring apparatus.
  • the mass spectrum of the main decomposition product was measured using the MALDI method.
  • the spectrum is shown in FIG.
  • BIFLEX-III manufactured by Bruker was used as a mass spectrometer.
  • an aqueous solution for injection excellent in storage stability comprising an aminobenzenesulfonic acid derivative represented by the general formula (I) or a salt thereof, or a hydrate or solvate thereof as an active ingredient. It is possible.
  • the present invention is based on Japanese Patent Application No. 2009-120485 filed in Japan, the contents of which are incorporated in full herein.

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Abstract

La présente invention concerne une solution pour injection aqueuse contenant un dérivé de l'acide aminobenzènesulfonique représenté par la formule générale (I) (dans laquelle R1 représente un atome d'hydrogène, un groupe alkyle en C1 à C6, un groupe cycloalkyle en C3 à C7, un groupe alkyle halogéné en C1 à C4, un atome d'halogène, ou un groupe aryle en C6 à C12; R2 représente un atome d'hydrogène, un groupe alkyle en C1 à C6, ou un groupe aralkyle en C7 à C12 qui peut avoir au moins un substituant choisi dans le groupe comprenant un groupe cyano, un groupe nitro, un groupe alcoxy en C1 à C6, un atome d'halogène, un groupe alkyle en C1 à C6 et un groupe amino; et n représente un entier de 1 à 4), un sel du dérivé, ou un hydrate ou un solvate du dérivé ou du sel et qui peut subir une hydrolyse progressive dans l'eau ou une solution saline physiologique, et dans lequel la production de toute substance décomposée peut être accélérée par l'action de la lumière, de la chaleur, du pH ou équivalents. La solution pour injection aqueuse contient de plus du trométamol pour prévenir la production de toute matière décomposée dans celle-ci, et est de ce fait stable.
PCT/JP2010/058471 2009-05-19 2010-05-19 Solution pour injection aqueuse contenant un dérivé de l'acide 5-méthyl-2-(1-pipérazinyl)benzènesulfonique Ceased WO2010134556A1 (fr)

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JP2009120485A JP2012176899A (ja) 2009-05-19 2009-05-19 ２−（１−ピペラジニル）−５−メチルベンゼンスルホン酸誘導体を含む注射用水溶液

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US10765672B2 (en) 2013-06-06 2020-09-08 Fibrogen, Inc. Pharmaceutical formulations of a HIF hydroxylase inhibitor

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US8883823B2 (en) 2012-07-16 2014-11-11 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
PL2872488T3 (pl) 2012-07-16 2019-01-31 Fibrogen, Inc. Postacie krystaliczne inhibitora hydroksylazy prolilowej

Citations (6)

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Publication number Priority date Publication date Assignee Title
JPH09221479A (ja) * 1995-12-15 1997-08-26 Mitsubishi Chem Corp アミノベンゼンスルホン酸誘導体一水和物及びその製造方法
JP2001520627A (ja) * 1994-12-21 2001-10-30 オーソ・フアーマシユーチカル・コーポレーシヨン ２−クロロ−２’−デオキシアデノシン配合物の安定な溶液
JP2001316266A (ja) * 2000-02-29 2001-11-13 Towa Yakuhin Kk 安定な塩酸ニカルジピン注射剤
JP2002265383A (ja) * 2001-03-14 2002-09-18 Mitsubishi Pharma Corp インターフェロンα注射用液状製剤
JP2008120798A (ja) * 2006-10-19 2008-05-29 Mochida Pharmaceut Co Ltd ヘパリン製剤
JP2008521884A (ja) * 2004-12-02 2008-06-26 ヴィーナス・レメディーズ・リミテッド 注射に有用なβ−ラクタマーゼ阻害剤を使用したβ−ラクタマーゼ媒介性の抗生物質耐性を抑制する組成物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001520627A (ja) * 1994-12-21 2001-10-30 オーソ・フアーマシユーチカル・コーポレーシヨン ２−クロロ−２’−デオキシアデノシン配合物の安定な溶液
JPH09221479A (ja) * 1995-12-15 1997-08-26 Mitsubishi Chem Corp アミノベンゼンスルホン酸誘導体一水和物及びその製造方法
JP2001316266A (ja) * 2000-02-29 2001-11-13 Towa Yakuhin Kk 安定な塩酸ニカルジピン注射剤
JP2002265383A (ja) * 2001-03-14 2002-09-18 Mitsubishi Pharma Corp インターフェロンα注射用液状製剤
JP2008521884A (ja) * 2004-12-02 2008-06-26 ヴィーナス・レメディーズ・リミテッド 注射に有用なβ−ラクタマーゼ阻害剤を使用したβ−ラクタマーゼ媒介性の抗生物質耐性を抑制する組成物
JP2008120798A (ja) * 2006-10-19 2008-05-29 Mochida Pharmaceut Co Ltd ヘパリン製剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10765672B2 (en) 2013-06-06 2020-09-08 Fibrogen, Inc. Pharmaceutical formulations of a HIF hydroxylase inhibitor

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