WO2015076340A1 - Injectable composition for general anesthesia and/or sedation - Google Patents

Injectable composition for general anesthesia and/or sedation Download PDF

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Publication number
WO2015076340A1
WO2015076340A1 PCT/JP2014/080791 JP2014080791W WO2015076340A1 WO 2015076340 A1 WO2015076340 A1 WO 2015076340A1 JP 2014080791 W JP2014080791 W JP 2014080791W WO 2015076340 A1 WO2015076340 A1 WO 2015076340A1
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Prior art keywords
methyl
composition
compound
pyridinyl
bromo
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PCT/JP2014/080791
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French (fr)
Japanese (ja)
Inventor
加藤　雅也
和彦 ▲高▼畑
誠一 谷川
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小野薬品工業株式会社
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Publication of WO2015076340A1 publication Critical patent/WO2015076340A1/en

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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
    • A61K31/55—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
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine used as a hypnotic sedative
  • the present invention relates to an injectable composition containing -4-yl] propanoate or a salt thereof.
  • the present invention relates to a freeze-dried composition that contains the salt and an additive described later, has excellent resolubility, and has no discoloration and suppresses the formation of decomposition products under storage conditions described later.
  • Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate is published internationally
  • the compound may form a pharmaceutically acceptable salt with benzenesulfonic acid or the like, and those active ingredients are combined with an acceptable carrier as a form of a pharmaceutical composition for parenteral administration such as an injectable composition. It is known that it may be used. Such compositions may then be aqueous or non-aqueous solutions, or liquid mixtures containing bacteriostatic agents, antioxidants, buffers or other pharmaceutically acceptable additives and are aqueous acidic at pH 2-4 Either a composition by a substance or a composition by using a cyclodextrin aqueous solution is described as being preferable (see Patent Document 1).
  • compositions may then be aqueous or non-aqueous solutions or liquid mixtures that may contain bacteriostatic agents, antioxidants, buffers or other pharmaceutically acceptable additives, pH 2-4 It is described that it is preferable to use a composition using an aqueous acidic medium or cyclodextrin (see Patent Document 2).
  • the inventors have identified methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl.
  • benzenesulfonate it was found that the lyophilized composition was re-dissolved.
  • the subject of the present invention is methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine-4 -Il] propanoate or a salt thereof, which is excellent in resolubility and contains methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2 -A] It is an object to provide a lyophilized composition that does not change color and suppresses the formation of [1,4] benzodiazepin-4-yl] propanoate as much as possible.
  • Compound A is “methyl 3-[(4S) -8-bromo-1-methyl-6- ( 2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate ”and“ Compound B ”is“ methyl 3-[(4S) -8-bromo-1- “Methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate” and “Compound C” are “methyl 3- [8 -Bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate ”can be appropriately read as appropriate. .
  • an injectable composition comprising (1) compound A which is an active ingredient or a salt thereof and (2) one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone ;
  • the additive is dextran 40, dextran 70, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin or polyvinylpyrrolidone K12;
  • the injectable composition according to any one of the preceding aspects wherein the additive is dextran 40;
  • the content of dextran 40 is from about 0.8 to about 3.2 parts by weight per 1 part by weight of Com
  • An injectable composition of [A09] The preceding embodiment, wherein the storage conditions are (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 years at room temperature
  • An injectable composition according to any one of [A10] The injectable composition according to any one of the preceding aspects, wherein decomposition of Compound A accompanying storage of the composition is suppressed; [A11] The composition for injection according to any one of the preceding aspects, wherein the residual ratio of compound A is 95% or more;
  • [A12] The injectable composition according to any one of the preceding aspects, wherein production of compound C accompanying storage of the composition is suppressed;
  • [A13] The injectable composition according to any one of the preceding embodiments, wherein compound C is substantially not produced or the amount of compound C produced is less than 0.2%; [A14] The injectable composition according to any one of the preceding aspects, wherein discoloration associated with storage of the composition is suppress
  • a lyophilized composition comprising about 27.2 mg of Compound B as an active ingredient and about 16 mg to about 64 mg of dextran 40 per unit form of the composition; [B02] A lyophilized composition comprising about 27.2 mg of Compound B as an active ingredient and about 16 mg of dextran 40 per unit form of the composition; [B03] A lyophilized composition comprising about 27.2 mg of compound B as an active ingredient and about 24 mg of dextran 40 per unit form of the composition; [B04] A lyophilized composition comprising about 27.2 mg of the active ingredient Compound B and about 32 mg of dextran 40 per unit form of the composition; [B05] A lyophilized composition comprising about 27.2 mg of compound B as an active ingredient and about 40 mg of dextran 40 per unit form of the composition; [B06] A lyophilized composition comprising about 27.2 mg of compound B as an active ingredient and about 48 mg of dextran 40 per unit form of the composition; [B07] A lyophilized composition comprising about 27.2
  • [C01] An aqueous solution containing Compound A or a salt thereof as an active ingredient, and (2) one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone; [C02] the aqueous solution according to the preceding embodiment, wherein the additive is dextran 40, dextran 70, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin or polyvinylpyrrolidone K12; [C03] The aqueous solution according to any one of the preceding embodiments, wherein the additive is dextran 40; [C04] The aqueous solution according to any one of the preceding embodiments, wherein the content of dextran 40 is from about 0.4 to about 12.8 parts by weight per part by weight of Compound A; [C05] The aqueous solution according to any one of the preceding embodiments, wherein the content of dextran 40 is from about 0.8 to about 3.2 parts by weight
  • One or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone are contained in an injectable composition, and stable injectable containing Compound A or a salt thereof A method for producing the composition;
  • the additive is dextran 40, dextran 70, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, or polyvinylpyrrolidone K12;
  • the additive is dextran 40;
  • the content of dextran 40 is about 0.4 to about 12.8 parts by weight per part by weight of Compound A;
  • the content of dextran 40 is from about 0.8 to about 3.2 parts by weight per part by weight of Compound A;
  • the production method according to any one of the aspects of the invention [D09] The previous embodiment, wherein the storage conditions are (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 years at room temperature The manufacturing method as described in any one of these; [D10] The production method according to any one of the preceding aspects, which is a production method of an injectable composition in which decomposition of Compound A accompanying storage of the composition is suppressed; [D11] The production method according to any one of the preceding aspects, which is a method for producing an injectable composition, wherein the residual ratio of compound A is 95% or more; [D12] The production method according to any one of the preceding aspects, which is a production method of an injectable composition in which production of compound C accompanying storage of the composition is suppressed; [D13] The production method according to any one of the preceding aspects, wherein the compound C is substantially not produced, or the production amount of the compound C is less
  • the additive is dextran 40, dextran 70, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin or polyvinylpyrrolidone K12;
  • the additive is dextran 40;
  • the content of dextran 40 is about 0.4 to about 12.8 parts by weight per part by weight of Compound A;
  • the stabilizer according to any one of the preceding embodiments, wherein the content of dextran 40 is from about 0.8 to about 3.2 parts by weight per part by weight of Compound A; [E06] The stabilizer according to any one of the previous embodiment
  • An injectable composition comprising Compound A or a salt thereof as an active ingredient and dextran 40, (2) a container, and (3) the composition is for general anesthesia and / or sedation Products, including instructions, instructions, package inserts, or product labels indicating that they can be used for [Y02] instructions, instructions, and instructions indicating that an injectable composition comprising Compound A or a salt thereof as an active ingredient and dextran 40 can be used for general anesthesia and / or sedation; Package insert or product label;
  • the injectable composition according to any one of the preceding embodiments wherein the pH adjusting agent is hydrochloric acid and / or sodium hydroxide; [Z04] The injectable composition according to any one of the preceding aspects, which is a lyophilized composition; [Z05] A stable lyophilized composition containing Compound B as an active ingredient, wherein (a) about 27.2 mg of Compound B, (b) about 32 mg of dextran 40, (c) per unit form of the composition ) Containing about 145 mg maltose, and (d) a pH regulator, and (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C.
  • Such lyophilized composition is a methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepine that has a harmful effect on the living body.
  • -4-yl] Propanoate and other degradation products are safe as they are produced under the above-mentioned storage conditions, and are highly re-dissolvable. Composition.
  • methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate (Hereinafter, it may be abbreviated as compound A.) is the formula (A): (CAS number: 308242-62-8), which is described in Example Ic-8 of WO 2000/069836 pamphlet, for example. Such a compound may also be referred to as Remimazolam or CNS7056.
  • examples of the salt of Compound A include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, salicylate, p-toluenesulfonate, tartrate, citrate, methanesulfone.
  • Acid salts maleates, formates, malonates, succinates, isethionates, lactobionates, naphthalene-2-sulfonates, sulfamates, ethanesulfonates and benzenesulfonates, Examples thereof include salts described in International Publication No. 2000/069836 pamphlet.
  • one preferred embodiment of the salt of Compound A is methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate.
  • Benzene sulfonate (hereinafter sometimes abbreviated as compound B) refers to formula (B): (CAS number: 1001415-66-2), for example, described as besylate in International Publication No. 2008/007071.
  • methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate (hereinafter referred to as compound) (May be abbreviated as C)) is the formula (C): It is a novel compound shown by these.
  • Compound C is formed as a decomposition product of the compound A or a salt thereof, or a composition containing compound B, and is an isomer of compound A.
  • Compound C has a harmful effect on a living body.
  • a dose of 5 mg / kg causes a deep breathing or irregular breathing immediately after administration, and 20 mg / kg.
  • this dose we have confirmed that there are deaths that may be caused by respiratory failure due to lung bleeding immediately after administration.
  • compound A and salts thereof typified by compound B are known methods, for example, the method described in WO2000 / 069836, the method described in WO2008 / 007071, Manufactured by appropriately combining the method described in International Publication No. 2008/007081 pamphlet, the method described in International Publication No. 2011/032692 pamphlet, the method described in International Publication No. 2012/062439 pamphlet, or a method equivalent thereto. can do.
  • general methods such as Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Second Edition (A Manufactured by using a combination of methods described in Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)), etc. Can do.
  • compound A and salts thereof typified by compound B are all classified as benzodiazepine compounds based on their structures.
  • the benzodiazepine-based compound is a general term for a group of compounds including a partial structure of a bicyclic heterocycle in which a benzene ring and a seven-membered ring having two nitrogen atoms are condensed in the structural formula.
  • Many benzodiazepine compounds have the action of inducing hypnosis by activating GABAA receptors and promoting the inflow of chloride ions, and they are hypnotic sedatives (benzodiazepine hypnotic sedatives) as benzodiazepine hypnotic sedatives. Used as an active ingredient.
  • injectable composition is one selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone as an additive in addition to the active ingredient.
  • injectable composition is one selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone as an additive in addition to the active ingredient.
  • the above is characterized in that it preferably contains dextran 40, dextran 70, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin or polyvinylpyrrolidone K12, particularly preferably dextran 40 in its composition. is there.
  • the injectable composition of the present invention contains these additives in the composition, thereby suppressing discoloration associated with storage of the composition and suppressing decomposition of Compound A and formation of Compound C in the composition. It is possible to achieve the effect of.
  • the injectable composition of the present invention usually includes those in the form of an aqueous solution and in the form of a lyophilized composition, as will be recognized by those skilled in the art. In the case of a freeze-dried composition, in addition to the above three effects, it can also be provided with rapid re-solubility.
  • an injectable composition in the form of an aqueous solution first, “(1) one or more selected from the group consisting of compound A as an active ingredient or a salt thereof and (2) dextran, cyclodextrin and polyvinylpyrrolidone” It is necessary to prepare an aqueous solution containing the additive (hereinafter sometimes abbreviated as the aqueous solution of the present invention).
  • an aqueous solution is prepared aseptically or non-aseptically, and may contain a pH adjuster and other additives as necessary.
  • the aqueous solution of the present invention can be easily prepared by dissolving the active ingredients and additives, and further, if necessary, the required amounts of pH adjusters and other additives in water for injection. Addition and mixing operations may be performed in accordance with ordinary pharmaceutical methods.
  • the aqueous solution of the present invention prepared aseptically is itself sterile, it can be used as it is as an injectable composition in the form of an aqueous solution.
  • the aqueous solution of the present invention prepared non-sterilely can be used as an injectable composition in the form of an aqueous solution by subjecting it to sterilization.
  • These aqueous solutions of the present invention are usually supplied after being formulated into suitable unit forms.
  • the aqueous solution of the present invention prepared aseptically is filled in a container for injection as it is, sealed, formulated as an injection solution, and supplied.
  • aqueous solution of the present invention prepared non-sterilely is aseptically filtered and filled in an injection container and sealed, or filled and sealed in an injection container and sterilized and injected. It is supplied after being formulated as a liquid for use.
  • the injectable composition in the form of a lyophilized composition can be prepared by subjecting the aqueous solution of the present invention prepared aseptically to lyophilization as it is, or after sterilizing the aqueous solution of the present invention prepared aseptically. It can be manufactured by freeze-drying. These are usually supplied in a suitable unit form after being formulated.
  • the aqueous solution of the present invention prepared aseptically is filled as it is into a container for injection and then freeze-dried and sealed, or it is freeze-dried as it is in a dedicated container and then directly filled into a container and sealed.
  • it is supplied after being formulated as a freeze-dried preparation for injection.
  • the aqueous solution of the present invention prepared non-aseptically is sterile filtered and filled in a container for injection and then freeze-dried and sealed, or sterile filtered and freeze-dried in a dedicated container and directly applied. Either filled into a container and sealed, formulated as a freeze-dried preparation for injection and supplied.
  • the freeze-drying operation may be performed according to a method known per se. Usually, freeze-drying involves freezing the lysate in an arbitrary container, then gradually raising the shelf temperature to the primary drying temperature while keeping the inside of the drying chamber vacuum, and performing the primary drying at the same temperature. Furthermore, it can carry out by heating up shelf temperature until it reaches secondary drying temperature, and performing secondary drying at the same temperature.
  • the injectable composition of the present invention in the form of an aqueous solution disclosed in the present invention and the injectable composition of the present invention in the form of a lyophilized composition can be easily handled. Mutually convertible. If the injectable composition of the present invention in the form of an aqueous solution is lyophilized, the injectable composition of the present invention in the form of a lyophilized composition can be obtained. Moreover, the injection composition of the present invention in the form of an aqueous solution can be obtained by adding a solvent used for injection, such as water for injection or physiological saline, to the injection composition of the present invention in the form of a lyophilized composition. Can do.
  • a solvent used for injection such as water for injection or physiological saline
  • the procedure itself in each step of the production is a conventional pharmaceutical method. Just follow.
  • regulates pH regarding the composition for injection of this invention may be performed.
  • the injectable composition of the present invention is in the form of an aqueous solution
  • the definition of such pH can be understood as the pH of the aqueous solution in accordance with ordinary scientific meaning.
  • the pH of the aqueous solution can be easily measured according to a method known per se, such as a pH measurement method described in a pharmacopoeia (eg, the 16th revised Japanese pharmacopoeia).
  • the injectable composition of the present invention when the injectable composition of the present invention is in the form of a lyophilized composition, the regulation of such pH is the pH of the aqueous solution before subjecting the lyophilized composition to lyophilization, or the lyophilized composition is injected. What is necessary is just to understand in any meaning of the pH of the redissolved solution which added the solvent to be used, for example, water for injection, or physiological saline. Production of the injectable composition of the present invention in the form of a lyophilized composition is usually carried out by subjecting an aqueous solution having a desired pH to a lyophilization using a pH adjuster.
  • the injectable composition of the present invention in the form of a freeze-dried composition having a defined pH is an injectable composition obtained by lyophilizing an aqueous solution having a target pH using a pH regulator.
  • a pH regulator a pH regulator
  • the pH of the solution when the lyophilized composition is redissolved can vary depending on the solvent used for the redissolution and the amount thereof. Therefore, in the present invention, in order to avoid ambiguity, “compound A or a salt thereof is contained in the“ lyophilized composition having a pH of 2.5 to 3.5 containing compound A or a salt thereof ”.
  • pH is about 3 or “pH is around 3” is sometimes used in the range of pH 2.5 to 3.5. In such a range, 2.7 to 3.3 are preferable, 2.9 to 3.1 are more preferable, and 3 is particularly preferable.
  • the container for injection used for the production of an injectable composition may be in any form as long as it is sealable and can maintain the sterility of the contents.
  • containers such as vials and ampoules used as containers for injections are preferred, and vials are particularly preferred.
  • These containers are preferably transparent and uncolored in order to confirm the presence or absence of insoluble foreign matter production, but may be opaque and colored. In the case of an opaque and colored container, the presence or absence of insoluble foreign matter can be confirmed by pulling it out with a syringe for injection during use.
  • the term “unit form” used in the present specification may be understood to mean a form that becomes a unit at the time of dispensing, such as 1 vial, 1 ampule, or the like.
  • the amount of the active ingredient contained per unit form is preferably about 40 mg to about 70 mg, more preferably about 50 mg to about 60 mg, and particularly preferably about 50 mg as the amount of Compound A. . 20 mg is also preferable. Assuming that about 50 mg is included per unit form as the amount of Compound A, 50 mg may be used as it is in the case of Compound A. However, in the case of a salt of a compound, the amount of “Compound A contained in the salt” is It is necessary to add a corresponding amount of a counter constituting the salt (for example, benzenesulfonic acid in the case of Compound B) so as to be 50 mg.
  • a counter constituting the salt for example, benzenesulfonic acid in the case of Compound B
  • the amount of Compound B containing 50 mg as the amount of Compound A is about 68 mg when the counter equivalent is added.
  • the amount of Compound B containing 20 mg as the amount of Compound A is about 27.2 mg when the counter equivalent is added.
  • the “compound A” or “salt of compound A” used in the production of these injectable compositions may be crystalline, amorphous, or any form of solid (for example, a mixture of crystal and amorphous). .
  • dextran used for the production of an injectable composition commercially available ones can be used without particular limitation.
  • a high molecular dextran produced by Leuconostoc mesenteroides Van Tieghem belonging to lactic acid bacteria can be used. Those obtained by partial hydrolysis, fractionation and purification can also be used.
  • the CAS number for Dextran is 9004-54-0.
  • dextran dextran having various molecular weights can be used, but dextran having an average molecular weight of 20,000 or more is usually preferable, and dextran having an average molecular weight of 30,000 or more is more preferable. Further, the upper limit of the average molecular weight of dextran is preferably 1,000,000 or less, and more preferably 100,000 or less. Examples of dextran suitable for the present invention include dextran 40 and dextran 70.
  • dextran 40 (Dextran® 40) and dextran 70 (Dextran® 70), commercially available ones can be used without any particular limitation. These are polysaccharides having an average molecular weight of about 40,000 for dextran 40 and about 70,000 for dextran 70. More detailed information on these dextrans is described in publicly known literatures, for example, Yakuji Nippo Inc. 2007 “Pharmaceutical Additives Encyclopedia” (edited by Japan Pharmaceutical Additives Association), page 182.
  • the content of dextran in the injectable composition of the present invention is preferably about 0.4 to about 12.8 parts by weight, for example, about 0.8 to about 3.2 parts by weight per part by weight of Compound A. Part is more preferred, and about 1.6 parts by weight is particularly preferred. That is, the content of dextran in an injectable composition containing about 50 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 20 mg to about 640 mg, more preferably about 40 mg to about 160 mg, 80 mg is particularly preferred. The content of dextran in an injectable composition containing about 20 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 8 mg to about 256 mg, more preferably about 16 mg to about 64 mg, 32 mg is particularly preferred.
  • the cyclodextrin used for the production of an injectable composition is a general term for D-glucose in which a cyclic structure is formed by ⁇ 1 ⁇ 4 bonds, and those that are commercially available can be used without particular limitation. .
  • some hydrogen atoms in the hydroxyl groups possessed by them are linear or branched alkyl groups, linear or branched Cyclodextrins substituted with alkenyl groups, linear or branched hydroxyalkyl groups, hydroxyaryl groups, acyl groups, glycosyl groups, maltosyl groups, imidazolyl groups, branched cyclodextrins, dimers of cyclodextrins or Multimers can also be used. Cyclodextrin analogues having 5 or less or 9 or more glucose units can be used in the same manner.
  • cyclodextrins are commercially available, such as ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclo Examples include dextrin, monoacetyl- ⁇ -cyclodextrin, triacetyl- ⁇ -cyclodextrin, and monochlorotriazinyl- ⁇ -cyclodextrin.
  • Suitable cyclodextrins in the present invention include, for example, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and the like.
  • ⁇ -cyclodextrin As ⁇ -cyclodextrin ( ⁇ -Cyclodextrin), commercially available ones can be used without particular limitation. ⁇ -Cyclodextrin is a cyclic dextrin having a molecular weight of about 972, and its CAS number is 10016-20-3. ⁇ -cyclodextrin may also be expressed as ⁇ -CD or ⁇ CD. More detailed information on ⁇ -cyclodextrin is described in publicly known documents, for example, Yakuji Nippo 2007 “Pharmaceutical Additives Encyclopedia” (edited by Japan Pharmaceutical Additives Association), page 125.
  • hydroxypropyl- ⁇ -cyclodextrin commercially available ones can be used without particular limitation.
  • Hydroxypropyl- ⁇ -cyclodextrin is a cyclic dextrin having a molecular weight of about 1541, and its CAS number is 128446-35-5.
  • Hydroxypropyl- ⁇ -cyclodextrin may be referred to as HP- ⁇ -CD or HP ⁇ CD. More detailed information on hydroxypropyl- ⁇ -cyclodextrin is described in known literature.
  • the content of cyclodextrin in the injectable composition of the present invention is not particularly limited, but preferably a cyclodextrin having the same degree as the content of dextran may be used. That is, the content of cyclodextrin in an injectable composition containing about 50 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 20 mg to about 640 mg, more preferably about 40 mg to about 160 mg. About 80 mg is particularly preferred. Similarly, the content of cyclodextrin in an injectable composition containing about 20 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 8 mg to about 256 mg, more preferably about 16 mg to about 64 mg. About 32 mg is particularly preferred.
  • Polyvinylpyrrolidone used for the production of an injectable composition is a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone, and commercially available compounds can be used without any particular limitation.
  • the CAS number of polyvinylpyrrolidone is 9003-39-8.
  • Polyvinyl pyrrolidone may also be written as PVP. More detailed information on polyvinylpyrrolidone can be found in publicly known literatures, for example, Yakuji Nippo 2007 “Pharmaceutical Additives Encyclopedia” (edited by the Japan Pharmaceutical Additives Association), pages 253-254; 16th revised Japanese Pharmacopoeia, 1280-1281.
  • Polyvinyl pyrrolidone is classified into, for example, polyvinyl pyrrolidone K12, polyvinyl pyrrolidone K15, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K90 using the K value which is a viscosity characteristic value correlated with the molecular weight.
  • the Examples of polyvinyl pyrrolidone suitable in the present invention include polyvinyl pyrrolidone K12.
  • K value means the value calculated by applying the relative viscosity value (25 degreeC) measured with a capillary viscometer to the formula of Fikentscher.
  • polyvinyl pyrrolidone K12 As polyvinyl pyrrolidone K12 (Polyvinylpyrrolidone K12), commercially available ones can be used without particular limitation. More detailed information on the polyvinylpyrrolidone K12 is described in publicly known literature or web pages, pamphlets, catalogs, materials, etc. provided by manufacturers and suppliers.
  • the content of polyvinylpyrrolidone in the injectable composition of the present invention is not particularly limited, but preferably polyvinylpyrrolidone having the same degree as the content of dextran may be used. That is, the content of polyvinylpyrrolidone in an injectable composition containing about 50 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 20 mg to about 640 mg, more preferably about 40 mg to about 160 mg, About 80 mg is particularly preferred. Similarly, the content of polyvinylpyrrolidone in an injectable composition containing about 20 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 8 mg to about 256 mg, more preferably about 16 mg to about 64 mg. About 32 mg is particularly preferred.
  • any pH adjuster that is generally used as a pH adjuster for injections can be used without particular limitation.
  • Preferred pH adjusters include, for example, organic acids such as citric acid, tartaric acid, acetic acid, and lactic acid, inorganic acids such as hydrochloric acid and phosphoric acid, and inorganic bases such as sodium bicarbonate, sodium carbonate, and sodium hydroxide. Can be mentioned. These may be used in a solid state or may be dissolved in an appropriate medium (for example, an aqueous solvent such as water for injection) and used as a solution. A plurality of components may be combined and used as a pH adjuster. Suitable pH adjusters in the present invention include, for example, hydrochloric acid and sodium hydroxide.
  • an excipient used when producing an injectable composition in the form of a lyophilized composition for example, at least one excipient selected from saccharides and sugar alcohols can be used.
  • the saccharide is not particularly limited as long as it is a saccharide generally used as an excipient of a freeze-dried composition.
  • monosaccharides such as glucose, mannose, fructose, ribose, xylose, arabinose, galactose
  • disaccharides such as maltose, isomaltose, cellobiose, lactose, sucrose, trehalose and maltotriose.
  • the sugar alcohol is not particularly limited as long as it is a sugar alcohol generally used as an excipient for a freeze-dried composition, and examples thereof include mannitol, erythritol, inositol, and sorbitol.
  • excipients suitable in the present invention include lactose and maltose. Particularly preferred is maltose.
  • maltose commercially available ones can be used without particular limitation.
  • Maltose is a white crystal or crystalline powder and its CAS number is 69-79-4 for anhydride. Maltose is also referred to as maltose. More detailed information on maltose is described in publicly known literatures, for example, Yakuji Nippo, 2007, “Pharmaceutical Additives Encyclopedia” (edited by Japan Pharmaceutical Additives Association), page 284. In addition, an appropriate hydrate such as maltose monohydrate (CAS number: 6363-53-7) can also be used.
  • the saccharides and sugar alcohols used in the production of an injectable composition in the form of a lyophilized composition should have a content particularly if it is an amount normally used as an excipient in the production of the lyophilized composition. It can be used without limitation. In the case of maltose, for example, about 3 to about 12.6 parts by weight, preferably about 6.5 to about 7.9 parts by weight, more preferably about 7.2 parts by weight per 1 part by weight of Compound A. Part by weight is particularly preferred.
  • the content of maltose in an injectable composition containing about 50 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 150 mg to about 630 mg, more preferably about 325 mg to about 395 mg, 360 mg is particularly preferred.
  • the content of maltose in an injectable composition containing about 20 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 60 mg to about 252 mg, more preferably about 130 mg to about 158 mg, 145 mg is particularly preferred.
  • the aforementioned saccharides and sugar alcohols may be added, and other additives generally used for injections may be appropriately blended.
  • additives include 70 v / v% N-hydroxyethyl lactamide aqueous solution (N-Hydroxyethyl-LactamideactSolution), D-Sorbitol, D-Mannitol, DL- Methionine (DL-Methionine), L-Aspartic Acid (L-Aspartic® Acid), L-Alanine (L-Alanine), L-Arginine, L-Glutamate L-Lysine-L-Glutamate ), Potassium L-glutamate (Monopotassium L-Glutamate Monohydrate), sodium L-glutamate (Monosodium L-Glutamate Monohydrate), L-cystine, L-cysteine (L-Cysteine), L-histidine (L- Histidine
  • additives are used according to the purpose of use, as described in the “Pharmaceutical Additives Dictionary” (edited by the Japan Pharmaceutical Additives Association) published in 2000.
  • stabilizers, surfactants, buffers, pH adjusters, solubilizers, antioxidants, antifoaming agents, tonicity agents, emulsifiers, suspending agents, preservatives, soothing agents It can be properly used as a solubilizer, a solubilizing agent or the like.
  • these additives can be added in combination of two or more components as desired.
  • polysorbate 80 (Polysorbate 80) exemplified as one of other additives can be used as a solubilizing agent, and by adding the necessary amount thereof, the injectable composition of the present invention can be used.
  • the solubility of “compound A” or “salt of compound A” as an active ingredient can be increased.
  • polysorbate 80 a commercially available one can be used without particular limitation.
  • Polysorbate 80 is a colorless to orange-yellow viscous liquid, and its CAS number is 9005-65-6.
  • Polysorbate 80 is also referred to as Emazole 4130, Tween 80, polyoxyethylene sorbitan monooleate (20E.O.) (Polyoxyethylene 20 sorbitan monooleate). More detailed information on the polysorbate 80 is described in publicly known documents, for example, Yakuji Nipposha 2007 “Pharmaceutical Additives Encyclopedia” (edited by Japan Pharmaceutical Additives Association), page 274.
  • the injectable composition of the present invention has the above-mentioned excellent effects by using one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone as additives. It is sufficiently preferable without adding polysorbate 80. If polysorbate 80 is added, its content is preferably, for example, about 0.04 to about 0.17 parts by weight, and about 0.07 to about 0.1 parts by weight per part by weight of Compound A. Part is more preferred. That is, the content of polysorbate 80 in an injectable composition containing about 50 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 2 mg to about 8.3 mg, and preferably about 3.5 mg to about 5 mg. Is more preferable. In addition, the content of polysorbate 80 in an injectable composition containing about 20 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 0.8 mg to about 3.4 mg, preferably about 1.4 mg to About 2 mg is more preferred.
  • the injectable composition of the present invention thus produced is, as described above, (a) decomposition of compound A, (b) formation of compound C, and / or (c) composition accompanying storage of the composition. Discoloration of objects can be suppressed. These effects are noticeable when the injectable composition of the present invention is a lyophilized composition. Further, as described above, when the injectable composition of the present invention is a freeze-dried composition, in addition to these effects, (d) a property of rapid resolubility can be provided. These words are explained below.
  • Decomposition of compound A means that compound A present in the injectable composition of the present invention changes to another substance other than compound A with storage. Similarly, in the injectable composition of the present invention comprising a salt of Compound A, for example, Compound B as an active ingredient, the portion of Compound A constituting the salt is changed to another substance that is not Compound A. Means.
  • the degree of decomposition of Compound A accompanying storage can be expressed as a numerical value by comparing the amount of Compound A before storage with the amount of Compound A after storage. In the present specification, “residual ratio of compound A” is used as an index representing the degree of decomposition of compound A.
  • the residual ratio of Compound A is the amount of Compound A after storage expressed as a percentage of the amount of Compound A before storage, and the unit is percent (%).
  • the method for measuring the amount of Compound A in the composition may be any method as long as it can measure the amount of the substance. For example, as described in the Examples, high performance liquid chromatography And the method of obtaining the area percentage from the peak area of Compound A is preferred.
  • the injectable composition of the present invention can suppress the degradation of Compound A, and the residual ratio of Compound A after storage is, for example, 90% or more, preferably 93% or more, more preferably 95% or more, particularly Preferably, it can be 98% or more.
  • the production of compound C means that the compound in the composition for injection of the present invention changes from a certain substance to compound C upon storage.
  • the substance that changes to compound C is not particularly limited, but the main substance is compound A.
  • compound A in the injectable composition of the present invention decomposes upon storage and changes to another substance, but at least one of the changed substances is considered to be compound C.
  • the degree of generation of Compound C accompanying storage can be expressed as a numerical value by comparing the amount of Compound C before storage with the amount of Compound C after storage. In the present specification, “amount of compound C produced” is used as an index representing the degree of compound C production.
  • the amount of compound C produced can be determined by subtracting the amount of compound C before storage from the amount of compound C after storage, but usually compound C is contained in the injectable composition of the present invention before storage. Since it does not exist, the amount of Compound C after storage can be regarded as the amount of Compound C produced. In the present specification, the amount of compound C produced may be indicated as a percentage (%). This is based on the total peak area detected using high performance liquid chromatography as described in the Examples. The peak area of Compound C is expressed as a percentage.
  • the injectable composition of the present invention can suppress the production of Compound C, and the amount of Compound C produced after storage is, for example, less than 1%, preferably less than 0.5%, more preferably 0.2. %, Particularly preferably below the limit of detection (ie substantially not produced).
  • Discoloration of the composition means that the color of the injectable composition of the present invention changes to another color with storage.
  • the injectable composition of the present invention is in the form of an aqueous solution
  • the difference between the color of the composition before storage and the color of the composition after storage can be confirmed visually or by a color difference meter.
  • the injectable composition of the present invention is a lyophilized composition
  • the difference in color between the composition before storage and the color after storage may be confirmed visually, or redissolved respectively. You may confirm by visual observation or a color difference meter after attaching.
  • the injectable composition of the present invention suppresses its own discoloration and does not substantially undergo discoloration even after storage (that is, the color does not substantially change from that before storage).
  • Whether or not discoloration has substantially occurred before and after storage can be judged by visually checking each sample or whether the color difference ( ⁇ E) of each sample is 0.8 or less. That's fine.
  • the color difference ( ⁇ E) of the sample can be easily measured by a method known per se.
  • the standard of judgment using the color difference ( ⁇ E) is shown in Table 1. If the color difference ( ⁇ E) is 0.8 or less, it is considered that there is no color difference by visual judgment (Table 1: Nippon Denshoku Industries Co., Ltd.).
  • Rapid resolubility means “good solubility” when preparing a solution for injection by adding a solvent used for injection, such as water for injection or physiological saline, to the lyophilized composition. means. Whether or not the lyophilized composition disclosed in the present invention has rapid re-solubility can usually be determined by the rate at which the lyophilized composition dissolves in the solvent added, that is, the re-dissolution rate. In the examples described later, in order to make a simple determination, the measurement was carried out after making conditions other than the factor changed intentionally, for example, the conditions such as the type and amount of the solvent, the temperature, the presence or absence of stirring, etc.
  • the time required for re-dissolution was used as an index of the re-dissolution rate. That is, if the re-dissolution time is long, the re-dissolution rate is slow, and if the re-dissolution time is short, the re-dissolution rate is fast. Since the lyophilized composition disclosed in the present invention has a rapid re-dissolution property, it is usually within 120 seconds, preferably within 90 seconds, more preferably within 60 seconds, particularly preferably after adding the solvent. An injectable solution can be prepared within 45 seconds. The solution for injection prepared in this way is clear and insoluble fine particles are not left, so that it can be safely administered to a living body.
  • the injectable composition of the present invention contains at least one additive selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone as an additive.
  • the solubility of Compound B in a pH 3 aqueous solution not containing dextran 40 is 19.5 mg / mL, but the solubility of Compound B in a pH 3 aqueous solution containing 25 mg / mL dextran 40 is 18.9 mg / mL. mL.
  • the injectable composition of the present invention which can improve re-solubility by coexisting with dextran 40 which is not usually used as a solubilizer and does not increase the solubility of Compound B, is itself It is considered amazing.
  • “product” is an injection comprising (1) an active ingredient, compound A or a salt thereof, and one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone.
  • (2) In addition to the container containing the composition, (3) The composition is used for general anesthesia and / or sedation in combination with an appropriate combination agent as necessary. Including at least one of instructions, instructions, package inserts, or product labels (including those corresponding to labels or labeling in the United States).
  • the package insert refers to the “package insert” (sometimes referred to as a booklet) in the Pharmaceutical Affairs Law in Japan, and the “Product Information Summary (Summary of Product Characteristics: SPC)” in the EU (EU) directive. or “SmPC”) in the United States, “US package (Insert): USPI” in the federal regulations, or in other countries, the necessary items for proper use of pharmaceuticals It means an official document attached to a medicine.
  • the label means what is directly displayed on the container, and the labeling means a concept including not only the label but also printing on packaging or printed matter accompanying the product.
  • the “container” is an injectable composition containing Compound A or a salt thereof as an active ingredient and one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone. It means what directly encloses an object, and generally includes, for example, ampoules, vials, tubes, syringes for injection and the like.
  • the container containing the injectable composition is usually combined with at least one of instructions, instructions, package inserts, or product labels (including those corresponding to labels or labeling in the United States). It can be packaged in an outer container or an outer wrapper and distributed in the market.
  • the present invention also relates to a method for advertising an injectable composition
  • an injectable composition comprising Compound A as an active ingredient or a salt thereof, and one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone. Also disclosed is a method comprising encouraging the intended audience to use the composition for general anesthesia and / or sedation.
  • compound A or a salt thereof, which is an active ingredient, and one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone are contained.
  • Information describing the usefulness of using the injectable composition, particularly the health benefits, is distributed to the public. Distribution of such information is performed through an appropriate advertising medium in addition to communication in a language.
  • advertising media include newspapers, magazines, television, radio, video, brochures, leaflets, posters, social networking systems, e-mails, electronic signs, digital signage, Internet advertisements (homepages / websites, banner advertisements, etc.), Outdoor advertisement (poster board, neon sign, large vision, etc.), traffic advertisement (car, bus, taxi, etc., advertisement on window, face value advertisement, station sticker advertisement, etc.), movie / slide advertisement (cinema screen) Ads), POP ads (store ads, in-store ads, etc.), direct ads (direct mail, newspaper insert ads, flyer ads, etc.), special ads (such as novelty ads such as calendars and ballpoint pens), and other ads (sky lighting, Use anything such as bench ads) It may be. Those skilled in the art can easily manufacture these advertising media.
  • [toxicity] it is possible to reduce the risk of exposure to the living body of Compound C, which exhibits a harmful effect on the living body. Since compound C or a salt thereof is harmful to a living body, it is not useful as a pharmaceutical product per se, but safety of compound A or a salt thereof or a pharmaceutical composition containing it as an active ingredient And / or useful as a comparison or preparation for assessing stability. As described above, compound A isomerizes under storage and has a risk of forming compound C. However, in order to confirm that compound C is not formed after storage by performing an appropriate storage test, a comparison object or sample As a compound C is required.
  • the compound C as a comparison target or standard is not chemically synthesized, for example, even if the analysis chart after storage of the compound A is viewed by a technique such as high performance liquid chromatography, it cannot be determined where the peak of the compound C is. However, even if a sample after storage of Compound A is administered to a living body and any harmful action occurs, it is not possible to understand which degradation product causes the harmful action. Compound C as a comparison target or standard sample is subjected to high performance liquid chromatography under the same conditions, and by confirming the difference in peak, it can be confirmed that Compound A is isomerized under storage for the first time to produce Compound C, which is harmful.
  • Compound C is necessary for evaluating the stability of Compound A or a salt thereof or a pharmaceutical composition containing them as an active ingredient, and in view of Compound C having a harmful effect on a living body. For example, it is also necessary to evaluate the safety of a pharmaceutical composition containing Compound A or a salt thereof or an active ingredient thereof.
  • the injectable composition of the present invention contains Compound A or a salt thereof as an active ingredient, it can be used for general anesthesia or sedation. Moreover, it is not restricted to these uses, For example, it can also be used for the arbitrary uses described in the international publication 2000/069836 pamphlet and the international publication 2008/007071 pamphlet. In addition, since the residual ratio of the active ingredient can be maintained high by suppressing the production of Compound C and other decomposition products that exhibit harmful effects on the living body, it can be stored for a long period of time and is safe. It is an injectable composition suitable for clinical use. Furthermore, since the composition for injection of the present invention does not cause discoloration during storage, it can be used with confidence even after long-term storage.
  • the compound name was named by ACD / Name (version 6.00, manufactured by Advanced Chemistry Development Inc.) or Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft).
  • the point of separation by chromatography and the solvent in parentheses shown in TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • the numerical value shown in the NMR part is the measured value of 1 H-NMR when using the described measuring solvent.
  • Example 1 Preparation of methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate
  • Compound C Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate, a known compound 1,8-Diazabicyclo [5,4,0] undec-7-ene (374 ⁇ L) was added to a solution of (Compound A) (500 mg) in tetrahydrofuran (5 mL), and the reaction mixture was stirred at 60 ° C.
  • Test conditions Detector UV absorption photometer (measurement wavelength: 230 nm); Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm packed with 3 ⁇ m of octadecylsilylated silica gel for liquid chromatography; Column temperature: constant temperature around 40 ° C; Mobile phase A: 10 mmol / L potassium dihydrogen phosphate solution; Mobile phase B: methanol; Mobile phase feeding: concentration gradient control by changing the mixing ratio of mobile phase A and mobile phase B (mixing mobile phase A and mobile phase B, and the mixing ratio of mobile phase A is in the range of 30% to 50%) The concentration gradient was controlled so that Flow rate: 1.0 mL per minute.
  • M3101 Dextran 40 (DX40) (M3102) Polysorbate 80 (PS80) (M3103) HCO-60 (M3104) ⁇ -Cyclodextrin ( ⁇ -CD) (M3105) Hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) (M3106) Macrogol 4000 (M3107) Polyvinylpyrrolidone K12 (PVP-K12) (M3108) Mannitol (M3109) Sucrose (M3110) Trehalose (M3111) Dextran 70 (DX70)
  • the re-dissolution rate was judged using the time required for re-dissolution (re-dissolution time) as an index.
  • the re-dissolution time was measured by measuring three specimens for each evaluation sample and measuring the time until redissolution when 10 mL of physiological saline was added to each specimen.
  • the time required for re-dissolution is measured between 60 seconds and 300 seconds. For those that have already dissolved at the time of 60 seconds, within 60 seconds, those that have not yet dissolved at the time of 300 seconds. Was determined to be 300 seconds or more. The average value is shown below.
  • the color difference ( ⁇ E) of the re-dissolved solution is the control of the re-dissolved solution of the sample immediately after manufacture of the sample (M3101) with the smallest color change between the sample immediately after manufacture (Initial) and the sample after storage test. As measured. A color difference meter (manufactured by Konica Minolta Sensing) was used for color difference measurement. The measured values are shown below.
  • Table 4 summarizes the results of the related substances obtained above, the redissolution rate, and the color difference ( ⁇ E) of the redissolved solution.
  • ⁇ E color difference
  • a color difference exceeding 0.8 was judged to be discolored, and was described in the item of “property (color tone / appearance)” including a description of the appearance change of the freeze-dried cake.
  • the description of the “isomer” of the related substance represents Compound C
  • the description of “slow” of the re-dissolution rate was judged as “slow” when the average re-dissolution time exceeded 75 seconds.
  • dextran 40 (M3101), ⁇ -cyclodextrin (M3104), hydroxypropyl- ⁇ -cyclodextrin (M3105), polyvinyl It was found that pyrrolidone K12 (M3107) and dextran 70 (M3111) showed good results.
  • dextran 40 20mg (DX040) 40mg (DX080) 80mg (DX160) 160mg (DX320) 320mg (DX640) 640mg
  • ⁇ Analysis> The sample subjected to the storage test was redissolved in a water / acetonitrile mixture and then analyzed by high performance liquid chromatography under the test conditions described in Example 2 to compare the amount of the related substance with that of the sample immediately after production (Initial). went. Moreover, after visually observing the color tone and appearance of the freeze-dried sample, the sample was redissolved with physiological saline, and the re-dissolution time was measured as an index of the rate of re-dissolution.
  • the re-dissolution rate was judged using the time required for re-dissolution (re-dissolution time) as an index.
  • the re-dissolution time was measured by measuring three specimens for each evaluation sample and measuring the time until redissolution when 10 mL of physiological saline was added to each specimen.
  • the time required for re-dissolution is measured between 60 seconds and 300 seconds. For those that have already dissolved at the time of 60 seconds, within 60 seconds, those that have not yet dissolved at the time of 300 seconds. Was determined to be 300 seconds or more. The average value is shown below.
  • dextran 40 showed good results in the range of 20 mg to 640 mg in terms of the formation of compound C, color tone and appearance. In terms of the re-dissolution rate, dextran 40 showed good results in the range of 20 mg to 160 mg. When the amount of dextran 40 added exceeds 320 mg, the re-dissolution rate tends to be slow.
  • Test conditions Detector UV absorption photometer (measurement wavelength: 230 nm); Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm packed with 3 ⁇ m of octadecylsilylated silica gel for liquid chromatography; Column temperature: constant temperature around 40 ° C; Mobile phase A: 10 mmol / L potassium dihydrogen phosphate solution; Mobile phase B: methanol; Mobile phase liquid feeding: concentration gradient control by changing the mixing ratio of mobile phase A and mobile phase B (mixing mobile phase A and mobile phase B, and the mixing ratio of mobile phase A is in the range of 35% to 50%) The concentration gradient was controlled so that Flow rate: 1.0 mL per minute.
  • the re-dissolution rate was judged using the time required for re-dissolution (re-dissolution time) as an index.
  • the re-dissolution time was measured by measuring two specimens for each evaluation sample and measuring the time until redissolution when 10 mL of physiological saline was added to each specimen.
  • the time required for re-dissolution is measured between 60 seconds and 300 seconds. For those that have already dissolved at the time of 60 seconds, within 60 seconds, those that have not yet dissolved at the time of 300 seconds. Was determined to be 300 seconds or more. The average value is shown below.
  • An injectable composition comprising 4-yl] propanoate or a salt thereof is stable under storage and is a decomposition product of methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl)- 6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate is an injectable composition that suppresses discoloration of the composition itself, and is therefore safe without quality deterioration. Can be provided to clinical sites.

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Abstract

An injectable composition which comprises (1) a methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propanoate or a salt thereof as an active ingredient and (2) one type or more of an additive selected from the group consisting of a dextran, cyclodextrin, and polyvinyl pyrrolidone.

Description

全身麻酔および／または鎮静のための注射用組成物Injectable composition for general anesthesia and / or sedation
　本発明は、催眠鎮静剤として用いられるメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩を含有してなる注射用組成物などに関する。詳しくは、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩と、後述の添加剤とを含有してなる、再溶解性に優れ、かつ後述の保存条件による分解物の生成を抑えた変色しない凍結乾燥組成物などに関する。 The present invention relates to methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine used as a hypnotic sedative The present invention relates to an injectable composition containing -4-yl] propanoate or a salt thereof. Specifically, methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate or The present invention relates to a freeze-dried composition that contains the salt and an additive described later, has excellent resolubility, and has no discoloration and suppresses the formation of decomposition products under storage conditions described later.
　メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートは、国際公開第２０００／０６９８３６号パンフレットに記載されたベンゾジアゼピン系化合物であり、術前の鎮静、不安緩解、および手術前後の記憶消失的使用；短い診断、手術、または内視鏡検査中の意識鎮静；他の麻酔薬の投与に先立つ、かつ／または同時の全身麻酔の誘導導入および維持のための成分として；ＩＣＵ鎮静の際に静脈投与するのに有用な短時間作用性のＣＮＳ抑制薬であることが知られている。また、同化合物は、ベンゼンスルホン酸などと医薬上許容される塩を形成してもよく、それらの有効成分は許容される担体とともに注射用組成物などの非経口投与用医薬組成物の形態として用いてもよい旨が知られている。そして、かかる組成物は、水性もしくは非水性溶液、または静菌剤、抗酸化物、バッファーまたは他の医薬上許容される添加剤を含有する液体混合物であってもよく、ｐＨ２乃至４の水性酸性物質による組成物か、またはシクロデキストリン水溶液の使用による組成物のいずれかが好ましい旨記載されている（特許文献１参照）。 Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate is published internationally A benzodiazepine-based compound described in the 2000/069836 pamphlet, preoperative sedation, anxiety relief, and memory loss before and after surgery; conscious sedation during short diagnosis, surgery, or endoscopy; Known as a short-acting CNS inhibitor useful for intravenous administration during ICU sedation as a component for induction and maintenance of general anesthesia prior to and / or prior to anesthetic administration It has been. In addition, the compound may form a pharmaceutically acceptable salt with benzenesulfonic acid or the like, and those active ingredients are combined with an acceptable carrier as a form of a pharmaceutical composition for parenteral administration such as an injectable composition. It is known that it may be used. Such compositions may then be aqueous or non-aqueous solutions, or liquid mixtures containing bacteriostatic agents, antioxidants, buffers or other pharmaceutically acceptable additives and are aqueous acidic at pH 2-4 Either a composition by a substance or a composition by using a cyclodextrin aqueous solution is described as being preferable (see Patent Document 1).
　また、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩は、国際公開第２００８／００７０７１号パンフレットに記載された化合物であり、薬学的に許容される担体、賦形剤、または希釈剤と一緒に、経口、直腸、局所、口腔および非経口投与に適した薬剤組成物として提供される旨が記載されている。そして、かかる薬剤組成物は、静菌剤、抗酸化剤、緩衝剤または他の薬学的に許容される添加剤を含み得る水性もしくは非水性溶液または液体の混合物であってもよく、ｐＨ２乃至４の水性酸性媒体またはシクロデキストリンを用いた組成物であることが好ましい旨記載されている（特許文献２参照）。 In addition, methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfone Acid salts are compounds described in WO 2008/007071 and are administered orally, rectally, topically, buccally and parenterally together with a pharmaceutically acceptable carrier, excipient or diluent. It is described that it is provided as a pharmaceutical composition suitable for. Such pharmaceutical compositions may then be aqueous or non-aqueous solutions or liquid mixtures that may contain bacteriostatic agents, antioxidants, buffers or other pharmaceutically acceptable additives, pH 2-4 It is described that it is preferable to use a composition using an aqueous acidic medium or cyclodextrin (see Patent Document 2).
　しかしながら、これらの先行技術文献には、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩を含有してなる注射用組成物、特に凍結乾燥組成物を製造した場合の問題点については記載されておらず、当然ながらその解決方法についても何ら記載はない。 However, these prior art documents include methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine. -4-yl] propanoate or a salt thereof, an injectable composition, particularly a problem in the case of producing a freeze-dried composition, is not described, and of course, no solution is described. .
国際公開第２０００／０６９８３６号International Publication No. 2000/069836 国際公開第２００８／００７０７１号International Publication No. 2008/007071
　本発明者らは、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩を含有してなる注射用組成物、特に凍結乾燥組成物の形態を有するそれを製造するべく、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩を用いて種々の検討を行った結果、凍結乾燥組成物の再溶解時における前記化合物の溶解性を確保するためには、再溶解時のｐＨが３付近であることが必要で、そして再溶解時のｐＨが３付近になるように調製した凍結乾燥組成物には医薬品組成物として懸念すべき２つの大きな問題点、すなわち、前記化合物は保存中に異性化し、分解物であるメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートを生成するということ、また組成物自体には保存に伴う変色が認められるということを見出した。かかる分解物には生体に有害な作用も認められることから、保存下においてメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートを生成する組成物は、医薬品として到底好ましいものではない。 The inventors have identified methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl. In order to produce an injectable composition comprising propanoate or a salt thereof, in particular in the form of a lyophilized composition, methyl 3-[(4S) -8-bromo-1-methyl-6- (2 -Pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate As a result of various studies using benzenesulfonate, it was found that the lyophilized composition was re-dissolved. In order to ensure the solubility of the compound, it is necessary that the pH at the time of redissolution is around 3, and the lyophilized composition prepared so that the pH at the time of redissolution is around 3 is used for the pharmaceutical composition. Concern as a thing Two major problems, namely, the compound isomerized during storage and the degradation product methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2- a) [1,4] benzodiazepin-4-yl] propanoate, and the composition itself has been found to exhibit discoloration associated with storage. Since this degradation product has a harmful effect on the living body, methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,2-a] [ Compositions that produce 1,4] benzodiazepin-4-yl] propanoate are far less preferred as pharmaceuticals.
　すなわち、本発明の課題は、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩を含有してなる、再溶解性に優れ、かつ保存に伴うメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの生成を極力抑えた、変色しない凍結乾燥組成物を提供することにある。 That is, the subject of the present invention is methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine-4 -Il] propanoate or a salt thereof, which is excellent in resolubility and contains methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2 -A] It is an object to provide a lyophilized composition that does not change color and suppresses the formation of [1,4] benzodiazepin-4-yl] propanoate as much as possible.
　本発明者らは前記の問題を解決すべく鋭意検討を行った結果、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩を含有してなる凍結乾燥組成物の保存に伴うメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの生成は、添加剤としてデキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤を用いることにより抑制することができること、ならびに添加剤としてそれらを用いれば保存に伴う組成物の変色も抑制され、さらに速やかな再溶解性をも具備した凍結乾燥組成物としうることを見出した。本発明者らはこれらの知見に基づき、さらに検討を重ねることにより本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have found that methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2 -A] [1,4] benzodiazepin-4-yl] propanoate methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) upon storage of a lyophilized composition containing benzenesulfonate ) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate is produced by adding one or more selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone as an additive Can be suppressed by using an agent, and if they are used as additives, discoloration of the composition accompanying storage is also suppressed, and more rapid re-dissolution. Found that can lyophilized composition also comprises sex. Based on these findings, the present inventors completed the present invention through further studies.
　以下、具体的な態様（embodiment）を挙げて本発明を詳述するが、以降の記載において、「化合物Ａ」は「メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート」に、「化合物Ｂ」は「メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩」に、「化合物Ｃ」は「メチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート」に、それぞれ適宜読み替えが可能であるものとする。 Hereinafter, the present invention will be described in detail with specific embodiments. In the following description, “Compound A” is “methyl 3-[(4S) -8-bromo-1-methyl-6- ( 2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate ”and“ Compound B ”is“ methyl 3-[(4S) -8-bromo-1- “Methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate” and “Compound C” are “methyl 3- [8 -Bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate ”can be appropriately read as appropriate. .
　すなわち、本発明は、
［Ａ０１］（１）有効成分である化合物Ａまたはその塩と、（２）デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤とを含有してなる注射用組成物；
［Ａ０２］添加剤が、デキストラン４０、デキストラン７０、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンまたはポリビニルピロリドンＫ１２である、先の態様に記載の注射用組成物；
［Ａ０３］添加剤が、デキストラン４０である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ０４］デキストラン４０の含有量が、化合物Ａ１重量部あたり約０．４重量部乃至約１２．８重量部である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ０５］デキストラン４０の含有量が、化合物Ａ１重量部あたり約０．８重量部乃至約３．２重量部である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ０６］デキストラン４０の含有量が、化合物Ａ１重量部あたり約１．６重量部である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ０７］有効成分が化合物Ｂである、先の態様のいずれか一項に記載の注射用組成物；
［Ａ０８］組成物の保存に伴う、（ａ）化合物Ａの分解、（ｂ）化合物Ｃの生成、および／または（ｃ）組成物の変色を抑制した、先の態様のいずれか一項に記載の注射用組成物；
［Ａ０９］保存条件が、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１０］組成物の保存に伴う化合物Ａの分解を抑制した、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１１］化合物Ａの残存率が９５％以上である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１２］組成物の保存に伴う化合物Ｃの生成を抑制した、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１３］化合物Ｃが実質的に生成されないか、または化合物Ｃの生成量が０．２％未満である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１４］組成物の保存に伴う変色を抑制した、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１５］変色が実質的に起こらない、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１６］凍結乾燥組成物である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１７］組成物１単位形態あたり、化合物Ａの量として約２０ｍｇ以上の有効成分を含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１８］組成物１単位形態あたり、化合物Ａの量として約２０ｍｇの有効成分を含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ１９］組成物１単位形態あたり、約２７．２ｍｇの化合物Ｂを有効成分として含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２０］組成物１単位形態あたり、化合物Ａの量として約４０ｍｇ乃至約７０ｍｇの有効成分を含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２１］組成物１単位形態あたり、化合物Ａの量として約５０ｍｇまたは約６０ｍｇの有効成分を含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２２］組成物１単位形態あたり、化合物Ａの量として約５０ｍｇの有効成分を含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２３］組成物１単位形態あたり、約６８ｍｇの化合物Ｂを有効成分として含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２４］組成物中にマルトースを含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２５］マルトースの含有量が化合物Ａ１重量部あたり約３重量部乃至約１２．６重量部である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２６］マルトースの含有量が化合物Ａ１重量部あたり約６．５重量部乃至約７．９重量部である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２７］組成物中にｐＨ調節剤を含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２８］ｐＨ調節剤が塩酸および／または水酸化ナトリウムである、先の態様のいずれか一項に記載の注射用組成物；
［Ａ２９］ｐＨが２．５乃至３．５である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ３０］組成物中にポリソルベート８０を含有する、先の態様のいずれか一項に記載の注射用組成物；
［Ａ３１］ポリソルベート８０の含有量が化合物Ａ１重量部あたり約０．０４重量部乃至約０．１７重量部である、先の態様のいずれか一項に記載の注射用組成物；
［Ａ３２］ポリソルベート８０の含有量が化合物Ａ１重量部あたり約０．０７重量部乃至約０．１重量部である、先の態様のいずれか一項に記載の注射用組成物； That is, the present invention
[A01] An injectable composition comprising (1) compound A which is an active ingredient or a salt thereof and (2) one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone ;
[A02] The injectable composition according to the previous embodiment, wherein the additive is dextran 40, dextran 70, α-cyclodextrin, hydroxypropyl-β-cyclodextrin or polyvinylpyrrolidone K12;
[A03] The injectable composition according to any one of the preceding aspects, wherein the additive is dextran 40;
[A04] The injectable composition according to any one of the preceding embodiments, wherein the content of dextran 40 is about 0.4 to about 12.8 parts by weight per part by weight of Compound A;
[A05] The injectable composition according to any one of the preceding embodiments, wherein the content of dextran 40 is from about 0.8 to about 3.2 parts by weight per 1 part by weight of Compound A;
[A06] The injectable composition according to any one of the preceding embodiments, wherein the content of dextran 40 is about 1.6 parts by weight per part by weight of Compound A;
[A07] The injectable composition according to any one of the preceding embodiments, wherein the active ingredient is Compound B;
[A08] The composition according to any one of the preceding aspects, wherein (a) decomposition of compound A, (b) formation of compound C, and / or (c) discoloration of the composition during storage of the composition is suppressed. An injectable composition of
[A09] The preceding embodiment, wherein the storage conditions are (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 years at room temperature An injectable composition according to any one of
[A10] The injectable composition according to any one of the preceding aspects, wherein decomposition of Compound A accompanying storage of the composition is suppressed;
[A11] The composition for injection according to any one of the preceding aspects, wherein the residual ratio of compound A is 95% or more;
[A12] The injectable composition according to any one of the preceding aspects, wherein production of compound C accompanying storage of the composition is suppressed;
[A13] The injectable composition according to any one of the preceding embodiments, wherein compound C is substantially not produced or the amount of compound C produced is less than 0.2%;
[A14] The injectable composition according to any one of the preceding aspects, wherein discoloration associated with storage of the composition is suppressed;
[A15] The injectable composition according to any one of the preceding aspects, wherein substantially no discoloration occurs;
[A16] The injectable composition according to any one of the preceding aspects, which is a lyophilized composition;
[A17] The composition for injection according to any one of the preceding aspects, containing about 20 mg or more of the active ingredient as an amount of Compound A per unit form of the composition;
[A18] The injectable composition according to any one of the preceding aspects, containing about 20 mg of the active ingredient as an amount of Compound A per unit form of the composition;
[A19] The injectable composition according to any one of the preceding aspects, containing about 27.2 mg of compound B as an active ingredient per unit form of the composition;
[A20] The injectable composition according to any one of the preceding aspects, containing about 40 mg to about 70 mg of the active ingredient in an amount of Compound A per unit form of the composition;
[A21] The injectable composition according to any one of the preceding aspects, containing about 50 mg or about 60 mg of the active ingredient as an amount of Compound A per unit form of the composition;
[A22] The injectable composition according to any one of the preceding aspects, containing about 50 mg of the active ingredient in an amount of Compound A per unit form of the composition;
[A23] The injectable composition according to any one of the preceding aspects, containing about 68 mg of compound B as an active ingredient per unit form of the composition;
[A24] The injectable composition according to any one of the preceding aspects, wherein maltose is contained in the composition;
[A25] The injectable composition according to any one of the preceding embodiments, wherein the content of maltose is about 3 parts by weight to about 12.6 parts by weight per 1 part by weight of compound A;
[A26] The injectable composition according to any one of the preceding embodiments, wherein the maltose content is about 6.5 parts by weight to about 7.9 parts by weight per part by weight of Compound A;
[A27] The injectable composition according to any one of the preceding aspects, comprising a pH adjuster in the composition;
[A28] The injectable composition according to any one of the preceding embodiments, wherein the pH regulator is hydrochloric acid and / or sodium hydroxide;
[A29] The injectable composition according to any one of the preceding aspects, wherein the pH is 2.5 to 3.5;
[A30] The injectable composition according to any one of the preceding aspects, comprising polysorbate 80 in the composition;
[A31] The injectable composition according to any one of the preceding embodiments, wherein the content of polysorbate 80 is about 0.04 to about 0.17 parts by weight per 1 part by weight of Compound A;
[A32] The injectable composition according to any one of the preceding embodiments, wherein the content of polysorbate 80 is about 0.07 parts by weight to about 0.1 parts by weight per part by weight of Compound A;
［Ｂ０１］組成物１単位形態あたり、有効成分である約２７．２ｍｇの化合物Ｂと、約１６ｍｇ乃至約６４ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ０２］組成物１単位形態あたり、有効成分である約２７．２ｍｇの化合物Ｂと、約１６ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ０３］組成物１単位形態あたり、有効成分である約２７．２ｍｇの化合物Ｂと、約２４ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ０４］組成物１単位形態あたり、有効成分である約２７．２ｍｇの化合物Ｂと、約３２ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ０５］組成物１単位形態あたり、有効成分である約２７．２ｍｇの化合物Ｂと、約４０ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ０６］組成物１単位形態あたり、有効成分である約２７．２ｍｇの化合物Ｂと、約４８ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ０７］組成物１単位形態あたり、有効成分である約２７．２ｍｇの化合物Ｂと、約５６ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ０８］組成物１単位形態あたり、有効成分である約２７．２ｍｇの化合物Ｂと、約６４ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ０９］さらに、約１４５ｍｇのマルトースを含有する、先の態様のいずれか一項に記載の凍結乾燥組成物；
［Ｂ１０］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約４０ｍｇ乃至約１６０ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ１１］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約４０ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ１２］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約６０ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ１３］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約８０ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ１４］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約１００ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ１５］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約１２０ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ１６］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約１４０ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ１７］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約１６０ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物；
［Ｂ１８］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約８０ｍｇのデキストラン７０とを含有してなる凍結乾燥組成物；
［Ｂ１９］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約８０ｍｇのα－シクロデキストリンとを含有してなる凍結乾燥組成物；
［Ｂ２０］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約８０ｍｇのヒドロキシプロピル－β－シクロデキストリンとを含有してなる凍結乾燥組成物；
［Ｂ２１］組成物１単位形態あたり、有効成分である約６８ｍｇの化合物Ｂと、約８０ｍｇのポリビニルピロリドンＫ１２とを含有してなる凍結乾燥組成物；
［Ｂ２２］さらに、約３６０ｍｇのマルトースを含有する、先の態様のいずれか一項に記載の凍結乾燥組成物； [B01] A lyophilized composition comprising about 27.2 mg of Compound B as an active ingredient and about 16 mg to about 64 mg of dextran 40 per unit form of the composition;
[B02] A lyophilized composition comprising about 27.2 mg of Compound B as an active ingredient and about 16 mg of dextran 40 per unit form of the composition;
[B03] A lyophilized composition comprising about 27.2 mg of compound B as an active ingredient and about 24 mg of dextran 40 per unit form of the composition;
[B04] A lyophilized composition comprising about 27.2 mg of the active ingredient Compound B and about 32 mg of dextran 40 per unit form of the composition;
[B05] A lyophilized composition comprising about 27.2 mg of compound B as an active ingredient and about 40 mg of dextran 40 per unit form of the composition;
[B06] A lyophilized composition comprising about 27.2 mg of compound B as an active ingredient and about 48 mg of dextran 40 per unit form of the composition;
[B07] A lyophilized composition comprising about 27.2 mg of Compound B as an active ingredient and about 56 mg of dextran 40 per unit form of the composition;
[B08] A lyophilized composition comprising about 27.2 mg of compound B as an active ingredient and about 64 mg of dextran 40 per unit form of the composition;
[B09] The lyophilized composition of any one of the previous embodiments, further comprising about 145 mg maltose;
[B10] A lyophilized composition comprising about 68 mg of Compound B as an active ingredient and about 40 mg to about 160 mg of dextran 40 per unit form of the composition;
[B11] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 40 mg of dextran 40 per unit form of the composition;
[B12] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 60 mg of dextran 40 per unit form of the composition;
[B13] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 80 mg of dextran 40 per unit form of the composition;
[B14] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 100 mg of dextran 40 per unit form of the composition;
[B15] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 120 mg of dextran 40 per unit form of the composition;
[B16] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 140 mg of dextran 40 per unit form of the composition;
[B17] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 160 mg of dextran 40 per unit form of the composition;
[B18] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 80 mg of dextran 70 per unit form of the composition;
[B19] A lyophilized composition comprising about 68 mg of Compound B as an active ingredient and about 80 mg of α-cyclodextrin per unit form of the composition;
[B20] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 80 mg of hydroxypropyl-β-cyclodextrin per unit form of the composition;
[B21] A lyophilized composition comprising about 68 mg of compound B as an active ingredient and about 80 mg of polyvinylpyrrolidone K12 per unit form of the composition;
[B22] The lyophilized composition according to any one of the previous embodiments, further comprising about 360 mg of maltose;
［Ｃ０１］（１）有効成分である化合物Ａまたはその塩と、（２）デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤とを含有してなる水溶液；
［Ｃ０２］添加剤が、デキストラン４０、デキストラン７０、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンまたはポリビニルピロリドンＫ１２である、先の態様に記載の水溶液；
［Ｃ０３］添加剤が、デキストラン４０である、先の態様のいずれか一項に記載の水溶液；
［Ｃ０４］デキストラン４０の含有量が、化合物Ａ１重量部あたり約０．４重量部乃至約１２．８重量部である、先の態様のいずれか一項に記載の水溶液；
［Ｃ０５］デキストラン４０の含有量が、化合物Ａ１重量部あたり約０．８重量部乃至約３．２重量部である、先の態様のいずれか一項に記載の水溶液；
［Ｃ０６］デキストラン４０の含有量が、化合物Ａ１重量部あたり約１．６重量部である、先の態様のいずれか一項に記載の水溶液；
［Ｃ０７］有効成分が化合物Ｂである、先の態様のいずれか一項に記載の水溶液；
［Ｃ０８］組成物の保存に伴う、（ａ）化合物Ａの分解、（ｂ）化合物Ｃの生成、および／または（ｃ）組成物の変色を抑制した注射用組成物の調製のための、先の態様のいずれか一項に記載の水溶液；
［Ｃ０９］保存条件が、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間である、先の態様のいずれか一項に記載の水溶液；
［Ｃ１０］組成物の保存に伴う化合物Ａの分解を抑制した注射用組成物の調製のための、先の態様のいずれか一項に記載の水溶液；
［Ｃ１１］化合物Ａの残存率が９５％以上である注射用組成物の調製のための、先の態様のいずれか一項に記載の水溶液；
［Ｃ１２］組成物の保存に伴う化合物Ｃの生成を抑制した注射用組成物の調製のための、先の態様のいずれか一項に記載の水溶液；
［Ｃ１３］化合物Ｃが実質的に生成されないか、または化合物Ｃの生成量が０．２％未満である注射用組成物の調製のための、先の態様のいずれか一項に記載の水溶液；
［Ｃ１４］組成物の保存に伴う変色を抑制した凍結乾燥組成物の調製のための、先の態様のいずれか一項に記載の水溶液；
［Ｃ１５］変色が実質的に起こらない注射用組成物の調製のための、先の態様のいずれか一項に記載の水溶液；
［Ｃ１６］凍結乾燥組成物の調製のための、先の態様のいずれか一項に記載の水溶液；
［Ｃ１７］さらにマルトースと、所望によってポリソルベート８０を含有し、ｐＨ調節剤にてｐＨ２．５乃至３．５に調節してなる、先の態様のいずれか一項に記載の水溶液；
［Ｃ１８］組成物１単位形態あたり、化合物Ａの量として約２０ｍｇ以上の有効成分を含有する、先の態様のいずれか一項に記載の水溶液；
［Ｃ１９］組成物１単位形態あたり、化合物Ａの量として約２０ｍｇの有効成分を含有する、先の態様のいずれか一項に記載の水溶液；
［Ｃ２０］組成物１単位形態あたり、約２７．２ｍｇの化合物Ｂを有効成分として含有する、先の態様のいずれか一項に記載の水溶液；
［Ｃ２１］組成物１単位形態あたり、化合物Ａの量として約４０ｍｇ乃至約７０ｍｇの有効成分を含有する、先の態様のいずれか一項に記載の水溶液；
［Ｃ２２］組成物１単位形態あたり、化合物Ａの量として約５０ｍｇまたは約６０ｍｇの有効成分を含有する、先の態様のいずれか一項に記載の水溶液；
［Ｃ２３］組成物１単位形態あたり、化合物Ａの量として約５０ｍｇの有効成分を含有する、先の態様のいずれか一項に記載の水溶液；
［Ｃ２４］組成物１単位形態あたり、約６８ｍｇの化合物Ｂを有効成分として含有する、先の態様のいずれか一項に記載の水溶液；
［Ｃ２５］先の態様のいずれか一項に記載の水溶液を凍結乾燥してなる凍結乾燥組成物；
［Ｃ２６］先の態様のいずれか一項に記載の凍結乾燥組成物を、注射用水または生理食塩液で再溶解してなる注射用溶液； [C01] (1) An aqueous solution containing Compound A or a salt thereof as an active ingredient, and (2) one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone;
[C02] the aqueous solution according to the preceding embodiment, wherein the additive is dextran 40, dextran 70, α-cyclodextrin, hydroxypropyl-β-cyclodextrin or polyvinylpyrrolidone K12;
[C03] The aqueous solution according to any one of the preceding embodiments, wherein the additive is dextran 40;
[C04] The aqueous solution according to any one of the preceding embodiments, wherein the content of dextran 40 is from about 0.4 to about 12.8 parts by weight per part by weight of Compound A;
[C05] The aqueous solution according to any one of the preceding embodiments, wherein the content of dextran 40 is from about 0.8 to about 3.2 parts by weight per part by weight of Compound A;
[C06] The aqueous solution according to any one of the preceding embodiments, wherein the content of dextran 40 is about 1.6 parts by weight per part by weight of Compound A;
[C07] The aqueous solution according to any one of the preceding embodiments, wherein the active ingredient is Compound B;
[C08] For preparation of an injectable composition in which (a) decomposition of compound A, (b) formation of compound C, and / or (c) discoloration of the composition is suppressed upon storage of the composition An aqueous solution according to any one of the embodiments;
[C09] The preceding embodiment, wherein the storage conditions are (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 years at room temperature An aqueous solution according to any one of
[C10] The aqueous solution according to any one of the preceding embodiments for the preparation of an injectable composition in which decomposition of Compound A during storage of the composition is suppressed;
[C11] The aqueous solution according to any one of the preceding embodiments for the preparation of an injectable composition, wherein the residual ratio of compound A is 95% or more;
[C12] The aqueous solution according to any one of the preceding aspects, for the preparation of an injectable composition that suppresses the formation of Compound C accompanying storage of the composition;
[C13] The aqueous solution according to any one of the preceding embodiments, for the preparation of an injectable composition wherein substantially no compound C is produced or the amount of compound C produced is less than 0.2%;
[C14] The aqueous solution according to any one of the preceding embodiments for the preparation of a lyophilized composition in which discoloration associated with storage of the composition is suppressed;
[C15] The aqueous solution according to any one of the preceding embodiments, for the preparation of an injectable composition wherein substantially no discoloration occurs;
[C16] An aqueous solution according to any one of the preceding embodiments for the preparation of a lyophilized composition;
[C17] The aqueous solution according to any one of the preceding aspects, further comprising maltose and, optionally, polysorbate 80, adjusted to pH 2.5 to 3.5 with a pH adjuster;
[C18] The aqueous solution according to any one of the preceding embodiments, containing about 20 mg or more of the active ingredient as the amount of Compound A per unit form of the composition;
[C19] The aqueous solution according to any one of the preceding embodiments, containing about 20 mg of active ingredient in an amount of Compound A per unit form of the composition;
[C20] The aqueous solution according to any one of the preceding embodiments, containing about 27.2 mg of compound B as an active ingredient per unit form of the composition;
[C21] The aqueous solution according to any one of the preceding embodiments, containing about 40 mg to about 70 mg of the active ingredient as the amount of Compound A per unit form of the composition;
[C22] The aqueous solution according to any one of the preceding embodiments, containing about 50 mg or about 60 mg of active ingredient as an amount of Compound A per unit form of the composition;
[C23] The aqueous solution according to any one of the preceding embodiments, containing about 50 mg of active ingredient in an amount of Compound A per unit form of the composition;
[C24] The aqueous solution according to any one of the preceding embodiments, containing about 68 mg of compound B as an active ingredient per unit form of the composition;
[C25] A lyophilized composition obtained by lyophilizing the aqueous solution according to any one of the preceding embodiments;
[C26] An injectable solution obtained by re-dissolving the lyophilized composition according to any one of the preceding aspects with water for injection or physiological saline;
［Ｄ０１］デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤を注射用組成物中に含有せしめることを特徴とする、化合物Ａまたはその塩を含有する安定な注射用組成物の製造方法；
［Ｄ０２］添加剤が、デキストラン４０、デキストラン７０、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンまたはポリビニルピロリドンＫ１２である、先の態様に記載の製造方法；
［Ｄ０３］添加剤が、デキストラン４０である、先の態様のいずれか一項に記載の製造方法；
［Ｄ０４］デキストラン４０の含有量が、化合物Ａ１重量部あたり約０．４重量部乃至約１２．８重量部である、先の態様のいずれか一項に記載の製造方法；
［Ｄ０５］デキストラン４０の含有量が、化合物Ａ１重量部あたり約０．８重量部乃至約３．２重量部である、先の態様のいずれか一項に記載の製造方法；
［Ｄ０６］デキストラン４０の含有量が、化合物Ａ１重量部あたり約１．６重量部である、先の態様のいずれか一項に記載の製造方法；
［Ｄ０７］化合物Ｂを含有する安定な注射用組成物の製造方法である、先の態様のいずれか一項に記載の製造方法；
［Ｄ０８］組成物の保存に伴う、（ａ）化合物Ａの分解、（ｂ）化合物Ｃの生成、および／または（ｃ）組成物の変色を抑制した注射用組成物の製造方法である、先の態様のいずれか一項に記載の製造方法；
［Ｄ０９］保存条件が、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間である、先の態様のいずれか一項に記載の製造方法；
［Ｄ１０］組成物の保存に伴う化合物Ａの分解を抑制した注射用組成物の製造方法である、先の態様のいずれか一項に記載の製造方法；
［Ｄ１１］化合物Ａの残存率が９５％以上である注射用組成物の製造方法である、先の態様のいずれか一項に記載の製造方法；
［Ｄ１２］組成物の保存に伴う化合物Ｃの生成を抑制した注射用組成物の製造方法である、先の態様のいずれか一項に記載の製造方法；
［Ｄ１３］化合物Ｃが実質的に生成されないか、または化合物Ｃの生成量が０．２％未満である注射用組成物の製造方法である、先の態様のいずれか一項に記載の製造方法；
［Ｄ１４］組成物の保存に伴う変色を抑制した注射用組成物の製造方法である、先の態様のいずれか一項に記載の製造方法；
［Ｄ１５］変色が実質的に起こらない注射用組成物の製造方法である、先の態様のいずれか一項に記載の製造方法；
［Ｄ１６］注射用組成物が凍結乾燥組成物である、先の態様のいずれか一項に記載の製造方法； [D01] One or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone are contained in an injectable composition, and stable injectable containing Compound A or a salt thereof A method for producing the composition;
[D02] The production method according to the previous embodiment, wherein the additive is dextran 40, dextran 70, α-cyclodextrin, hydroxypropyl-β-cyclodextrin, or polyvinylpyrrolidone K12;
[D03] The production method according to any one of the preceding aspects, wherein the additive is dextran 40;
[D04] The production method according to any one of the preceding embodiments, wherein the content of dextran 40 is about 0.4 to about 12.8 parts by weight per part by weight of Compound A;
[D05] The production method according to any one of the preceding embodiments, wherein the content of dextran 40 is from about 0.8 to about 3.2 parts by weight per part by weight of Compound A;
[D06] The production method according to any one of the preceding embodiments, wherein the content of dextran 40 is about 1.6 parts by weight per 1 part by weight of Compound A;
[D07] The production method according to any one of the preceding aspects, which is a production method of a stable injectable composition containing Compound B;
[D08] A method for producing an injectable composition wherein (a) decomposition of compound A, (b) formation of compound C, and / or (c) discoloration of the composition is suppressed, which is accompanied by storage of the composition. The production method according to any one of the aspects of the invention;
[D09] The previous embodiment, wherein the storage conditions are (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 years at room temperature The manufacturing method as described in any one of these;
[D10] The production method according to any one of the preceding aspects, which is a production method of an injectable composition in which decomposition of Compound A accompanying storage of the composition is suppressed;
[D11] The production method according to any one of the preceding aspects, which is a method for producing an injectable composition, wherein the residual ratio of compound A is 95% or more;
[D12] The production method according to any one of the preceding aspects, which is a production method of an injectable composition in which production of compound C accompanying storage of the composition is suppressed;
[D13] The production method according to any one of the preceding aspects, wherein the compound C is substantially not produced, or the production amount of the compound C is less than 0.2%. ;
[D14] The production method according to any one of the preceding aspects, which is a production method of an injectable composition in which discoloration associated with storage of the composition is suppressed;
[D15] The production method according to any one of the preceding aspects, which is a production method of an injectable composition in which discoloration does not substantially occur;
[D16] The production method according to any one of the preceding embodiments, wherein the injectable composition is a lyophilized composition;
［Ｅ０１］デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤を含有してなる、化合物Ａまたはその塩の安定化剤；
［Ｅ０２］添加剤が、デキストラン４０、デキストラン７０、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンまたはポリビニルピロリドンＫ１２である、先の態様に記載の安定化剤；
［Ｅ０３］添加剤が、デキストラン４０である、先の態様のいずれか一項に記載の安定化剤；
［Ｅ０４］デキストラン４０の含有量が、化合物Ａ１重量部あたり約０．４重量部乃至約１２．８重量部である、先の態様のいずれか一項に記載の安定化剤；
［Ｅ０５］デキストラン４０の含有量が、化合物Ａ１重量部あたり約０．８重量部乃至約３．２重量部である、先の態様のいずれか一項に記載の安定化剤；
［Ｅ０６］デキストラン４０の含有量が、化合物Ａ１重量部あたり約１．６重量部である、先の態様のいずれか一項に記載の安定化剤；
［Ｅ０７］化合物Ｂの安定化剤である、先の態様のいずれか一項に記載の安定化剤；
［Ｅ０８］安定化が、組成物の保存に伴う、（ａ）化合物Ａの分解抑制、（ｂ）化合物Ｃの生成抑制、および／または（ｃ）組成物の変色抑制である、先の態様のいずれか一項に記載の安定化剤；
［Ｅ０９］保存条件が、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間である、先の態様のいずれか一項に記載の安定化剤；
［Ｅ１０］組成物の保存に伴う化合物Ａの分解を抑制する、先の態様のいずれか一項に記載の安定化剤；
［Ｅ１１］化合物Ａの残存率を９５％以上とする、先の態様のいずれか一項に記載の安定化剤；
［Ｅ１２］組成物の保存に伴う化合物Ｃの生成を抑制する、先の態様のいずれか一項に記載の安定化剤；
［Ｅ１３］化合物Ｃを実質的に生成させないか、または化合物Ｃの生成量を０．２％未満とする、先の態様のいずれか一項に記載の安定化剤；
［Ｅ１４］組成物の保存に伴う変色を抑制する、先の態様のいずれか一項に記載の安定化剤；
［Ｅ１５］変色を実質的に起こさせない、先の態様のいずれか一項に記載の安定化剤；
［Ｅ１６］有効成分として化合物Ａまたはその塩を含有してなる注射用組成物における安定化剤である、先の態様のいずれか一項に記載の安定化剤；
［Ｅ１７］化合物Ａまたはその塩を含有する水性溶液もしくはそれを凍結乾燥してなる凍結乾燥組成物中における安定化剤である、先の態様のいずれか一項に記載の安定化剤； [E01] A stabilizer for compound A or a salt thereof, comprising one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone;
[E02] The stabilizer according to the preceding embodiment, wherein the additive is dextran 40, dextran 70, α-cyclodextrin, hydroxypropyl-β-cyclodextrin or polyvinylpyrrolidone K12;
[E03] The stabilizer according to any one of the previous embodiments, wherein the additive is dextran 40;
[E04] The stabilizer according to any one of the preceding embodiments, wherein the content of dextran 40 is about 0.4 to about 12.8 parts by weight per part by weight of Compound A;
[E05] The stabilizer according to any one of the preceding embodiments, wherein the content of dextran 40 is from about 0.8 to about 3.2 parts by weight per part by weight of Compound A;
[E06] The stabilizer according to any one of the previous embodiments, wherein the content of dextran 40 is about 1.6 parts by weight per part by weight of Compound A;
[E07] The stabilizer according to any one of the preceding embodiments, which is a stabilizer for compound B;
[E08] In the above aspect, the stabilization is (a) suppression of decomposition of compound A, (b) suppression of formation of compound C, and / or (c) suppression of discoloration of the composition, associated with storage of the composition. The stabilizer according to any one of the above;
[E09] The preceding embodiment, wherein the storage conditions are (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 years at room temperature A stabilizer according to any one of
[E10] The stabilizer according to any one of the preceding aspects, which suppresses the decomposition of Compound A accompanying storage of the composition;
[E11] The stabilizer according to any one of the preceding aspects, wherein the residual ratio of compound A is 95% or more;
[E12] The stabilizer according to any one of the preceding aspects, which suppresses the production of Compound C accompanying storage of the composition;
[E13] The stabilizer according to any one of the preceding embodiments, wherein the stabilizer does not substantially produce Compound C, or the production amount of Compound C is less than 0.2%;
[E14] The stabilizer according to any one of the preceding aspects, which suppresses discoloration associated with storage of the composition;
[E15] The stabilizer according to any one of the preceding embodiments, which does not substantially cause discoloration;
[E16] The stabilizer according to any one of the preceding aspects, which is a stabilizer in an injectable composition comprising Compound A or a salt thereof as an active ingredient;
[E17] The stabilizer according to any one of the preceding embodiments, which is a stabilizer in an aqueous solution containing Compound A or a salt thereof or a lyophilized composition obtained by lyophilizing the same;
［Ｆ０１］デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤を用いることを特徴とする、化合物Ａまたはその塩の安定化方法；
［Ｆ０２］添加剤が、デキストラン４０、デキストラン７０、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンまたはポリビニルピロリドンＫ１２である、先の態様に記載の安定化方法；
［Ｆ０３］添加剤が、デキストラン４０である、先の態様のいずれか一項に記載の安定化方法；
［Ｆ０４］デキストラン４０の使用量が、化合物Ａ１重量部あたり約０．４重量部乃至約１２．８重量部である、先の態様のいずれか一項に記載の安定化方法；
［Ｆ０５］デキストラン４０の使用量が、化合物Ａ１重量部あたり約０．８重量部乃至約３．２重量部である、先の態様のいずれか一項に記載の安定化方法；
［Ｆ０６］デキストラン４０の使用量が、化合物Ａ１重量部あたり約１．６重量部である、先の態様のいずれか一項に記載の安定化方法；
［Ｆ０７］化合物Ｂの安定化方法である、先の態様のいずれか一項に記載の安定化方法；
［Ｆ０８］安定化が、組成物の保存に伴う、（ａ）化合物Ａの分解抑制、（ｂ）化合物Ｃの生成抑制、および／または（ｃ）組成物の変色抑制である、先の態様のいずれか一項に記載の安定化方法；
［Ｆ０９］保存条件が、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間である、先の態様のいずれか一項に記載の安定化方法；
［Ｆ１０］組成物の保存に伴う化合物Ａの分解を抑制する、先の態様のいずれか一項に記載の安定化方法；
［Ｆ１１］化合物Ａの残存率を９５％以上とする、先の態様のいずれか一項に記載の安定化方法；
［Ｆ１２］組成物の保存に伴う化合物Ｃの生成を抑制する、先の態様のいずれか一項に記載の安定化方法；
［Ｆ１３］化合物Ｃを実質的に生成させないか、または化合物Ｃの生成量を０．２％未満とする、先の態様のいずれか一項に記載の安定化方法；
［Ｆ１４］組成物の保存に伴う変色を抑制する、先の態様のいずれか一項に記載の安定化方法；
［Ｆ１５］変色を実質的に起こさせない、先の態様のいずれか一項に記載の安定化方法；
［Ｆ１６］有効成分として化合物Ａまたはその塩を含有してなる注射用組成物における安定化方法である、先の態様のいずれか一項に記載の安定化方法；
［Ｆ１７］化合物Ａまたはその塩を含有する水性溶液もしくはそれを凍結乾燥してなる凍結乾燥組成物中における安定化方法である、先の態様のいずれか一項に記載の安定化方法； [F01] A method for stabilizing Compound A or a salt thereof, comprising using one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone;
[F02] The stabilization method according to the previous embodiment, wherein the additive is dextran 40, dextran 70, α-cyclodextrin, hydroxypropyl-β-cyclodextrin or polyvinylpyrrolidone K12;
[F03] The stabilization method according to any one of the preceding embodiments, wherein the additive is dextran 40;
[F04] The stabilization method according to any one of the preceding embodiments, wherein the amount of dextran 40 used is about 0.4 to about 12.8 parts by weight per part by weight of Compound A;
[F05] The stabilization method according to any one of the preceding embodiments, wherein the amount of dextran 40 used is about 0.8 to about 3.2 parts by weight per part by weight of Compound A;
[F06] The stabilization method according to any one of the preceding embodiments, wherein the amount of dextran 40 used is about 1.6 parts by weight per part by weight of Compound A;
[F07] The stabilization method according to any one of the preceding embodiments, which is a stabilization method of Compound B;
[F08] In the previous embodiment, the stabilization is (a) suppression of decomposition of compound A, (b) suppression of formation of compound C, and / or (c) suppression of discoloration of the composition, which is accompanied by storage of the composition. The stabilization method according to any one of the above;
[F09] The preceding embodiment, wherein the storage conditions are (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 years at room temperature The stabilization method according to any one of
[F10] The stabilization method according to any one of the preceding embodiments, which suppresses the decomposition of Compound A accompanying storage of the composition;
[F11] The stabilization method according to any one of the preceding aspects, wherein the residual ratio of Compound A is 95% or more;
[F12] The stabilization method according to any one of the preceding aspects, wherein the formation of Compound C accompanying storage of the composition is suppressed;
[F13] The stabilization method according to any one of the preceding embodiments, wherein substantially no compound C is produced or the amount of compound C produced is less than 0.2%;
[F14] The stabilization method according to any one of the preceding aspects, which suppresses discoloration associated with storage of the composition;
[F15] The stabilization method according to any one of the preceding aspects, which does not substantially cause discoloration;
[F16] The stabilization method according to any one of the preceding embodiments, which is a stabilization method in an injectable composition comprising Compound A or a salt thereof as an active ingredient;
[F17] The stabilization method according to any one of the preceding embodiments, which is a stabilization method in an aqueous solution containing Compound A or a salt thereof or a freeze-dried composition obtained by freeze-drying the same;
［Ｇ０１］化合物Ａまたはその塩の安定化のための、デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤；
［Ｇ０２］添加剤が、デキストラン４０、デキストラン７０、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンまたはポリビニルピロリドンＫ１２である、先の態様に記載の添加剤；
［Ｇ０３］添加剤が、デキストラン４０である、先の態様のいずれか一項に記載の添加剤；
［Ｇ０４］デキストラン４０の使用量が、化合物Ａ１重量部あたり約０．４重量部乃至約１２．８重量部である、先の態様のいずれか一項に記載の添加剤；
［Ｇ０５］デキストラン４０の使用量が、化合物Ａ１重量部あたり約０．８重量部乃至約３．２重量部である、先の態様のいずれか一項に記載の添加剤；
［Ｇ０６］デキストラン４０の使用量が、化合物Ａ１重量部あたり約１．６重量部である、先の態様のいずれか一項に記載の添加剤；
［Ｇ０７］化合物Ｂの安定化のための、先の態様のいずれか一項に記載の添加剤；
［Ｇ０８］安定化が、組成物の保存に伴う、（ａ）化合物Ａの分解抑制、（ｂ）化合物Ｃの生成抑制、および／または（ｃ）組成物の変色抑制である、先の態様のいずれか一項に記載の添加剤；
［Ｇ０９］保存条件が、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間である、先の態様のいずれか一項に記載の添加剤；
［Ｇ１０］組成物の保存に伴う化合物Ａの分解を抑制するための、先の態様のいずれか一項に記載の添加剤；
［Ｇ１１］化合物Ａの残存率を９５％以上とするための、先の態様のいずれか一項に記載の添加剤；
［Ｇ１２］組成物の保存に伴う化合物Ｃの生成を抑制するための、先の態様のいずれか一項に記載の添加剤；
［Ｇ１３］化合物Ｃを実質的に生成させないか、または化合物Ｃの生成量を０．２％未満とするための、先の態様のいずれか一項に記載の添加剤；
［Ｇ１４］組成物の保存に伴う変色を抑制するための、先の態様のいずれか一項に記載の添加剤；
［Ｇ１５］変色を実質的に起こさせないための、先の態様のいずれか一項に記載の添加剤；
［Ｇ１６］有効成分として化合物Ａまたはその塩を含有してなる注射用組成物における化合物Ａまたはその塩の安定化のための、先の態様のいずれか一項に記載の添加剤；
［Ｇ１７］化合物Ａまたはその塩を含有する水性溶液もしくはそれを凍結乾燥してなる凍結乾燥組成物中における化合物Ａまたはその塩の安定化のための、先の態様のいずれか一項に記載の添加剤； [G01] one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone for stabilizing Compound A or a salt thereof;
[G02] The additive according to the previous embodiment, wherein the additive is dextran 40, dextran 70, α-cyclodextrin, hydroxypropyl-β-cyclodextrin or polyvinylpyrrolidone K12;
[G03] The additive according to any one of the preceding aspects, wherein the additive is dextran 40;
[G04] The additive according to any one of the preceding embodiments, wherein the amount of dextran 40 used is about 0.4 to about 12.8 parts by weight per part by weight of Compound A;
[G05] The additive according to any one of the preceding embodiments, wherein the amount of dextran 40 used is about 0.8 to about 3.2 parts by weight per part by weight of Compound A;
[G06] The additive according to any one of the previous embodiments, wherein the amount of dextran 40 used is about 1.6 parts by weight per part by weight of Compound A;
[G07] Additive according to any one of the preceding aspects, for the stabilization of compound B;
[G08] In the above aspect, the stabilization is (a) suppression of decomposition of compound A, (b) suppression of formation of compound C, and / or (c) suppression of discoloration of the composition, associated with storage of the composition. The additive according to any one of the above;
[G09] The preceding embodiment, wherein the storage conditions are (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 years at room temperature Additive according to any one of
[G10] The additive according to any one of the preceding aspects, for suppressing decomposition of Compound A accompanying storage of the composition;
[G11] The additive according to any one of the preceding aspects, for making the residual ratio of compound A 95% or more;
[G12] The additive according to any one of the preceding aspects, for suppressing the formation of Compound C accompanying storage of the composition;
[G13] The additive according to any one of the preceding aspects, so as not to substantially produce compound C or to reduce the production amount of compound C to less than 0.2%;
[G14] The additive according to any one of the preceding aspects, for suppressing discoloration associated with storage of the composition;
[G15] The additive according to any one of the preceding aspects, which does not substantially cause discoloration;
[G16] The additive according to any one of the preceding embodiments, for stabilizing Compound A or a salt thereof in an injectable composition comprising Compound A or a salt thereof as an active ingredient;
[G17] The aqueous solution containing Compound A or a salt thereof or a freeze-dried composition obtained by lyophilizing the same according to any one of the preceding embodiments for stabilizing Compound A or a salt thereof Additive;
［Ｈ０１］化合物Ａまたはその塩の安定化のための、デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤の使用；
［Ｈ０２］添加剤が、デキストラン４０、デキストラン７０、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンまたはポリビニルピロリドンＫ１２である、先の態様に記載の使用；
［Ｈ０３］添加剤が、デキストラン４０の使用である、先の態様のいずれか一項に記載の使用；
［Ｈ０４］デキストラン４０の使用量が、化合物Ａ１重量部あたり約０．４重量部乃至約１２．８重量部である、先の態様のいずれか一項に記載の使用；
［Ｈ０５］デキストラン４０の使用量が、化合物Ａ１重量部あたり約０．８重量部乃至約３．２重量部である、先の態様のいずれか一項に記載の使用；
［Ｈ０６］デキストラン４０の使用量が、化合物Ａ１重量部あたり約１．６重量部である、先の態様のいずれか一項に記載の使用；
［Ｈ０７］化合物Ｂの安定化のための、先の態様のいずれか一項に記載の使用；
［Ｈ０８］安定化が、組成物の保存に伴う、（ａ）化合物Ａの分解抑制、（ｂ）化合物Ｃの生成抑制、および／または（ｃ）組成物の変色抑制である、先の態様のいずれか一項に記載の使用；
［Ｈ０９］保存条件が、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間である、先の態様のいずれか一項に記載の使用；
［Ｈ１０］組成物の保存に伴う化合物Ａの分解を抑制するための、先の態様のいずれか一項に記載の使用；
［Ｈ１１］化合物Ａの残存率を９５％以上とするための、先の態様のいずれか一項に記載の使用；
［Ｈ１２］組成物の保存に伴う化合物Ｃの生成を抑制するための、先の態様のいずれか一項に記載の使用；
［Ｈ１３］化合物Ｃを実質的に生成させないか、または化合物Ｃの生成量を０．２％未満とするための、先の態様のいずれか一項に記載の使用；
［Ｈ１４］組成物の保存に伴う変色を抑制するための、先の態様のいずれか一項に記載の使用；
［Ｈ１５］変色を実質的に起こさせないための、先の態様のいずれか一項に記載の使用；
［Ｈ１６］有効成分として化合物Ａまたはその塩を含有してなる注射用組成物における化合物Ａまたはその塩の安定化のための、先の態様のいずれか一項に記載の使用；
［Ｈ１７］化合物Ａまたはその塩を含有する水性溶液もしくはそれを凍結乾燥してなる凍結乾燥組成物中における化合物Ａまたはその塩の安定化のための、先の態様のいずれか一項に記載の使用； [H01] Use of one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone for the stabilization of Compound A or a salt thereof;
[H02] Use according to the preceding embodiment, wherein the additive is dextran 40, dextran 70, α-cyclodextrin, hydroxypropyl-β-cyclodextrin or polyvinylpyrrolidone K12;
[H03] The use according to any one of the previous embodiments, wherein the additive is the use of dextran 40;
[H04] The use according to any one of the preceding embodiments, wherein the amount of dextran 40 used is from about 0.4 to about 12.8 parts by weight per part by weight of Compound A;
[H05] The use according to any one of the preceding embodiments, wherein the amount of dextran 40 used is from about 0.8 to about 3.2 parts by weight per part by weight of Compound A;
[H06] The use according to any one of the previous embodiments, wherein the amount of dextran 40 used is about 1.6 parts by weight per part by weight of Compound A;
[H07] Use according to any one of the preceding embodiments for the stabilization of compound B;
[H08] In the above aspect, the stabilization is (a) suppression of decomposition of compound A, (b) suppression of formation of compound C, and / or (c) suppression of discoloration of the composition, associated with storage of the composition. Use according to any one of the above;
[H09] The preceding embodiment, wherein the storage conditions are (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 years at room temperature Use according to any one of
[H10] Use according to any one of the preceding embodiments for inhibiting degradation of compound A associated with storage of the composition;
[H11] The use according to any one of the preceding embodiments to make the residual ratio of compound A 95% or more;
[H12] Use according to any one of the preceding aspects for inhibiting the formation of compound C upon storage of the composition;
[H13] The use according to any one of the preceding embodiments, so as not to substantially produce compound C or to reduce the production amount of compound C to less than 0.2%;
[H14] Use according to any one of the preceding aspects for inhibiting discoloration associated with storage of the composition;
[H15] Use according to any one of the preceding aspects, in order not to cause substantial discoloration;
[H16] The use according to any one of the preceding embodiments for stabilizing Compound A or a salt thereof in an injectable composition comprising Compound A or a salt thereof as an active ingredient;
[H17] The solution according to any one of the preceding embodiments, for stabilizing Compound A or a salt thereof in an aqueous solution containing Compound A or a salt thereof or a lyophilized composition obtained by lyophilizing the solution. use;
［Ｘ０１］化合物Ｃまたはその塩；
［Ｘ０２］化合物Ａまたはその塩もしくはそれらを有効成分として含有する医薬組成物の安全性および／または安定性を評価するための化合物Ｃまたはその塩； [X01] Compound C or a salt thereof;
[X02] Compound C or a salt thereof for evaluating the safety and / or stability of Compound A or a salt thereof or a pharmaceutical composition containing them as an active ingredient;
［Ｙ０１］（１）有効成分である化合物Ａまたはその塩とデキストラン４０とを含有してなる注射用組成物と、（２）容器と、（３）前記組成物が全身麻酔および／または鎮静のために使用することができる旨を示す、指示書、説明書、添付文書、または製品ラベルとを含む、製品；
［Ｙ０２］有効成分である化合物Ａまたはその塩とデキストラン４０とを含有してなる注射用組成物が全身麻酔および／または鎮静のために使用することができる旨を示す、指示書、説明書、添付文書、または製品ラベル； [Y01] (1) An injectable composition comprising Compound A or a salt thereof as an active ingredient and dextran 40, (2) a container, and (3) the composition is for general anesthesia and / or sedation Products, including instructions, instructions, package inserts, or product labels indicating that they can be used for
[Y02] instructions, instructions, and instructions indicating that an injectable composition comprising Compound A or a salt thereof as an active ingredient and dextran 40 can be used for general anesthesia and / or sedation; Package insert or product label;
［Ｚ０１］化合物Ｂ、デキストラン４０、マルトースおよびｐＨ調節剤を含有するｐＨ２．５乃至３．５の注射用組成物；
［Ｚ０２］化合物Ｂ、デキストラン４０、マルトースおよびｐＨ調節剤を含有するｐＨ２．５乃至３．５の注射用組成物であり、かつ、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間の保存後において、化合物Ｃが実質的に生成されないか、または化合物Ｃの生成量が０．２％未満である注射用組成物；
［Ｚ０３］ｐＨ調節剤が塩酸および／または水酸化ナトリウムである、先の態様のいずれか一項に記載の注射用組成物；
［Ｚ０４］凍結乾燥組成物である、先の態様のいずれか一項に記載の注射用組成物；
［Ｚ０５］有効成分として化合物Ｂを含有する安定な凍結乾燥組成物であって、組成物１単位形態あたり、（ａ）約２７．２ｍｇの化合物Ｂ、（ｂ）約３２ｍｇのデキストラン４０、（ｃ）約１４５ｍｇのマルトース、および（ｄ）ｐＨ調節剤を含有し、かつ、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間の保存後において、化合物Ｃが実質的に生成されないか、または化合物Ｃの生成量が０．２％未満である、ｐＨ２．５乃至３．５の凍結乾燥組成物；および
［Ｚ０６］有効成分として化合物Ｂを含有する安定な凍結乾燥組成物であって、組成物１単位形態あたり、（ａ）約６８ｍｇの化合物Ｂ、（ｂ）約８０ｍｇのデキストラン４０、（ｃ）約３６０ｍｇのマルトース、および（ｄ）ｐＨ調節剤を含有し、かつ、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間の保存後において、化合物Ｃが実質的に生成されないか、または化合物Ｃの生成量が０．２％未満である、ｐＨ２．５乃至３．５の凍結乾燥組成物；
などに関する。 [Z01] pH 2.5 to 3.5 injectable composition containing Compound B, dextran 40, maltose and pH regulator;
[Z02] An injectable composition having a pH of 2.5 to 3.5 containing Compound B, dextran 40, maltose and a pH regulator, and (1) one month at a temperature of 60 ° C. and (2) a temperature of 40 No substantial production of Compound C or less than 0.2% of Compound C produced after storage for 3 months at 0 ° C., 75% relative humidity for 6 months and / or (3) room temperature Injectable composition;
[Z03] The injectable composition according to any one of the preceding embodiments, wherein the pH adjusting agent is hydrochloric acid and / or sodium hydroxide;
[Z04] The injectable composition according to any one of the preceding aspects, which is a lyophilized composition;
[Z05] A stable lyophilized composition containing Compound B as an active ingredient, wherein (a) about 27.2 mg of Compound B, (b) about 32 mg of dextran 40, (c) per unit form of the composition ) Containing about 145 mg maltose, and (d) a pH regulator, and (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or ( 3) a lyophilized composition having a pH of 2.5 to 3.5, wherein substantially no Compound C is produced or less than 0.2% of Compound C is produced after storage for 3 years at room temperature; and [Z06] A stable lyophilized composition containing Compound B as an active ingredient, wherein (a) about 68 mg of Compound B, (b) about 80 mg of dextran 40, (c) about 360 mg of maltau And (d) a pH regulator and (1) 1 month at a temperature of 60 ° C., (2) 6 months at a temperature of 40 ° C. and 75% relative humidity, and / or (3) 3 at room temperature. A lyophilized composition having a pH of 2.5 to 3.5, wherein substantially no compound C is produced or the amount of compound C produced is less than 0.2% after years of storage;
And so on.
　本発明によって、全身麻酔および／または鎮静のために用いられるメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩を含有してなる注射用組成物、とりわけ、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間の保存下においても安定で、分解物であるメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの生成や組成物自体の変色を抑えた、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩の凍結乾燥組成物を提供することができる。かかる凍結乾燥組成物は、生体に有害な作用を有するメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートやその他の分解物の、上記の保存条件下における生成を極力抑えたものであるため安全で、しかも再溶解性に優れているため、使用に際しての利便性が極めて高い注射用組成物である。 According to the present invention, methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,2-a] [used for general anesthesia and / or sedation 1,4] benzodiazepin-4-yl] propanoate or a salt thereof, in particular, (1) one month at 60 ° C., (2) 6 at 40 ° C. and 75% relative humidity. Methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1] which is stable even under storage for 3 months at room temperature and / or (3) at room temperature for 3 years , 2-a] [1,4] benzodiazepin-4-yl] propanoate and methyl 3-[(4S) -8-bromo-1-methyl-6- (2- Pyridinyl) -4H-imida [1,2-a] [1,4] can provide a lyophilized composition benzodiazepine-4-yl] propanoate benzenesulfonate. Such lyophilized composition is a methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepine that has a harmful effect on the living body. -4-yl] Propanoate and other degradation products are safe as they are produced under the above-mentioned storage conditions, and are highly re-dissolvable. Composition.
　本発明において、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート（以下、化合物Ａと略記する場合がある。）とは、式（Ａ）：
Figure JPOXMLDOC01-appb-C000001
 で示される公知の化合物（ＣＡＳ番号：308242-62-8）であり、例えば、国際公開第２０００／０６９８３６号パンフレットの実施例Ｉｃ－８に記載されている。また、かかる化合物は、レミマゾラム（Remimazolam）またはＣＮＳ７０５６と称されることもある。 In the present invention, methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate (Hereinafter, it may be abbreviated as compound A.) is the formula (A):
Figure JPOXMLDOC01-appb-C000001
 (CAS number: 308242-62-8), which is described in Example Ic-8 of WO 2000/069836 pamphlet, for example. Such a compound may also be referred to as Remimazolam or CNS7056.
　なお、本発明においては、特に断わらない限り、当業者にとって明らかなように記号：
Figure JPOXMLDOC01-appb-C000002
 は、紙面の向こう側（すなわち、α－配置）に結合していることを表し、記号：
Figure JPOXMLDOC01-appb-C000003
 は、紙面の手前側（すなわち、β－配置）に結合していることを表し、記号：
Figure JPOXMLDOC01-appb-C000004
 は、α－配置、β－配置またはそれらの任意の割合の混合物であることを表す。 In the present invention, unless otherwise specified, the symbol:
Figure JPOXMLDOC01-appb-C000002
 Indicates binding to the other side of the page (ie, α-configuration), and the symbol:
Figure JPOXMLDOC01-appb-C000003
 Represents binding to the front side of the paper (that is, β-configuration), and symbol:
Figure JPOXMLDOC01-appb-C000004
 Represents an α-configuration, a β-configuration or a mixture thereof in any proportion.
　本発明において、化合物Ａの塩としては、例えば、塩酸塩、臭化水素酸塩、硫酸塩、硝酸塩、リン酸塩、サリチル酸塩、ｐ－トルエンスルホン酸塩、酒石酸塩、クエン酸塩、メタンスルホン酸塩、マレイン酸塩、蟻酸塩、マロン酸塩、コハク酸塩、イセチオン酸塩、ラクトビオン酸塩、ナフタレン－２－スルホン酸塩、スルファミン酸塩、エタンスルホン酸塩およびベンゼンスルホン酸塩などの、国際公開第２０００／０６９８３６号パンフレットに記載の塩などが挙げられる。 In the present invention, examples of the salt of Compound A include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, salicylate, p-toluenesulfonate, tartrate, citrate, methanesulfone. Acid salts, maleates, formates, malonates, succinates, isethionates, lactobionates, naphthalene-2-sulfonates, sulfamates, ethanesulfonates and benzenesulfonates, Examples thereof include salts described in International Publication No. 2000/069836 pamphlet.
　本発明において、化合物Ａの塩の好ましい態様の一つとしては、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩を挙げることができる。 In the present invention, one preferred embodiment of the salt of Compound A is methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate.
　本発明において、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩（以下、化合物Ｂと略記する場合がある。）とは、式（Ｂ）：
Figure JPOXMLDOC01-appb-C000005
 で示される公知の化合物（ＣＡＳ番号：1001415-66-2）であり、例えば、国際公開第２００８／００７０７１号パンフレットにベシル酸塩として記載されている。 In the present invention, methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate Benzene sulfonate (hereinafter sometimes abbreviated as compound B) refers to formula (B):
Figure JPOXMLDOC01-appb-C000005
 (CAS number: 1001415-66-2), for example, described as besylate in International Publication No. 2008/007071.
　本発明において、メチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート（以下、化合物Ｃと略記する場合がある。）とは、式（Ｃ）：
Figure JPOXMLDOC01-appb-C000006
 で示される新規な化合物である。化合物Ｃは化合物Ａまたはその塩、もしくは化合物Ｂを含有する組成物中でその分解物として生成するものであり、化合物Ａの異性化体である。化合物Ｃは生体に対して有害な作用を有しており、例えば、ラットに対する単回静脈内急速投与試験において、５ｍｇ／ｋｇの投与量では投与直後に呼吸深大や呼吸不整が、２０ｍｇ／ｋｇの投与量では投与直後に肺の出血による呼吸不全が原因と考えられる死亡例が認められることが当社で確認されている。 In the present invention, methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate (hereinafter referred to as compound) (May be abbreviated as C)) is the formula (C):
Figure JPOXMLDOC01-appb-C000006
 It is a novel compound shown by these. Compound C is formed as a decomposition product of the compound A or a salt thereof, or a composition containing compound B, and is an isomer of compound A. Compound C has a harmful effect on a living body. For example, in a single intravenous rapid administration test for rats, a dose of 5 mg / kg causes a deep breathing or irregular breathing immediately after administration, and 20 mg / kg. At this dose, we have confirmed that there are deaths that may be caused by respiratory failure due to lung bleeding immediately after administration.
　本発明において、化合物Ａ、ならびに化合物Ｂに代表されるその塩は、公知の方法、例えば、国際公開第２０００／０６９８３６号パンフレットに記載の方法、国際公開第２００８／００７０７１号パンフレットに記載の方法、国際公開第２００８／００７０８１号パンフレットに記載の方法、国際公開第２０１１／０３２６９２号パンフレットに記載の方法、国際公開第２０１２／０６２４３９号パンフレットに記載の方法、もしくはそれらに準ずる方法などを適宜組み合わせて製造することができる。また、これらの方法の他にも、一般的な方法、例えば、コンプリヘンシヴ・オーガニック・トランスフォーメーションズ：ア・ガイド・トゥ・ファンクショナル・グループ・プレパレーションズ、セカンド・エディション（Comprehensive Organic Transformations：A Guide to Functional Group Preparations、2nd Edition（Richard C. Larock，John Wiley & Sons Inc，1999））などに記載された方法、またはそれらの方法を一部改変した方法などを組み合わせて用いることでも製造することができる。 In the present invention, compound A and salts thereof typified by compound B are known methods, for example, the method described in WO2000 / 069836, the method described in WO2008 / 007071, Manufactured by appropriately combining the method described in International Publication No. 2008/007081 pamphlet, the method described in International Publication No. 2011/032692 pamphlet, the method described in International Publication No. 2012/062439 pamphlet, or a method equivalent thereto. can do. In addition to these methods, general methods such as Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Second Edition (A Manufactured by using a combination of methods described in Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)), etc. Can do.
　本発明において、化合物Ａ、ならびに化合物Ｂに代表されるその塩は、その構造から、いずれもベンゾジアゼピン系化合物に分類される。ベンゾジアゼピン系化合物とは、その構造式中に、ベンゼン環と２個の窒素原子を有する７員環とが縮合した２環式ヘテロ環の部分構造を含む化合物群の総称である。ベンゾジアゼピン系化合物には、ＧＡＢＡＡ受容体を賦活化し、クロライドイオンの流入を促進することによって催眠を誘導する作用を有するものが多く、それらはベンゾジアゼピン系催眠鎮静薬として、催眠鎮静剤（ベンゾジアゼピン系催眠鎮静剤）の有効成分に用いられている。 In the present invention, compound A and salts thereof typified by compound B are all classified as benzodiazepine compounds based on their structures. The benzodiazepine-based compound is a general term for a group of compounds including a partial structure of a bicyclic heterocycle in which a benzene ring and a seven-membered ring having two nitrogen atoms are condensed in the structural formula. Many benzodiazepine compounds have the action of inducing hypnosis by activating GABAA receptors and promoting the inflow of chloride ions, and they are hypnotic sedatives (benzodiazepine hypnotic sedatives) as benzodiazepine hypnotic sedatives. Used as an active ingredient.
　本発明において開示される「（１）有効成分である化合物Ａまたはその塩と、（２）デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤とを含有してなる注射用組成物」（以下、本発明の注射用組成物と略記する場合がある。）は、有効成分のほかに添加剤として、デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上を、好ましくはデキストラン４０、デキストラン７０、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンまたはポリビニルピロリドンＫ１２を、特に好ましくはデキストラン４０を、その組成物中に含有することを特徴とするものである。本発明の注射用組成物は、これらの添加剤を組成物中に配合することによって、かかる組成物の保存に伴う変色を抑え、組成物中における、化合物Ａの分解や化合物Ｃの生成を抑制するという効果を具備することができる。本発明の注射用組成物には、通常、当業者によって認識されるように、水溶液の形態のものと、凍結乾燥組成物の形態のものとが含まれるが、本発明の注射用組成物が凍結乾燥組成物である場合に及んでは、前記の３つの効果に加えて、速やかな再溶解性をも備えることができる。 “(1) Compound A or salt thereof as an active ingredient” disclosed in the present invention and (2) one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone The “injectable composition” (hereinafter sometimes abbreviated as the injectable composition of the present invention) is one selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone as an additive in addition to the active ingredient. The above is characterized in that it preferably contains dextran 40, dextran 70, α-cyclodextrin, hydroxypropyl-β-cyclodextrin or polyvinylpyrrolidone K12, particularly preferably dextran 40 in its composition. is there. The injectable composition of the present invention contains these additives in the composition, thereby suppressing discoloration associated with storage of the composition and suppressing decomposition of Compound A and formation of Compound C in the composition. It is possible to achieve the effect of. The injectable composition of the present invention usually includes those in the form of an aqueous solution and in the form of a lyophilized composition, as will be recognized by those skilled in the art. In the case of a freeze-dried composition, in addition to the above three effects, it can also be provided with rapid re-solubility.
　水溶液の形態の注射用組成物を製造するにあたっては、まず「（１）有効成分である化合物Ａまたはその塩と、（２）デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤とを含有してなる水溶液」（以下、本発明の水溶液と略記する場合がある。）を調製する必要がある。かかる水溶液は無菌的または非無菌的に調製され、必要に応じて、ｐＨ調節剤や他の添加剤を含んでいてもよい。なお、本発明の水溶液は、有効成分と添加剤、さらには必要に応じてｐＨ調節剤や他の添加剤の必要量を、注射用水に溶解させることで容易に調製することができる。添加や混合の操作自体は通常の製剤学的手法に従えばよい。 In producing an injectable composition in the form of an aqueous solution, first, “(1) one or more selected from the group consisting of compound A as an active ingredient or a salt thereof and (2) dextran, cyclodextrin and polyvinylpyrrolidone” It is necessary to prepare an aqueous solution containing the additive (hereinafter sometimes abbreviated as the aqueous solution of the present invention). Such an aqueous solution is prepared aseptically or non-aseptically, and may contain a pH adjuster and other additives as necessary. The aqueous solution of the present invention can be easily prepared by dissolving the active ingredients and additives, and further, if necessary, the required amounts of pH adjusters and other additives in water for injection. Addition and mixing operations may be performed in accordance with ordinary pharmaceutical methods.
　無菌的に調製された本発明の水溶液は、それ自体無菌なので、そのまま水溶液の形態の注射用組成物として使用することができる。また、非無菌的に調製された本発明の水溶液は、滅菌処理を施すことで、水溶液の形態の注射用組成物として使用することができる。これら本発明の水溶液は、通常、適当な単位形態にわけ、製剤化したうえで供給される。例えば、無菌的に調製された本発明の水溶液は、そのまま注射剤用の容器に充填して密封され、注射用液剤として製剤化されたうえで供給される。また、非無菌的に調製された本発明の水溶液は、無菌濾過したのちに注射剤用の容器に充填して密封され、あるいは注射剤用の容器に充填して密封したのちに滅菌され、注射用液剤として製剤化されたうえで供給される。 Since the aqueous solution of the present invention prepared aseptically is itself sterile, it can be used as it is as an injectable composition in the form of an aqueous solution. Moreover, the aqueous solution of the present invention prepared non-sterilely can be used as an injectable composition in the form of an aqueous solution by subjecting it to sterilization. These aqueous solutions of the present invention are usually supplied after being formulated into suitable unit forms. For example, the aqueous solution of the present invention prepared aseptically is filled in a container for injection as it is, sealed, formulated as an injection solution, and supplied. In addition, the aqueous solution of the present invention prepared non-sterilely is aseptically filtered and filled in an injection container and sealed, or filled and sealed in an injection container and sterilized and injected. It is supplied after being formulated as a liquid for use.
　凍結乾燥組成物の形態の注射用組成物は、無菌的に調製された本発明の水溶液をそのまま凍結乾燥に付すか、あるいは非無菌的に調製された本発明の水溶液に滅菌処理を施したあと凍結乾燥に付すかして製造することができる。これらは通常、適当な単位形態にわけ、製剤化したうえで供給される。例えば、無菌的に調製された本発明の水溶液は、そのまま注射剤用の容器に充填した後に凍結乾燥して密封するか、あるいはそのまま専用容器で凍結乾燥した後に直接の容器に充填して密封するかして、注射用凍結乾燥製剤として製剤化されたうえで供給される。また、非無菌的に調製された本発明の水溶液は、無菌濾過し、注射剤用の容器に充填した後に凍結乾燥して密封するか、あるいは無菌濾過し、専用容器で凍結乾燥した後に直接の容器に充填して密封するかして、注射用凍結乾燥製剤として製剤化されたうえで供給される。ここで、凍結乾燥の操作は自体公知の方法に従って行えばよい。通常、凍結乾燥は、溶解液を任意の容器で凍結した後、乾燥庫内を真空に保ちながら棚温を徐々に１次乾燥温度まで昇温し、同温度で１次乾燥を行ったのち、さらに棚温を２次乾燥温度に到達するまで昇温し、同温度で２次乾燥を行うことによって行うことができる。 The injectable composition in the form of a lyophilized composition can be prepared by subjecting the aqueous solution of the present invention prepared aseptically to lyophilization as it is, or after sterilizing the aqueous solution of the present invention prepared aseptically. It can be manufactured by freeze-drying. These are usually supplied in a suitable unit form after being formulated. For example, the aqueous solution of the present invention prepared aseptically is filled as it is into a container for injection and then freeze-dried and sealed, or it is freeze-dried as it is in a dedicated container and then directly filled into a container and sealed. Thus, it is supplied after being formulated as a freeze-dried preparation for injection. In addition, the aqueous solution of the present invention prepared non-aseptically is sterile filtered and filled in a container for injection and then freeze-dried and sealed, or sterile filtered and freeze-dried in a dedicated container and directly applied. Either filled into a container and sealed, formulated as a freeze-dried preparation for injection and supplied. Here, the freeze-drying operation may be performed according to a method known per se. Usually, freeze-drying involves freezing the lysate in an arbitrary container, then gradually raising the shelf temperature to the primary drying temperature while keeping the inside of the drying chamber vacuum, and performing the primary drying at the same temperature. Furthermore, it can carry out by heating up shelf temperature until it reaches secondary drying temperature, and performing secondary drying at the same temperature.
　当業者には容易に理解できることではあるが、本発明で開示する水溶液の形態の本発明の注射用組成物と、凍結乾燥組成物の形態の本発明の注射用組成物は、簡単な操作で相互に変換可能である。水溶液の形態の本発明の注射用組成物を凍結乾燥すれば、凍結乾燥組成物の形態の本発明の注射用組成物を得ることができる。また、凍結乾燥組成物の形態の本発明の注射用組成物に注射に用いる溶媒、例えば、注射用水または生理食塩液などを添加すれば、水溶液の形態の本発明の注射用組成物を得ることができる。 As will be readily understood by those skilled in the art, the injectable composition of the present invention in the form of an aqueous solution disclosed in the present invention and the injectable composition of the present invention in the form of a lyophilized composition can be easily handled. Mutually convertible. If the injectable composition of the present invention in the form of an aqueous solution is lyophilized, the injectable composition of the present invention in the form of a lyophilized composition can be obtained. Moreover, the injection composition of the present invention in the form of an aqueous solution can be obtained by adding a solvent used for injection, such as water for injection or physiological saline, to the injection composition of the present invention in the form of a lyophilized composition. Can do.
　本発明の注射用組成物を製造するにあたっては、それが水溶液の形態のものであれ、凍結乾燥組成物の形態のものであれ、製造の各ステップにおける手技操作自体は通常の製剤学的手法に従えばよい。 In producing the injectable composition of the present invention, regardless of whether it is in the form of an aqueous solution or in the form of a lyophilized composition, the procedure itself in each step of the production is a conventional pharmaceutical method. Just follow.
　なお、本明細書においては、本発明の注射用組成物に関してｐＨを規定する表現を行う場合がある。本発明の注射用組成物が水溶液の形態である場合、かかるｐＨの規定は通常の科学的意味に従って、その水溶液のｐＨと解すればよい。水溶液のｐＨは、例えば、薬局方（例：第十六改正日本薬局方など）に記載されたｐＨ測定法などの、自体公知の方法に従い容易に測定することができる。また、本発明の注射用組成物が凍結乾燥組成物の形態である場合、かかるｐＨの規定は前記凍結乾燥組成物を凍結乾燥に付す前の水溶液のｐＨ、もしくは前記凍結乾燥組成物を注射に用いる溶媒、例えば、注射用水または生理食塩液などを添加した再溶解液のｐＨの、いずれかの意味に解すればよい。凍結乾燥組成物の形態である本発明の注射用組成物の製造は、通常、ｐＨ調節剤を用いて所望のｐＨとした水溶液を凍結乾燥に付すことで行われる。従って、ｐＨを規定した凍結乾燥組成物の形態である本発明の注射用組成物は、ｐＨ調節剤を使用して目的とするｐＨとした水溶液を凍結乾燥して得られた注射用組成物と考えることができる。また、当業者には容易に理解できることではあるが、凍結乾燥組成物を再溶解した際の溶液のｐＨは、再溶解に用いる溶媒とその量によって変動しうる。従って、本発明においては、曖昧さを回避するために、「化合物Ａまたはその塩を含有してなるｐＨ２．５乃至３．５の凍結乾燥組成物」について、「化合物Ａまたはその塩を含有するｐＨ２．５乃至３．５の水溶液を凍結乾燥した注射用組成物」と「化合物Ａの濃度が１０ｍｇ／ｍＬとなるように注射用水または生理食塩液（好ましくは注射用水）を用いて再溶解した溶液のｐＨが２．５乃至３．５となる凍結乾燥組成物」のいずれか一方、または双方に該当するものと定義する。 In addition, in this specification, the expression which prescribes | regulates pH regarding the composition for injection of this invention may be performed. When the injectable composition of the present invention is in the form of an aqueous solution, the definition of such pH can be understood as the pH of the aqueous solution in accordance with ordinary scientific meaning. The pH of the aqueous solution can be easily measured according to a method known per se, such as a pH measurement method described in a pharmacopoeia (eg, the 16th revised Japanese pharmacopoeia). Further, when the injectable composition of the present invention is in the form of a lyophilized composition, the regulation of such pH is the pH of the aqueous solution before subjecting the lyophilized composition to lyophilization, or the lyophilized composition is injected. What is necessary is just to understand in any meaning of the pH of the redissolved solution which added the solvent to be used, for example, water for injection, or physiological saline. Production of the injectable composition of the present invention in the form of a lyophilized composition is usually carried out by subjecting an aqueous solution having a desired pH to a lyophilization using a pH adjuster. Therefore, the injectable composition of the present invention in the form of a freeze-dried composition having a defined pH is an injectable composition obtained by lyophilizing an aqueous solution having a target pH using a pH regulator. Can think. Further, as can be easily understood by those skilled in the art, the pH of the solution when the lyophilized composition is redissolved can vary depending on the solvent used for the redissolution and the amount thereof. Therefore, in the present invention, in order to avoid ambiguity, “compound A or a salt thereof is contained in the“ lyophilized composition having a pH of 2.5 to 3.5 containing compound A or a salt thereof ”. Reconstituted with water for injection or physiological saline solution (preferably water for injection) so that the concentration of Compound A is 10 mg / mL. It is defined as corresponding to one or both of the “lyophilized composition in which the pH of the solution is 2.5 to 3.5”.
　なお、本明細書においては、ｐＨ２．５乃至３．５の範囲について、「ｐＨが約３」あるいは「ｐＨが３付近」という表現をとることもある。かかる範囲においては、２．７乃至３．３が好ましく、２．９乃至３．１がより好ましく、３がとりわけ好ましい。 In this specification, the expression “pH is about 3” or “pH is around 3” is sometimes used in the range of pH 2.5 to 3.5. In such a range, 2.7 to 3.3 are preferable, 2.9 to 3.1 are more preferable, and 3 is particularly preferable.
　注射用組成物の製造に用いられる注射剤用の容器は、密封可能であり、内容物の無菌性を保つことができる容器であればどのような形態のものであってもよいが、一般的に注射剤の容器として用いられる、バイアル、アンプルなどの容器が好ましく、特にバイアルが好適である。また、これらの容器は、不溶性異物生成の有無を確認するために透明で無着色のものが好ましいが、不透明で着色されたものであっても構わない。不透明で着色された容器の場合、使用時に注射用シリンジなどで抜き取ることによって不溶性異物生成の有無を確認することができる。なお、本明細書で用いる用語「単位形態」とは、例えば、１バイアル、１アンプルなどといった調剤時、もしくは製造時の単位となる形態を意味するものと解すればよい。 The container for injection used for the production of an injectable composition may be in any form as long as it is sealable and can maintain the sterility of the contents. In addition, containers such as vials and ampoules used as containers for injections are preferred, and vials are particularly preferred. These containers are preferably transparent and uncolored in order to confirm the presence or absence of insoluble foreign matter production, but may be opaque and colored. In the case of an opaque and colored container, the presence or absence of insoluble foreign matter can be confirmed by pulling it out with a syringe for injection during use. The term “unit form” used in the present specification may be understood to mean a form that becomes a unit at the time of dispensing, such as 1 vial, 1 ampule, or the like.
　本発明の注射用組成物において、１単位形態あたりに含まれる有効成分の量は、化合物Ａの量として、約４０ｍｇ乃至約７０ｍｇが好ましく、約５０ｍｇ乃至約６０ｍｇがより好ましく、約５０ｍｇがとりわけ好ましい。また、２０ｍｇも好ましい。化合物Ａの量として約５０ｍｇを１単位形態あたりに含めようとすれば、化合物Ａであればそのまま５０ｍｇを用いればよいが、化合物の塩であれば「塩中に含まれる化合物Ａ」の量が５０ｍｇとなるように、塩を構成するカウンター（例えば、化合物Ｂであればベンゼンスルホン酸）の相当分を加算する必要がある。例えば、化合物Ａの量として５０ｍｇを含む化合物Ｂの量は、カウンター相当分を加算して、約６８ｍｇとなる。同様に、化合物Ａの量として２０ｍｇを含む化合物Ｂの量は、カウンター相当分を加算して、約２７．２ｍｇとなる。これら注射用組成物の製造に用いられる「化合物Ａ」または「化合物Ａの塩」は、結晶でも、アモルファスでも、またはいかなる形態の固体（例えば、結晶とアモルファスの混合物など）であっても構わない。 In the injectable composition of the present invention, the amount of the active ingredient contained per unit form is preferably about 40 mg to about 70 mg, more preferably about 50 mg to about 60 mg, and particularly preferably about 50 mg as the amount of Compound A. . 20 mg is also preferable. Assuming that about 50 mg is included per unit form as the amount of Compound A, 50 mg may be used as it is in the case of Compound A. However, in the case of a salt of a compound, the amount of “Compound A contained in the salt” is It is necessary to add a corresponding amount of a counter constituting the salt (for example, benzenesulfonic acid in the case of Compound B) so as to be 50 mg. For example, the amount of Compound B containing 50 mg as the amount of Compound A is about 68 mg when the counter equivalent is added. Similarly, the amount of Compound B containing 20 mg as the amount of Compound A is about 27.2 mg when the counter equivalent is added. The “compound A” or “salt of compound A” used in the production of these injectable compositions may be crystalline, amorphous, or any form of solid (for example, a mixture of crystal and amorphous). .
　注射用組成物の製造に用いられるデキストランとしては、商業的に入手可能なものを特に制限することなく使用することができるほか、例えば、乳酸菌に属するLeuconostoc mesenteroides Van Tieghemなどが生産する高分子デキストランを部分的に加水分解し、分画、精製することにより得たものも使用することもできる。デキストランのＣＡＳ番号は9004-54-0である。デキストランとしては、種々の分子量のデキストランを用いることができるが、通常、平均分子量２万以上のデキストランが好ましく、平均分子量３万以上のデキストランがより好ましい。また、デキストランの平均分子量の上限は、１００万以下が好ましく、１０万以下がより好ましい。本発明において好適なデキストランとしては、例えば、デキストラン４０、デキストラン７０などが挙げられる。 As a dextran used for the production of an injectable composition, commercially available ones can be used without particular limitation. For example, a high molecular dextran produced by Leuconostoc mesenteroides Van Tieghem belonging to lactic acid bacteria can be used. Those obtained by partial hydrolysis, fractionation and purification can also be used. The CAS number for Dextran is 9004-54-0. As dextran, dextran having various molecular weights can be used, but dextran having an average molecular weight of 20,000 or more is usually preferable, and dextran having an average molecular weight of 30,000 or more is more preferable. Further, the upper limit of the average molecular weight of dextran is preferably 1,000,000 or less, and more preferably 100,000 or less. Examples of dextran suitable for the present invention include dextran 40 and dextran 70.
　ここで、デキストラン４０（Dextran 40）やデキストラン７０（Dextran 70）としては、商業的に入手可能なものを特に制限することなく使用することができる。これらは多糖類であり、その平均分子量は、デキストラン４０が約４万、デキストラン７０が約７万である。これらデキストランに関するより詳しい情報は、公知の文献、例えば、薬事日報社２００７年刊「医薬品添加物事典」（日本医薬品添加剤協会編集）、１８２頁などに記載されている。 Here, as dextran 40 (Dextran® 40) and dextran 70 (Dextran® 70), commercially available ones can be used without any particular limitation. These are polysaccharides having an average molecular weight of about 40,000 for dextran 40 and about 70,000 for dextran 70. More detailed information on these dextrans is described in publicly known literatures, for example, Yakuji Nippo Inc. 2007 “Pharmaceutical Additives Encyclopedia” (edited by Japan Pharmaceutical Additives Association), page 182.
　本発明の注射用組成物におけるデキストランの含有量は、化合物Ａ１重量部あたり、例えば、約０．４重量部乃至約１２．８重量部が好ましく、約０．８重量部乃至約３．２重量部がより好ましく、約１．６重量部が特に好ましい。すなわち、組成物１単位形態あたり化合物Ａの量として約５０ｍｇの有効成分を含有する注射用組成物におけるデキストランの含有量は、約２０ｍｇ乃至約６４０ｍｇが好ましく、約４０ｍｇ乃至約１６０ｍｇがより好ましく、約８０ｍｇが特に好ましい。また、組成物１単位形態あたり化合物Ａの量として約２０ｍｇの有効成分を含有する注射用組成物におけるデキストランの含有量は、約８ｍｇ乃至約２５６ｍｇが好ましく、約１６ｍｇ乃至約６４ｍｇがより好ましく、約３２ｍｇが特に好ましい。 The content of dextran in the injectable composition of the present invention is preferably about 0.4 to about 12.8 parts by weight, for example, about 0.8 to about 3.2 parts by weight per part by weight of Compound A. Part is more preferred, and about 1.6 parts by weight is particularly preferred. That is, the content of dextran in an injectable composition containing about 50 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 20 mg to about 640 mg, more preferably about 40 mg to about 160 mg, 80 mg is particularly preferred. The content of dextran in an injectable composition containing about 20 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 8 mg to about 256 mg, more preferably about 16 mg to about 64 mg, 32 mg is particularly preferred.
　注射用組成物の製造に用いられるシクロデキストリンは、Ｄ－グルコースがα１→４結合で環状構造を形成したものの総称であり、商業的に入手可能なものを特に制限することなく使用することができる。例えば、α－シクロデキストリン、β－シクロデキストリン、γ－シクロデキストリンなどのほか、それらが有する水酸基のうち一部の水素原子が、直鎖または分枝鎖のアルキル基、直鎖または分枝鎖のアルケニル基、直鎖または分枝鎖のヒドロキシアルキル基、ヒドロキシアリール基、アシル基、グリコシル基、マルトシル基、イミダゾリル基などで置換されたシクロデキストリンや、分枝シクロデキストリン、シクロデキストリンの２量体あるいは多量体なども使用することができる。またグルコース単位が５以下または９以上のシクロデキストリン類縁体も同様に使用することができる。これらは単独または２種以上を組み合わせて使用してもよい。シクロデキストリンの具体的な例としては、商業的に入手することが容易な、例えば、α－シクロデキストリン、β－シクロデキストリン、γ－シクロデキストリン、メチル－β－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリン、モノアセチル－β－シクロデキストリン、トリアセチル－β－シクロデキストリン、モノクロロトリアジニル－β－シクロデキストリンなどを挙げることができる。本発明において好適なシクロデキストリンとしては、例えば、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンなどが挙げられる。 The cyclodextrin used for the production of an injectable composition is a general term for D-glucose in which a cyclic structure is formed by α1 → 4 bonds, and those that are commercially available can be used without particular limitation. . For example, in addition to α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, etc., some hydrogen atoms in the hydroxyl groups possessed by them are linear or branched alkyl groups, linear or branched Cyclodextrins substituted with alkenyl groups, linear or branched hydroxyalkyl groups, hydroxyaryl groups, acyl groups, glycosyl groups, maltosyl groups, imidazolyl groups, branched cyclodextrins, dimers of cyclodextrins or Multimers can also be used. Cyclodextrin analogues having 5 or less or 9 or more glucose units can be used in the same manner. You may use these individually or in combination of 2 or more types. Specific examples of cyclodextrins are commercially available, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclo Examples include dextrin, monoacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, and monochlorotriazinyl-β-cyclodextrin. Suitable cyclodextrins in the present invention include, for example, α-cyclodextrin, hydroxypropyl-β-cyclodextrin and the like.
　α－シクロデキストリン（α-Cyclodextrin）としては、商業的に入手可能なものを特に制限することなく使用することができる。α－シクロデキストリンは、分子量が約９７２の環状デキストリンであり、そのＣＡＳ番号は10016-20-3である。α－シクロデキストリンは、α－ＣＤやαＣＤとも表記されることがある。α－シクロデキストリンに関するより詳しい情報は、公知の文献、例えば、薬事日報社２００７年刊「医薬品添加物事典」（日本医薬品添加剤協会編集）、１２５頁などに記載されている。 As α-cyclodextrin (α-Cyclodextrin), commercially available ones can be used without particular limitation. α-Cyclodextrin is a cyclic dextrin having a molecular weight of about 972, and its CAS number is 10016-20-3. α-cyclodextrin may also be expressed as α-CD or αCD. More detailed information on α-cyclodextrin is described in publicly known documents, for example, Yakuji Nippo 2007 “Pharmaceutical Additives Encyclopedia” (edited by Japan Pharmaceutical Additives Association), page 125.
　ヒドロキシプロピル－β－シクロデキストリン（Hydroxypropyl-β-cyclodextrin）としては、商業的に入手可能なものを特に制限することなく使用することができる。ヒドロキシプロピル－β－シクロデキストリンは、分子量が約１５４１の環状デキストリンであり、そのＣＡＳ番号は128446-35-5である。ヒドロキシプロピル－β－シクロデキストリンは、ＨＰ－β－ＣＤやＨＰβＣＤとも表記されることがある。ヒドロキシプロピル－β－シクロデキストリンに関するより詳しい情報は、公知の文献などに記載されている。 As hydroxypropyl-β-cyclodextrin, commercially available ones can be used without particular limitation. Hydroxypropyl-β-cyclodextrin is a cyclic dextrin having a molecular weight of about 1541, and its CAS number is 128446-35-5. Hydroxypropyl-β-cyclodextrin may be referred to as HP-β-CD or HPβCD. More detailed information on hydroxypropyl-β-cyclodextrin is described in known literature.
　本発明の注射用組成物におけるシクロデキストリンの含有量は特に限定されないが、好適には、前記デキストランの含有量と同程度のシクロデキストリンを用いればよい。すなわち、組成物１単位形態あたり化合物Ａの量として約５０ｍｇの有効成分を含有する注射用組成物におけるシクロデキストリンの含有量は、約２０ｍｇ乃至約６４０ｍｇが好ましく、約４０ｍｇ乃至約１６０ｍｇがより好ましく、約８０ｍｇが特に好ましい。同様に、組成物１単位形態あたり化合物Ａの量として約２０ｍｇの有効成分を含有する注射用組成物におけるシクロデキストリンの含有量は、約８ｍｇ乃至約２５６ｍｇが好ましく、約１６ｍｇ乃至約６４ｍｇがより好ましく、約３２ｍｇが特に好ましい。 The content of cyclodextrin in the injectable composition of the present invention is not particularly limited, but preferably a cyclodextrin having the same degree as the content of dextran may be used. That is, the content of cyclodextrin in an injectable composition containing about 50 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 20 mg to about 640 mg, more preferably about 40 mg to about 160 mg. About 80 mg is particularly preferred. Similarly, the content of cyclodextrin in an injectable composition containing about 20 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 8 mg to about 256 mg, more preferably about 16 mg to about 64 mg. About 32 mg is particularly preferred.
　注射用組成物の製造に用いられるポリビニルピロリドンとは、Ｎ－ビニル－２－ピロリドンの重合した高分子化合物であり、商業的に入手可能なものを特に制限することなく使用することができる。ポリビニルピロリドンのＣＡＳ番号は9003-39-8である。ポリビニルピロリドンは、ＰＶＰとも表記されることがある。ポリビニルピロリドンに関するより詳しい情報は、公知の文献、例えば、薬事日報社２００７年刊「医薬品添加物事典」（日本医薬品添加剤協会編集）、２５３－２５４頁；第十六改正日本薬局方、１２８０－１２８１頁；ＴＨＥ　ＭＥＲＣＫ　ＩＮＤＥＸ（ＥＬＥＶＥＮＴＨ　ＥＤＩＴＩＯＮ）、７７００－７７０１頁などに記載されている。ポリビニルピロリドンは、分子量と相関する粘性特性値であるＫ値を用いて、例えば、ポリビニルピロリドンＫ１２、ポリビニルピロリドンＫ１５、ポリビニルピロリドンＫ１７、ポリビニルピロリドンＫ２５、ポリビニルピロリドンＫ３０、ポリビニルピロリドンＫ９０などのように分類される。本発明において好適なポリビニルピロリドンとしては、例えば、ポリビニルピロリドンＫ１２などが挙げられる。なお、Ｋ値は毛細管粘度計により測定される相対粘度値（２５℃）を、フィケンチャー（Fikentscher）の式に適用して算出される値を意味する。 Polyvinylpyrrolidone used for the production of an injectable composition is a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone, and commercially available compounds can be used without any particular limitation. The CAS number of polyvinylpyrrolidone is 9003-39-8. Polyvinyl pyrrolidone may also be written as PVP. More detailed information on polyvinylpyrrolidone can be found in publicly known literatures, for example, Yakuji Nippo 2007 “Pharmaceutical Additives Encyclopedia” (edited by the Japan Pharmaceutical Additives Association), pages 253-254; 16th revised Japanese Pharmacopoeia, 1280-1281. Page: THE MERCK INDEX (ELEVENTH EDITION), pages 7700-7701, and the like. Polyvinyl pyrrolidone is classified into, for example, polyvinyl pyrrolidone K12, polyvinyl pyrrolidone K15, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K90 using the K value which is a viscosity characteristic value correlated with the molecular weight. The Examples of polyvinyl pyrrolidone suitable in the present invention include polyvinyl pyrrolidone K12. In addition, K value means the value calculated by applying the relative viscosity value (25 degreeC) measured with a capillary viscometer to the formula of Fikentscher.
　ポリビニルピロリドンＫ１２（Polyvinylpyrrolidone K12）としては、商業的に入手可能なものを特に制限することなく使用することができる。ポリビニルピロリドンＫ１２に関するより詳しい情報は、公知の文献、あるいは製造業者や供給業者が提供するウェブページやパンフレット、カタログ、資料などに記載されている。 As polyvinyl pyrrolidone K12 (Polyvinylpyrrolidone K12), commercially available ones can be used without particular limitation. More detailed information on the polyvinylpyrrolidone K12 is described in publicly known literature or web pages, pamphlets, catalogs, materials, etc. provided by manufacturers and suppliers.
　本発明の注射用組成物におけるポリビニルピロリドンの含有量は特に限定されないが、好適には、前記デキストランの含有量と同程度のポリビニルピロリドンを用いればよい。すなわち、組成物１単位形態あたり化合物Ａの量として約５０ｍｇの有効成分を含有する注射用組成物におけるポリビニルピロリドンの含有量は、約２０ｍｇ乃至約６４０ｍｇが好ましく、約４０ｍｇ乃至約１６０ｍｇがより好ましく、約８０ｍｇが特に好ましい。同様に、組成物１単位形態あたり化合物Ａの量として約２０ｍｇの有効成分を含有する注射用組成物におけるポリビニルピロリドンの含有量は、約８ｍｇ乃至約２５６ｍｇが好ましく、約１６ｍｇ乃至約６４ｍｇがより好ましく、約３２ｍｇが特に好ましい。 The content of polyvinylpyrrolidone in the injectable composition of the present invention is not particularly limited, but preferably polyvinylpyrrolidone having the same degree as the content of dextran may be used. That is, the content of polyvinylpyrrolidone in an injectable composition containing about 50 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 20 mg to about 640 mg, more preferably about 40 mg to about 160 mg, About 80 mg is particularly preferred. Similarly, the content of polyvinylpyrrolidone in an injectable composition containing about 20 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 8 mg to about 256 mg, more preferably about 16 mg to about 64 mg. About 32 mg is particularly preferred.
　溶解液の液性を調節するために用いられるｐＨ調節剤としては、一般に注射剤のｐＨ調節剤として用いられるものであれば特に制限無く用いることができる。好ましいｐＨ調節剤としては、例えば、クエン酸、酒石酸、酢酸、乳酸などの有機酸、例えば、塩酸、リン酸などの無機酸、例えば、炭酸水素ナトリウム、炭酸ナトリウム、水酸化ナトリウムなどの無機塩基などを挙げることができる。これらは固体の状態で用いてもよいほか、適当な媒体（例えば、注射用水などの水性溶媒）に溶解し、溶液として用いてもよい。また、複数の成分を組み合わせてｐＨ調節剤として用いても構わない。本発明において好適なｐＨ調節剤としては、例えば、塩酸と水酸化ナトリウムなどが挙げられる。 As the pH adjuster used for adjusting the liquid property of the solution, any pH adjuster that is generally used as a pH adjuster for injections can be used without particular limitation. Preferred pH adjusters include, for example, organic acids such as citric acid, tartaric acid, acetic acid, and lactic acid, inorganic acids such as hydrochloric acid and phosphoric acid, and inorganic bases such as sodium bicarbonate, sodium carbonate, and sodium hydroxide. Can be mentioned. These may be used in a solid state or may be dissolved in an appropriate medium (for example, an aqueous solvent such as water for injection) and used as a solution. A plurality of components may be combined and used as a pH adjuster. Suitable pH adjusters in the present invention include, for example, hydrochloric acid and sodium hydroxide.
　凍結乾燥組成物の形態の注射用組成物を製造する際に用いられる賦形剤としては、例えば、糖類および糖アルコール類から選択される少なくとも１種類以上の賦形剤を用いることができる。ここで、糖類としては、一般に凍結乾燥組成物の賦形剤として使用されている糖類であれば特に限定されないが、例えば、グルコース、マンノース、フルクトース、リボース、キシロース、アラビノース、ガラクトースなどの単糖類や、例えば、マルトース、イソマルトース、セロビオース、ラクトース、スクロース、トレハロース、マルトトリオースなどの二糖類などを挙げることができる。糖アルコール類としては、一般に凍結乾燥組成物の賦形剤として使用されている糖アルコール類であれば特に限定されないが、例えば、マンニトール、エリスリトール、イノシトールおよびソルビトールなどを挙げることができる。本発明において好適な賦形剤としては、例えば、ラクトースやマルトースなどが挙げられる。特に好ましくは、マルトースである。 As an excipient used when producing an injectable composition in the form of a lyophilized composition, for example, at least one excipient selected from saccharides and sugar alcohols can be used. Here, the saccharide is not particularly limited as long as it is a saccharide generally used as an excipient of a freeze-dried composition. For example, monosaccharides such as glucose, mannose, fructose, ribose, xylose, arabinose, galactose, Examples thereof include disaccharides such as maltose, isomaltose, cellobiose, lactose, sucrose, trehalose and maltotriose. The sugar alcohol is not particularly limited as long as it is a sugar alcohol generally used as an excipient for a freeze-dried composition, and examples thereof include mannitol, erythritol, inositol, and sorbitol. Examples of excipients suitable in the present invention include lactose and maltose. Particularly preferred is maltose.
　マルトース（Maltose）としては、商業的に入手可能なものを特に制限することなく使用することができる。マルトースは、白色の結晶または結晶性粉末であり、そのＣＡＳ番号は、無水物で69-79-4である。マルトースはまた、麦芽糖とも称される。マルトースに関するより詳しい情報は、公知の文献、例えば、薬事日報社２００７年刊「医薬品添加物事典」（日本医薬品添加剤協会編集）、２８４頁などに記載されている。また、適当な水和物、例えば、マルトース一水和物（ＣＡＳ番号：6363-53-7）などを用いることも可能である。 As the maltose, commercially available ones can be used without particular limitation. Maltose is a white crystal or crystalline powder and its CAS number is 69-79-4 for anhydride. Maltose is also referred to as maltose. More detailed information on maltose is described in publicly known literatures, for example, Yakuji Nippo, 2007, “Pharmaceutical Additives Encyclopedia” (edited by Japan Pharmaceutical Additives Association), page 284. In addition, an appropriate hydrate such as maltose monohydrate (CAS number: 6363-53-7) can also be used.
　凍結乾燥組成物の形態の注射用組成物を製造する際に用いられる糖類や糖アルコール類は、それが凍結乾燥組成物の製造において賦形剤として通常用いられる量であれば、特に含有量を制限することなく用いることができる。マルトースの例を挙げれば、化合物Ａ１重量部あたり、例えば、約３重量部乃至約１２．６重量部が好ましく、約６．５重量部乃至約７．９重量部がより好ましく、約７．２重量部が特に好ましい。すなわち、組成物１単位形態あたり化合物Ａの量として約５０ｍｇの有効成分を含有する注射用組成物におけるマルトースの含有量は、約１５０ｍｇ乃至約６３０ｍｇが好ましく、約３２５ｍｇ乃至約３９５ｍｇがより好ましく、約３６０ｍｇが特に好ましい。また、組成物１単位形態あたり化合物Ａの量として約２０ｍｇの有効成分を含有する注射用組成物におけるマルトースの含有量は、約６０ｍｇ乃至約２５２ｍｇが好ましく、約１３０ｍｇ乃至約１５８ｍｇがより好ましく、約１４５ｍｇが特に好ましい。 The saccharides and sugar alcohols used in the production of an injectable composition in the form of a lyophilized composition should have a content particularly if it is an amount normally used as an excipient in the production of the lyophilized composition. It can be used without limitation. In the case of maltose, for example, about 3 to about 12.6 parts by weight, preferably about 6.5 to about 7.9 parts by weight, more preferably about 7.2 parts by weight per 1 part by weight of Compound A. Part by weight is particularly preferred. That is, the content of maltose in an injectable composition containing about 50 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 150 mg to about 630 mg, more preferably about 325 mg to about 395 mg, 360 mg is particularly preferred. In addition, the content of maltose in an injectable composition containing about 20 mg of the active ingredient as the amount of Compound A per unit form of the composition is preferably about 60 mg to about 252 mg, more preferably about 130 mg to about 158 mg, 145 mg is particularly preferred.
　本発明の注射用組成物の製造に際しては、前記の糖類や糖アルコール類を加えてもよいほか、一般に注射剤に使用される他の添加剤を適宜配合してもよい。このような添加剤としては、例えば、７０ｖ／ｖ％Ｎ－ヒドロキシエチルラクタマイド水溶液（N-Hydroxyethyl-Lactamide Solution）、Ｄ－ソルビトール（D-Sorbitol）、Ｄ－マンニトール（D-Mannitol）、ＤＬ－メチオニン（DL-Methionine）、Ｌ－アスパラギン酸（L-Aspartic Acid）、Ｌ－アラニン（L-Alanine）、Ｌ－アルギニン（L-Arginine）、Ｌ－グルタミン酸Ｌ－リジン（L-Lysine-L-Glutamate）、Ｌ－グルタミン酸カリウム（Monopotassium L-Glutamate Monohydrate）、Ｌ－グルタミン酸ナトリウム（Monosodium L-Glutamate Monohydrate）、Ｌ－シスチン（L-Cystine）、Ｌ－システイン（L-Cysteine）、Ｌ－ヒスチジン（L-Histidine）、Ｌ－メチオニン（L-Methionine）、Ｎ，Ｎ－ジメチルアセタミド（N,N-Dimethyl Acetamide）、アスコルビン酸（Ascorbic Acid）、アセチルトリプトファンナトリウム（Sodium Acetyl Tryptophan）、アミノエチルスルホン酸（Aminoethyl Sulfonic Acid）、アミノ酢酸（Aminoacetic Acid）、アラビアゴム（Acacia）、アラビアゴム末（Powdered Acacia）、アルファチオグリセリン（a-Thioglycerol）、アルブミン（Albumin）、イノシトール（Inositol）、エタノール（Ethanol）、エチル尿素（Ethylurea）、エチレンジアミン（Ethylenediamine）、エデト酸カルシウムナトリウム（Calcium Disodium Edetate）、エデト酸ナトリウム（Disodium Edetate）、オレイン酸（Oleic Acid）、カプリル酸ナトリウム（Sodium Caprylate）、カルメロースナトリウム（Carmellose Sodium）、キシリトール（Xylitol）、クエン酸（Citric Acid）、クエン酸ナトリウム（Sodium Citrate）、クエン酸二ナトリウム（Dibasic Sodium Citrate）、グリセリン（Glycerin）、グルコン酸カルシウム（Calcium Gluconate）、グルコン酸ナトリウム（Sodium Gluconate）、グルコン酸マグネシウム（Magnesium Gluconate）、クレアチニン（Creatinine）、クロロブタノール（Chlorobutanol）、ゲンチジン酸エタノールアミド（Gentisylethanolamidｅ）、コハク酸（Succinic Acid）、ゴマ油（Sesame Oil）、コンドロイチン硫酸ナトリウム（Sodium Chondroitin Sulfate）、サリチル酸ナトリウム（Sodium Salicylate）、ジエタノールアミン（Diethanolamine）、ジエチレントリアミン五酢酸（Diethylenetriaminepentaacetic Acid）、セスキオレイン酸ソルビタン（Sorbitan Sesquioleate）、ゼラチン（Gelatin）、ゼラチン加水分解物（Hydrolyzed Gelatin）、ソルビタン脂肪酸エステル（Sorbitan Esters of Fatty Acid）、ダイズ油（Soybean Oil）、チオグリコール酸（Tioglycolic Acid）、チオグリコール酸ナトリウム（Sodium Tioglycolate）、チオシアン酸カリウム（Potassium Thiocyanate）、チオリンゴ酸ナトリウム（Sodium Thiomalate）、チオ硫酸ナトリウム（Sodium Thiosulfate）、ツバキ油（Camellia Oil）、デスオキシコール酸ナトリウム（Sodium Desoxycholate）、トリエタノールアミン（Triethanolamine）、トロメタモール（Trometamol）、ナトリウムホルムアルデヒドスルホキシレート（Sodium Formaldehydesulfoxylate）、ニコチン酸アミド（Nicotinamide）、パラオキシ安息香酸エチル（Ethyl Parahydroxybenzoate）、パラオキシ安息香酸ブチル（Butyl Parahydroxybenzoate）、パラオキシ安息香酸プロピル（Propyl Parahydroxybenzoate）、パラオキシ安息香酸メチル（Methyl Parahydroxybenzoate）、ヒドロキシプロピルセルロース（Hydroxypropylcellulose）、ヒマシ油（Castor Oil）、ピロ亜硫酸カリウム（Potassium Pyrosulfite）、ピロ亜硫酸ナトリウム（Sodium Pyrosulfite）、フェノール（Phenol）、ブチルヒドロキシアニソール（Butylhydroxyanisol）、ブドウ糖（Glucose）、プロピレングリコール（Propylene Glycol）、ヘパリンナトリウム（Heparin Sodium）、ベンジルアルコール（Benzyl Alcohol）、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール（Polyoxyethylene (160) Polyoxypropylene (30) Glycol）、ポリオキシエチレンヒマシ油（Polyoxyethylene Castor Oil）、ポリオキシエチレン硬化ヒマシ油（Polyoxyethylene Hydrogenated Castor Oil）、ポリオキシエチレン硬化ヒマシ油５０（Polyoxyethylene Hydrogenated Castor Oil 50）、ポリオキシエチレン硬化ヒマシ油６０（Polyoxyethylene Hydrogenated Castor Oil 60）、ポリソルベート８０（Polysorbate 80）、マクロゴール４００（Macrogol 400）、マクロゴール４０００（Macrogol 4000）、マルトース（Maltose）、メグルミン（Meglumine）、メタンスルホ安息香酸ナトリウム（Sodium Metasulfobenzoate）、モノエタノールアミン（Monoethanol Amine）、モノステアリン酸アルミニウム（Aluminum Monostearate）、モノラウリン酸ポリオキシエチレンソルビタン（20E.O.）（Polyoxyethylene Sorbitan Monolaurate）、ラッカセイ油（Peanut Oil）、リン酸（Phosphoric Acid）、リン酸三ナトリウム（Tribasic Sodium Phosphate）、リン酸水素ナトリウム（Dibasic Sodium Phosphate）、リン酸二カリウム（Dibasic Potassium Phosphate）、リン酸二水素カリウム（Monobasic Potassium Phosphate）、リン酸二水素ナトリウム（Monobasic Sodium Phosphate）、リン酸二水素ナトリウム一水和物（Sodium Dihydrogen Phosphate Monohydrate）、亜硫酸ナトリウム（Sodium Sulfite）、亜硫酸水素ナトリウム（Sodium Bisulfite）、安息香酸（Benzoic Acid）、安息香酸ナトリウム（Sodium Benzoate）、安息香酸ベンジル（Benzyl Benzoate）、塩化アルミニウム（Aluminium Chloride）、塩化ナトリウム（Sodium Chloride）、塩化ベンザルコニウム（Benzalkonium Chloride）、塩化ベンゼトニウム（Benzethonium Chloride）、塩化マグネシウム（Magnesium Chloride）、塩化亜鉛（Zinc Chloride）、塩化亜鉛溶液（Zinc Chloride Solution）、塩化第一すず（Stannous Chloride）、塩化第二鉄（Ferric Chloride）、塩酸（Hydrochloric Acid）、塩酸アルギニン（Arginine Hydrochloride）、塩酸システイン（Cysteine Hydrochloride）、塩酸リジン（Lysine Hydrochloride）、果糖（Fructose）、乾燥アルミニウムゲル（Dried Aluminum Hydroxide Gel）、乾燥亜硫酸ナトリウム（Dried Sodium Sulfite）、乾燥炭酸ナトリウム（Dried Sodium Carbonate）、希塩酸（Dilute Hydrochloric Acid）、結晶リン酸二水素ナトリウム（Sodium Dihydrogen Phosphate Dihydrate）、高度精製卵黄レシチン（Highly Purified Yolk Lecithin）、酸化カルシウム（Calcium Oxide）、酸化亜鉛（Zinc Oxide）、酒石酸（Tartaric Acid）、臭化カルシウム（Calcium Bromide）、臭化ナトリウム（Sodium Bromide）、酢酸（Acetic Acid）、酢酸アンモニウム（Ammonium Acetate）、酢酸ナトリウム（Sodium Acetate）、酢酸亜鉛（Zinc Acetate）、水酸化アルミニウム（Aliminum Hydroxide）、水酸化ナトリウム（Sodium Hydroxide）、精製ゼラチン（Purified Gelatin）、精製大豆レシチン（Purified Soybean Lecithin）、精製大豆油（Purified Soybean Oil）、精製白糖（Purified Sucrose）、精製卵黄レシチン（Purified Yolk Lecithin）、炭酸ナトリウム（Sodium Carbonate）、炭酸水素ナトリウム（Sodium Bicarbonate）、注射用水（Water for Injection）、糖酸カルシウム（Calcium D-Saccharate）、乳酸（Lactic Acid）、乳酸エチル（Ethyl Lactate）、乳酸ナトリウム液（Sodium Lactate Solution）、乳糖（Lactose）、尿素（Urea）、濃グリセリン（Concentrated Glycerin）、氷酢酸（Glacial Acetic Acid）、無水エタノール（Dehydrated Ethanol）、無水クエン酸（Anhydrous Citric Acid）、無水ピロリン酸ナトリウム（Sodium Pyrophospate,Anhydrous）、無水マレイン酸（Malein Anhydride）、無水リン酸一水素ナトリウム（Disodium Hydrogen Phosphate Anhydrous）、無水リン酸二水素ナトリウム（Sodium Dihydrogen Phosophate Anhydrous）、無水塩化第一すず（Anhydrous Stannous Chloride）、無水酢酸ナトリウム（Sodium Acetate, Anhydrous）、無水炭酸ナトリウム（Sodium Carbonate, Anhydrous）、硫酸（Sulfuric Acid）、硫酸アルミニウムカリウム（Aluminum Potassium Sulfate）、硫酸カリウム（Potassium Sulfate）、硫酸マグネシウム（Magnesium Sulfate）等が挙げられる。これらの添加剤は、一般に注射剤に通常用いられる割合で配合される。 In the production of the injectable composition of the present invention, the aforementioned saccharides and sugar alcohols may be added, and other additives generally used for injections may be appropriately blended. Examples of such additives include 70 v / v% N-hydroxyethyl lactamide aqueous solution (N-Hydroxyethyl-LactamideactSolution), D-Sorbitol, D-Mannitol, DL- Methionine (DL-Methionine), L-Aspartic Acid (L-Aspartic® Acid), L-Alanine (L-Alanine), L-Arginine, L-Glutamate L-Lysine-L-Glutamate ), Potassium L-glutamate (Monopotassium L-Glutamate Monohydrate), sodium L-glutamate (Monosodium L-Glutamate Monohydrate), L-cystine, L-cysteine (L-Cysteine), L-histidine (L- Histidine, L-methionine, N, N-dimethylacetamide (N, N-DimethylDiAcetamide), ascorbic acid (Ascorbic Acid), sodium acetyltryptophan (Sodium Ac) etyl Tryptophan, aminoethylsulfonic acid (Aminoethyl Sulfonic Acid), aminoacetic acid (Aminoacetic Acid), gum arabic (Acacia), gum arabic powder (Powdered Acacia), alpha thioglycerin (a-Thioglycerol), albumin (Albumin), inositol (Inositol), ethanol (Ethanol), ethylurea (Ethylurea), ethylenediamine (Ethylenediamine), calcium sodium edetate (CalciumCalcDisodium Edetate), sodium edetate (Disodium Edetate), oleic acid (Oleic Acid), sodium caprylate (Sodium) Caprylate), Carmellose sodium (Carmellose Sodium), Xylitol, Citric acid (Citric Acid), Sodium citrate (Sodium Citrate), Disodium citrate (Dibasic Sodium Citrate), Glycerin (Glycerin), Calcium gluconate ( Calcium Gluconate) Sodium konnate (Sodium Gluconate), Magnesium Gluconate, Creatinine, Chlorobutanol, Gentisylethanolamide, Succinic acid, Sesame oil, Chondroitin sulfate Sodium (Sodium Chondroitin Sulfate), sodium salicylate (Sodium Salicylate), diethanolamine (Diethanolamine), diethylenetriaminepentaacetic Acid, sorbitan sesquioleate (Sorbitan Sesquioleate), gelatin (Gelatin), gelatin hydrolyzate (Gydroly) Sorbitan fatty acid ester (Sorbitan Esters of Fatty Acid), soybean oil (Soybean Oil), thioglycolic acid (Tioglycolic Acid), sodium thioglycolate (Sodium Tioglycolate), thiocyanate Potassium (Potassium Thiocyanate), Sodium thiomalate (Sodium Thiomalate), Sodium thiosulfate (Sodium ioThiosulfate), Camellia oil (Camellia Oil), Sodium desoxycholate (Sodium Desoxycholate), Triethanolamine (Trometamol) , Sodium formaldehydesulfoxylate, Nicotinamide, EthylateParahydroxybenzoate, Butyl Parahydroxybenzoate, Propyl Parahydroxybenzoate, Methyl parahydroxybenzoate ( Methyl Parahydroxybenzoate, Hydroxypropylcellulose, Castor Oil, Potassium pyrosulfite, Sodium pyrosulfite Pyrosulfite), Phenol, Butylhydroxyanisol, Glucose, Propylene Glycol, Heparin Sodium, Benzyl Alcohol, Polyoxyethylene (160) Polyoxypropylene (30) Glycol (Polyoxyethylene (160) Polyoxypropylene (30) Glycol), Polyoxyethylene ヒ Castor Oil, Polyoxyethylene hydrogenated castor oil (Polyoxyethylene Hydrogenated Castor Oil), Polyoxyethylene hydrogenated castor oil 50 (Polyoxyethylene Hydrogen Oil) Castor Oil 50), Polyoxyethylene hydrogenated castor oil 60 (Polyoxyethylene Hydrogenated Castor Oil 60), Polysorbate 80 (Polysorbate 80), Macrogol 400 (Macrogol 400), Macrogol 4000 (Macrogol 4000), Maltose, Meglumine, Sodium methanesulfobenzoate (Sodium Metasulfobenzoate), Monoethanolamine (Monoethanol Amine), Aluminum monostearate (Aluminum Monostearate), Polyoxyethylene sorbitan monolaurate (20E.O.) (Polyoxyethylene) Sorbitan Monolaurate), peanut oil (Peanut Oil), phosphoric acid (Phosphoric Acid), trisodium phosphate (Tribasic Sodium Phosphate), sodium hydrogenphosphate (Dibasic Sodium Phosphate), dipotassium phosphate (Dibasic Potassium Phosphate), phosphoric acid Potassium dihydrogen (Monobasic Potassium ho Phosphate), Sodium dihydrogen phosphate (Monobasic Sodium Phosphate), Sodium dihydrogen phosphate monohydrate (Sodium Dihydrogen Phosphate Monohydrate), Sodium sulfite (Sodium Sulfite), Sodium sulfite (Sodium Bisulfite) , Cheap Benzoic Acid, Sodium Benzoate, Benzyl Benzoate, Aluminum Chloride, Sodium Chloride, Benzalkonium Chloride, Benzethonium Chloride Chloride), Magnesium Chloride, Zinc Chloride, Zinc Chloride Solution, Stannous Chloride, Ferric Chloride, Hydrochloric Acid, Arginine Hydrochloride, Cysteine Hydrochloride, Lysine Hydrochloride, Fructose, Dry Aluminum Gel (Dried Aluminum Hydrooxide Gel), Dried Sodium Sulfite, Dried Sodium Carbonate (Dried) Sodium Carbonate), Dilute Hydrochlori c Acid), crystalline sodium dihydrogen phosphate (Sodium Dihydrogen Phosphate Dihydrate), highly purified egg yolk lecithin (Highly Purified Yolk Lecithin), calcium oxide (Calcium Oxide), zinc oxide (Zinc Oxide), tartaric acid (Tartaric Acid), bromide Calcium (Bromide), Sodium bromide, Acetic (Acetic) Acid, Ammonium acetate (Ammonium), Sodium acetate (Sodium Acetate), Zinc acetate (Zinc Acetate), Aluminum hydroxide (Aliminum Hydroxide), Water Sodium oxide (Sodium Hydroxide), purified gelatin (Purified Gelatin), refined soybean lecithin (Purified Soybean Lecithin), refined soybean oil (Purified Soybean Oil), refined white sugar (Purified Sucrose), purified egg yolk lecithin (Purified Yolk Lecithin), sodium carbonate (Sodium Carbonate), Sodium bicarbonate (Sodium Bicarbonate), Water for injection (Water for Injection), calcium sugar (Calcium D-Saccharate), lactic acid (Lactic Acid), ethyl lactate (Ethyl Lactate), sodium lactate solution (Sodium Lactate Solution), lactose (Lactose), urea (Urea), concentrated glycerin (Concentrated) Glycerin), glacial acetic acid (Glacial Acetic Acid), anhydrous ethanol (Dehydrated Ethanol), anhydrous citric acid (Anhydrous Citric Acid), anhydrous sodium pyrophosphate (Sodium Pyrophospate, Anhydrous), maleic anhydride (Malein Anhydride), monophosphoric anhydride Sodium hydrogen (Disodium Hydrogen Phosphate Anhydrous), anhydrous sodium dihydrogen phosphate (Sodium Dihydrogen Phosophate Anhydrous), anhydrous stannous chloride (Anhydrous Stannous Chloride), anhydrous sodium acetate (Sodium Acetate, Anhydrous), anhydrous sodium carbonate (Sodium Carbonate, Anhydrous), sulfuric acid (Sulfuric Acid), potassium aluminum sulfate (Aluminum Potassium) Sulfate), potassium sulfate (Potassium Sulfate), and the like magnesium sulfate (Magnesium Sulfate). These additives are generally blended in a proportion usually used for injections.
　当業者にとっては容易なことであり、また、薬事日報社2000年刊「医薬品添加物辞典」（日本医薬品添加剤協会編集）等にも記載されている様に、これらの添加剤は使用目的に応じて、例えば、安定化剤、界面活性剤、緩衝剤、ｐＨ調節剤、可溶化剤、抗酸化剤、消泡剤、等張化剤、乳化剤、懸濁化剤、保存剤、無痛化剤、溶解剤、溶解補助剤等として使い分けることが可能である。また、これらの添加剤は、所望によって、２以上の成分を組み合わせ、添加することもできる。 It is easy for those skilled in the art, and these additives are used according to the purpose of use, as described in the “Pharmaceutical Additives Dictionary” (edited by the Japan Pharmaceutical Additives Association) published in 2000. For example, stabilizers, surfactants, buffers, pH adjusters, solubilizers, antioxidants, antifoaming agents, tonicity agents, emulsifiers, suspending agents, preservatives, soothing agents, It can be properly used as a solubilizer, a solubilizing agent or the like. Further, these additives can be added in combination of two or more components as desired.
　例えば、他の添加剤のひとつとして例示したポリソルベート８０（Polysorbate 80）は、可溶化剤として使うことができることが知られており、その必要量を添加することで、本発明の注射用組成物の有効成分である「化合物Ａ」もしくは「化合物Ａの塩」の溶解性をあげることができる。ポリソルベート８０は、商業的に入手可能なものを特に制限することなく使用することができる。ポリソルベート８０は、無色乃至橙黄色の粘稠性のある液体で、そのＣＡＳ番号は9005-65-6である。ポリソルベート８０はまた、エマゾール４１３０、ツィーン８０（Tween 80）、モノオレイン酸ポリオキシエチレンソルビタン（20E.O.）（Polyoxyethylene 20 sorbitan monooleate）とも称される。ポリソルベート８０に関するより詳しい情報は、公知の文献、例えば、薬事日報社２００７年刊「医薬品添加物事典」（日本医薬品添加剤協会編集）、２７４頁などに記載されている。 For example, it is known that polysorbate 80 (Polysorbate 80) exemplified as one of other additives can be used as a solubilizing agent, and by adding the necessary amount thereof, the injectable composition of the present invention can be used. The solubility of “compound A” or “salt of compound A” as an active ingredient can be increased. As the polysorbate 80, a commercially available one can be used without particular limitation. Polysorbate 80 is a colorless to orange-yellow viscous liquid, and its CAS number is 9005-65-6. Polysorbate 80 is also referred to as Emazole 4130, Tween 80, polyoxyethylene sorbitan monooleate (20E.O.) (Polyoxyethylene 20 sorbitan monooleate). More detailed information on the polysorbate 80 is described in publicly known documents, for example, Yakuji Nipposha 2007 “Pharmaceutical Additives Encyclopedia” (edited by Japan Pharmaceutical Additives Association), page 274.
　もちろん、本発明の注射用組成物は、添加剤としてデキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤を用いることにより前述の優れた効果を備えるものであるため、ポリソルベート８０を加えずとも充分に好ましい。仮にポリソルベート８０を加える場合には、その含有量は、化合物Ａ１重量部あたり、例えば、約０．０４重量部乃至約０．１７重量部が好ましく、約０．０７重量部乃至約０．１重量部がより好ましい。すなわち、組成物１単位形態あたり化合物Ａの量として約５０ｍｇの有効成分を含有する注射用組成物におけるポリソルベート８０の含有量は、約２ｍｇ乃至約８．３ｍｇが好ましく、約３．５ｍｇ乃至約５ｍｇがより好ましい。また、組成物１単位形態あたり化合物Ａの量として約２０ｍｇの有効成分を含有する注射用組成物におけるポリソルベート８０の含有量は、約０．８ｍｇ乃至約３．４ｍｇが好ましく、約１．４ｍｇ乃至約２ｍｇがより好ましい。 Of course, the injectable composition of the present invention has the above-mentioned excellent effects by using one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone as additives. It is sufficiently preferable without adding polysorbate 80. If polysorbate 80 is added, its content is preferably, for example, about 0.04 to about 0.17 parts by weight, and about 0.07 to about 0.1 parts by weight per part by weight of Compound A. Part is more preferred. That is, the content of polysorbate 80 in an injectable composition containing about 50 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 2 mg to about 8.3 mg, and preferably about 3.5 mg to about 5 mg. Is more preferable. In addition, the content of polysorbate 80 in an injectable composition containing about 20 mg of active ingredient as the amount of Compound A per unit form of the composition is preferably about 0.8 mg to about 3.4 mg, preferably about 1.4 mg to About 2 mg is more preferred.
　斯様にして製造された本発明の注射用組成物は、前述のとおり、組成物の保存に伴う、（ａ）化合物Ａの分解、（ｂ）化合物Ｃの生成、および／または（ｃ）組成物の変色を抑制することができる。これらの効果は、本発明の注射用組成物が凍結乾燥組成物である場合に顕著に認められる。また、前述のとおり本発明の注射用組成物が凍結乾燥組成物である場合においては、これらの効果に加え、（ｄ）速やかな再溶解性という性質をも備えることができる。これらの文言について、説明を以下に行う。 The injectable composition of the present invention thus produced is, as described above, (a) decomposition of compound A, (b) formation of compound C, and / or (c) composition accompanying storage of the composition. Discoloration of objects can be suppressed. These effects are noticeable when the injectable composition of the present invention is a lyophilized composition. Further, as described above, when the injectable composition of the present invention is a freeze-dried composition, in addition to these effects, (d) a property of rapid resolubility can be provided. These words are explained below.
　（ａ）化合物Ａの分解とは、本発明の注射用組成物中に存在する化合物Ａが、保存に伴って、化合物Ａではない別の物質に変化することを意味する。同様に、化合物Ａの塩、例えば、化合物Ｂを有効成分とする本発明の注射用組成物にあっては、塩を構成する化合物Ａの部分が、化合物Ａではない別の物質に変化することを意味する。保存に伴う化合物Ａの分解の程度は、保存前の化合物Ａの量と、保存後の化合物Ａの量とを比較することで数値として表すことができる。本明細書においては、化合物Ａの分解の程度を表す指標として、「化合物Ａの残存率」を使用する。化合物Ａの残存率は、保存後の化合物Ａの量を、保存前の化合物Ａの量に対する百分率で表したものであり、単位にはパーセント（％）を使用する。なお、組成物中の化合物Ａの量を測定する方法は、物質の量を測定できる方法であればどのような方法を用いても構わないが、例えば、実施例に記載のごとく高速液体クロマトグラフィーを使用して、化合物Ａのピーク面積から面積百分率で求める方法が好適である。本発明の注射用組成物は、化合物Ａの分解を抑制することができ、保存後における化合物Ａの残存率を、例えば、９０％以上、好ましくは９３％以上、より好ましくは９５％以上、特に好ましくは９８％以上にすることができる。 (A) Decomposition of compound A means that compound A present in the injectable composition of the present invention changes to another substance other than compound A with storage. Similarly, in the injectable composition of the present invention comprising a salt of Compound A, for example, Compound B as an active ingredient, the portion of Compound A constituting the salt is changed to another substance that is not Compound A. Means. The degree of decomposition of Compound A accompanying storage can be expressed as a numerical value by comparing the amount of Compound A before storage with the amount of Compound A after storage. In the present specification, “residual ratio of compound A” is used as an index representing the degree of decomposition of compound A. The residual ratio of Compound A is the amount of Compound A after storage expressed as a percentage of the amount of Compound A before storage, and the unit is percent (%). The method for measuring the amount of Compound A in the composition may be any method as long as it can measure the amount of the substance. For example, as described in the Examples, high performance liquid chromatography And the method of obtaining the area percentage from the peak area of Compound A is preferred. The injectable composition of the present invention can suppress the degradation of Compound A, and the residual ratio of Compound A after storage is, for example, 90% or more, preferably 93% or more, more preferably 95% or more, particularly Preferably, it can be 98% or more.
　（ｂ）化合物Ｃの生成とは、本発明の注射用組成物中で、保存に伴って、ある物質から化合物Ｃに変化することを意味する。化合物Ｃに変化する物質は特に限定されないが、主たる物質は化合物Ａである。前述のとおり、本発明の注射用組成物中の化合物Ａは保存に伴って分解し、別の物質に変化するが、その変化した物質の少なくともひとつが化合物Ｃであると考えられる。保存に伴う化合物Ｃの生成の程度は、保存前の化合物Ｃの量と、保存後の化合物Ｃの量とを比較することで数値として表すことができる。本明細書においては、化合物Ｃの生成の程度を表す指標として、「化合物Ｃの生成量」を使用する。化合物Ｃの生成量は、保存後の化合物Ｃの量から保存前の化合物Ｃの量を減ずることで求めることができるが、通常、保存前の本発明の注射用組成物中には化合物Ｃは存在しないので、保存後の化合物Ｃの量を化合物Ｃの生成量と見なすことができる。なお、本明細書においては、化合物Ｃの生成量をパーセント（％）で示す場合があるが、これは、実施例に記載のごとく高速液体クロマトグラフィーを使用して、検出される総ピーク面積に対する化合物Ｃのピーク面積を百分率表示したものである。本発明の注射用組成物は、化合物Ｃの生成を抑制することができ、保存後における化合物Ｃの生成量を、例えば、１％未満、好ましくは０．５％未満、より好ましくは０．２％未満、特に好ましくは検出限界以下（すなわち、実質的に生成されない）にすることができる。 (B) The production of compound C means that the compound in the composition for injection of the present invention changes from a certain substance to compound C upon storage. The substance that changes to compound C is not particularly limited, but the main substance is compound A. As described above, compound A in the injectable composition of the present invention decomposes upon storage and changes to another substance, but at least one of the changed substances is considered to be compound C. The degree of generation of Compound C accompanying storage can be expressed as a numerical value by comparing the amount of Compound C before storage with the amount of Compound C after storage. In the present specification, “amount of compound C produced” is used as an index representing the degree of compound C production. The amount of compound C produced can be determined by subtracting the amount of compound C before storage from the amount of compound C after storage, but usually compound C is contained in the injectable composition of the present invention before storage. Since it does not exist, the amount of Compound C after storage can be regarded as the amount of Compound C produced. In the present specification, the amount of compound C produced may be indicated as a percentage (%). This is based on the total peak area detected using high performance liquid chromatography as described in the Examples. The peak area of Compound C is expressed as a percentage. The injectable composition of the present invention can suppress the production of Compound C, and the amount of Compound C produced after storage is, for example, less than 1%, preferably less than 0.5%, more preferably 0.2. %, Particularly preferably below the limit of detection (ie substantially not produced).
　（ｃ）組成物の変色とは、本発明の注射用組成物の色が、保存に伴って、別の色に変化することを意味する。本発明の注射用組成物が水溶液の形態のものである場合、保存前の組成物の色と保存後の組成物の色の違いは、目視や色差計などで確認することができる。また、本発明の注射用組成物が凍結乾燥組成物の場合、保存前の組成物の色と保存後の組成物の色の違いは、そのまま目視で確認してもよいし、それぞれ再溶解に付した後に目視や色差計などで確認してもよい。本発明の注射用組成物は、それ自身の変色を抑制したものであり、保存後においても変色が実質的に起こらない（すなわち、保存前と実質的に色が変化しない）ものである。保存の前後で変色が実質的に起こっていないかどうかは、それぞれのサンプルを目視で確認して判断するか、あるいはそれぞれのサンプルの色差（ΔＥ）が０．８以下となるかどうかで判断すればよい。サンプルの色差（ΔＥ）は自体公知の方法により容易に測定することができる。色差（ΔＥ）を用いた判断の目安を表１に示したが、色差（ΔＥ）が０．８以下であれば、目視判定で色差は無いと考えられている（表１：日本電色工業株式会社ホームページ内「色の許容差の事例」より抜粋：インターネット＜ＵＲＬ：https://www.nippondenshoku.co.jp/web/japanese/colorstory/08_allowance_by_color.htm＞）。
Figure JPOXMLDOC01-appb-T000007
 (C) Discoloration of the composition means that the color of the injectable composition of the present invention changes to another color with storage. When the injectable composition of the present invention is in the form of an aqueous solution, the difference between the color of the composition before storage and the color of the composition after storage can be confirmed visually or by a color difference meter. In addition, when the injectable composition of the present invention is a lyophilized composition, the difference in color between the composition before storage and the color after storage may be confirmed visually, or redissolved respectively. You may confirm by visual observation or a color difference meter after attaching. The injectable composition of the present invention suppresses its own discoloration and does not substantially undergo discoloration even after storage (that is, the color does not substantially change from that before storage). Whether or not discoloration has substantially occurred before and after storage can be judged by visually checking each sample or whether the color difference (ΔE) of each sample is 0.8 or less. That's fine. The color difference (ΔE) of the sample can be easily measured by a method known per se. The standard of judgment using the color difference (ΔE) is shown in Table 1. If the color difference (ΔE) is 0.8 or less, it is considered that there is no color difference by visual judgment (Table 1: Nippon Denshoku Industries Co., Ltd.). Excerpt from “Example of Color Tolerance” on the website: Internet <URL: https://www.nippondenshoku.co.jp/web/japanese/colorstory/08_allowance_by_color.htm>).
Figure JPOXMLDOC01-appb-T000007
　（ｄ）速やかな再溶解性とは、凍結乾燥組成物に対して注射に用いる溶媒、例えば、注射用水または生理食塩液などを添加して注射用溶液を調製する際の「溶けの良さ」を意味する。本発明で開示する凍結乾燥組成物が速やかな再溶解性を有しているか否かは、通常、凍結乾燥組成物が添加した溶媒に溶け込む速度、すなわち再溶解速度を以て判断することができるが、後記の実施例においては、簡便に判断するために、意図的に変化させたファクター以外の条件、例えば、溶媒の種類や量、温度、撹拌の有無などの条件を一定にしたうえで測定した「再溶解に要した時間（再溶解時間）」を以て、再溶解速度の指標とした。すなわち、再溶解時間が長ければ再溶解速度が遅い、再溶解時間が短ければ再溶解速度が速いと判断することとした。本発明で開示する凍結乾燥組成物は速やかな再溶解性を有しているので、前記溶媒を添加して、通常１２０秒以内、好ましくは９０秒以内、より好ましくは６０秒以内、特に好ましくは４５秒以内に注射用溶液を調製することができる。このように調製した注射用溶液は澄明で、不溶性の微粒子なども残らないため、安全に生体に投与することができる。前述のとおり、本発明の注射用組成物は、添加剤としてデキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤を含有するものであるところ、デキストランについては化合物Ｂの溶解度に影響を与えないことが実験結果として得られている。具体的には、デキストラン４０を含まないｐＨ３の水溶液中における化合物Ｂの溶解度は１９．５ｍｇ／ｍＬであるが、デキストラン４０を２５ｍｇ／ｍＬ含むｐＨ３の水溶液中における化合物Ｂの溶解度は１８．９ｍｇ／ｍＬである。通常、可溶化剤として用いられることもなく、化合物Ｂの溶解度をあげることもないデキストラン４０を共存させることにより、再溶解性を向上させることができた本発明の注射用組成物は、それ自体驚くべきものであると考えられる。 (D) Rapid resolubility means “good solubility” when preparing a solution for injection by adding a solvent used for injection, such as water for injection or physiological saline, to the lyophilized composition. means. Whether or not the lyophilized composition disclosed in the present invention has rapid re-solubility can usually be determined by the rate at which the lyophilized composition dissolves in the solvent added, that is, the re-dissolution rate. In the examples described later, in order to make a simple determination, the measurement was carried out after making conditions other than the factor changed intentionally, for example, the conditions such as the type and amount of the solvent, the temperature, the presence or absence of stirring, etc. The time required for re-dissolution (re-dissolution time) was used as an index of the re-dissolution rate. That is, if the re-dissolution time is long, the re-dissolution rate is slow, and if the re-dissolution time is short, the re-dissolution rate is fast. Since the lyophilized composition disclosed in the present invention has a rapid re-dissolution property, it is usually within 120 seconds, preferably within 90 seconds, more preferably within 60 seconds, particularly preferably after adding the solvent. An injectable solution can be prepared within 45 seconds. The solution for injection prepared in this way is clear and insoluble fine particles are not left, so that it can be safely administered to a living body. As described above, the injectable composition of the present invention contains at least one additive selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone as an additive. Experimental results have shown that it does not affect the solubility. Specifically, the solubility of Compound B in a pH 3 aqueous solution not containing dextran 40 is 19.5 mg / mL, but the solubility of Compound B in a pH 3 aqueous solution containing 25 mg / mL dextran 40 is 18.9 mg / mL. mL. The injectable composition of the present invention, which can improve re-solubility by coexisting with dextran 40 which is not usually used as a solubilizer and does not increase the solubility of Compound B, is itself It is considered amazing.
　なお、本明細書において用いられる「保存」の文言は、一般的な文言として解釈されるべきであるが、具体的な例として、例えば、ＩＣＨガイドラインで定められている苛酷試験の条件（温度６０℃）での１ヶ月間の保存や、同じくＩＣＨガイドラインで定められている加速試験の条件（温度４０℃、相対湿度７５％）での６ヶ月間の保存、あるいはこれらの条件での保存に相当すると考えられている室温での約３年間の保存などが挙げられる。 Note that the term “storage” used in the present specification should be interpreted as a general term, but as a specific example, for example, conditions of severe tests (temperature 60 stipulated in the ICH guidelines). ℃) for 1 month, 6 months under accelerated test conditions (temperature 40 ° C, relative humidity 75%) stipulated in the ICH guidelines, or storage under these conditions One example is storage for about 3 years at room temperature.
　本発明において、「製品」は、（１）有効成分である化合物Ａまたはその塩と、デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤とを含有してなる注射用組成物と、（２）前記の組成物を含む容器に加え、（３）前記の組成物が、必要に応じて適当な併用剤と組み合わせ、全身麻酔および／または鎮静のために使用することができる旨を示す、指示書、説明書、添付文書、または製品ラベル（米国におけるラベルまたはラベリングに相当するものも含む）などの少なくともひとつを含む。 In the present invention, “product” is an injection comprising (1) an active ingredient, compound A or a salt thereof, and one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone. (2) In addition to the container containing the composition, (3) The composition is used for general anesthesia and / or sedation in combination with an appropriate combination agent as necessary. Including at least one of instructions, instructions, package inserts, or product labels (including those corresponding to labels or labeling in the United States).
　ここで、添付文書とは、日本においては薬事法でいう「添付文書」（能書と呼ばれることもある）、欧州連合（ＥＵ）においては指令でいう「製品情報概要（Summary of Product Characteristics : SPC or SmPC）」、米国においては連邦規則でいう「米国添付文書（US Package Insert : USPI）」、あるいはその他の国においてはこれらの文書に相当する、医薬品の適正使用に必要な事項を記載して医薬品に添付する公的文書のことを意味するものである。 Here, the package insert refers to the “package insert” (sometimes referred to as a booklet) in the Pharmaceutical Affairs Law in Japan, and the “Product Information Summary (Summary of Product Characteristics: SPC)” in the EU (EU) directive. or “SmPC”) in the United States, “US package (Insert): USPI” in the federal regulations, or in other countries, the necessary items for proper use of pharmaceuticals It means an official document attached to a medicine.
　これらの文書に記載する事項については、例えば、日本の添付文書であれば、薬事法第５２条、第５４条、及び第６８条の４など（必要に応じて、平成９年４月２５日付薬発第６０６号、６０７号、および／または関連する通知などを参照のこと）に、欧州連合の製品情報概要であればDirective 2001/83/EC Article 11など（必要に応じて、A guideline on SmPC、および／または関連するガイドラインなどを参照のこと）に、米国の米国添付文書であれば21 CFR 201.100など（必要に応じて、21 CFR 201.57、および／または関連する連邦規則などを参照のこと）に詳しく規定されているが、通常、適応症、用法、用量、投与方法、警告、および／または禁忌などについての情報が含まれる。 Regarding the matters described in these documents, for example, in the case of Japanese package inserts, Article 52, Article 54, and Article 68-4 of the Pharmaceutical Affairs Law (as required, dated April 25, 1997) For more information on product information of the European Union, see Directive 2001/83 / EC Article 13, etc. (A guideline on, if necessary) SmPC and / or related guidelines, etc.), for example, 21 CFR 201.100 for US package inserts (if necessary, see 21 CFR 201.57 and / or relevant federal regulations) ), But usually includes information about indications, usage, doses, administration methods, warnings, and / or contraindications.
　なお、米国においては、前記米国添付文書の他に、ラベル（Label）もしくはラベリング（Labeling or Labelling）として、米国添付文書に記載された内容の一部もしくは全部を記載することが21 CFR 201 Subpart Bに定められている。ここで、ラベルとは、容器に直接表示されているものを意味し、ラベリングとは、ラベルに加えて包装上の印刷や製品に付随する印刷物などをも包含する概念を意味する。 In the US, in addition to the US package insert, a part or all of the contents described in the US package insert may be described as a label or labeling. It is stipulated in. Here, the label means what is directly displayed on the container, and the labeling means a concept including not only the label but also printing on packaging or printed matter accompanying the product.
　本発明において、「容器」とは、有効成分である化合物Ａまたはその塩と、デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤とを含有してなる注射用組成物を直接内包するものを意味し、一般的には、例えば、アンプル、バイアル、チューブ、注射用シリンジなどが含まれる。 In the present invention, the “container” is an injectable composition containing Compound A or a salt thereof as an active ingredient and one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone. It means what directly encloses an object, and generally includes, for example, ampoules, vials, tubes, syringes for injection and the like.
　注射用組成物を内包する容器は、前述のとおり、指示書、説明書、添付文書、または製品ラベル（米国におけるラベル又はラベリングに相当するものも含む）などの少なくともひとつを組み合わせた状態で、通常、外部の容器（outer container）または外部の被包（outer wrapper）により包装され、市場に流通しうる。 As described above, the container containing the injectable composition is usually combined with at least one of instructions, instructions, package inserts, or product labels (including those corresponding to labels or labeling in the United States). It can be packaged in an outer container or an outer wrapper and distributed in the market.
　また、本発明は、有効成分である化合物Ａまたはその塩と、デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤とを含有してなる注射用組成物の広告方法であって、対象とする視聴者に、全身麻酔および／または鎮静のための前記組成物の使用を促すことを含む方法をも開示する。 The present invention also relates to a method for advertising an injectable composition comprising Compound A as an active ingredient or a salt thereof, and one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone. Also disclosed is a method comprising encouraging the intended audience to use the composition for general anesthesia and / or sedation.
　前記方法においては、全身麻酔および／または鎮静に際し、有効成分である化合物Ａまたはその塩と、デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤とを含有してなる注射用組成物を用いることの有用性、特に健康面での利点を記述する情報が公衆に配給（public distribution）される。かかる情報の配給は、言語によるコミュニケーションの他、適当な広告媒体を介して行われる。ここで、広告媒体としては、新聞、雑誌、テレビ、ラジオ、ビデオ、パンフレット、リーフレット、ポスター、ソーシャルネットワーキングシステム、電子メール、電子看板、デジタルサイネージ、インターネット広告（ホームページ／ウェブサイト、バナー広告など）、屋外広告（ポスターボード、ネオンサイン、大型ビジョンなど）、交通広告（電車・バス・タクシーなどの中吊り広告、窓上広告、額面広告、駅貼広告など）、映画・スライド広告（映画館のスクリーン広告など）、ＰＯＰ広告（店頭広告、店内広告など）、直接広告（ダイレクトメール、新聞折込広告、チラシ広告など）、特殊広告（カレンダーやボールペンなどのノベルティ広告など）、その他の広告（スカイライティング、ベンチ広告など）など、任意のものを用いてもよい。当業者であれば、これら広告媒体を製造することは容易である。 In the above method, in general anesthesia and / or sedation, compound A or a salt thereof, which is an active ingredient, and one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone are contained. Information describing the usefulness of using the injectable composition, particularly the health benefits, is distributed to the public. Distribution of such information is performed through an appropriate advertising medium in addition to communication in a language. Here, advertising media include newspapers, magazines, television, radio, video, brochures, leaflets, posters, social networking systems, e-mails, electronic signs, digital signage, Internet advertisements (homepages / websites, banner advertisements, etc.), Outdoor advertisement (poster board, neon sign, large vision, etc.), traffic advertisement (car, bus, taxi, etc., advertisement on window, face value advertisement, station sticker advertisement, etc.), movie / slide advertisement (cinema screen) Ads), POP ads (store ads, in-store ads, etc.), direct ads (direct mail, newspaper insert ads, flyer ads, etc.), special ads (such as novelty ads such as calendars and ballpoint pens), and other ads (sky lighting, Use anything such as bench ads) It may be. Those skilled in the art can easily manufacture these advertising media.
　［毒性］
　本発明によって、生体に対して有害な作用を示す化合物Ｃの生体への曝露の危険性を減らすことができる。化合物Ｃまたはその塩は、生体に対して有害な作用を有するため、それ自体は医薬品として有用ではないが、化合物Ａまたはその塩の、あるいはそれを有効成分として含有する医薬組成物の、安全性および／または安定性を評価するための比較対象もしくは標品としては有用である。前述のとおり化合物Ａは保存下で異性化し、化合物Ｃを生成する危険性を有するが、適切な保存試験を施して、保存後に化合物Ｃが生成しないことを確認するためには比較対象もしくは標品としての化合物Ｃが必要である。比較対象もしくは標品としての化合物Ｃを化学合成しなければ、例えば、高速液体クロマトグラフィーなどの手法で化合物Ａの保存後の分析チャートを見ても、化合物Ｃのピークがどこにあるのかすら判別できないし、仮に化合物Ａの保存後のサンプルを生体に投与して何らかの有害な作用が出た場合にも、どの分解物がその有害な作用の原因となっているか理解できないのである。比較対象もしくは標品としての化合物Ｃを同条件による高速液体クロマトグラフィーにかけ、ピークの異同を確認することで初めて化合物Ａが保存下で異性化して化合物Ｃを生成することを確認できるし、有害な作用をもたらしうる原因物質を特定することによって、初めてその原因物質の生成を抑制する必要があると思い至るのである。従って、化合物Ｃは、化合物Ａまたはその塩もしくはそれらを有効成分として含有する医薬組成物の安定性を評価するために必要であるし、化合物Ｃが生体に対して有害な作用を有することを鑑みれば、化合物Ａまたはその塩もしくはそれらを有効成分として含有する医薬組成物の安全性を評価するためにも必要である。 [toxicity]
According to the present invention, it is possible to reduce the risk of exposure to the living body of Compound C, which exhibits a harmful effect on the living body. Since compound C or a salt thereof is harmful to a living body, it is not useful as a pharmaceutical product per se, but safety of compound A or a salt thereof or a pharmaceutical composition containing it as an active ingredient And / or useful as a comparison or preparation for assessing stability. As described above, compound A isomerizes under storage and has a risk of forming compound C. However, in order to confirm that compound C is not formed after storage by performing an appropriate storage test, a comparison object or sample As a compound C is required. If the compound C as a comparison target or standard is not chemically synthesized, for example, even if the analysis chart after storage of the compound A is viewed by a technique such as high performance liquid chromatography, it cannot be determined where the peak of the compound C is. However, even if a sample after storage of Compound A is administered to a living body and any harmful action occurs, it is not possible to understand which degradation product causes the harmful action. Compound C as a comparison target or standard sample is subjected to high performance liquid chromatography under the same conditions, and by confirming the difference in peak, it can be confirmed that Compound A is isomerized under storage for the first time to produce Compound C, which is harmful. By identifying a causative substance that can have an effect, it is necessary to suppress the generation of the causative substance for the first time. Therefore, Compound C is necessary for evaluating the stability of Compound A or a salt thereof or a pharmaceutical composition containing them as an active ingredient, and in view of Compound C having a harmful effect on a living body. For example, it is also necessary to evaluate the safety of a pharmaceutical composition containing Compound A or a salt thereof or an active ingredient thereof.
　［医薬品への適用］
　本発明の注射用組成物は、有効成分に化合物Ａまたはその塩を含有するものであるので、全身麻酔や鎮静のためにこれを使用することができる。また、これらの用途に限らず、例えば、国際公開第２０００／０６９８３６号パンフレットや、国際公開第２００８／００７０７１号パンフレットに記載された任意の用途に使用することもできる。しかも、生体に対して有害な作用を示す化合物Ｃやその他の分解物の生成も抑えることにより有効成分の残存率を高く維持することができるので、長期間の保存が可能で、かつ安全な、臨床に好適な注射用組成物である。さらには、本発明の注射用組成物は、保存に伴う変色も起こらないので、長期間の保存後でも安心して使用することができる。 [Application to pharmaceutical products]
Since the injectable composition of the present invention contains Compound A or a salt thereof as an active ingredient, it can be used for general anesthesia or sedation. Moreover, it is not restricted to these uses, For example, it can also be used for the arbitrary uses described in the international publication 2000/069836 pamphlet and the international publication 2008/007071 pamphlet. In addition, since the residual ratio of the active ingredient can be maintained high by suppressing the production of Compound C and other decomposition products that exhibit harmful effects on the living body, it can be stored for a long period of time and is safe. It is an injectable composition suitable for clinical use. Furthermore, since the composition for injection of the present invention does not cause discoloration during storage, it can be used with confidence even after long-term storage.
　なお、本明細書において、明示的に引用される全ての特許文献および非特許文献もしくは参考文献の内容は、全て本明細書の一部としてここに引用し得るものとする。 It should be noted that the contents of all patent documents and non-patent documents or references explicitly cited in this specification can be cited here as a part of this specification.
　また、他に定義されない限り、本明細書で使用される全ての技術的、科学的用語、及び略語は、本発明の分野に属する当業者によって普通に理解されるものと同様の意味を有するものとする。 Unless defined otherwise, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. And
　以下、実施例により本発明を詳述するが、本発明はこれらに限定されるものではない。化合物名は、ＡＣＤ／Ｎａｍｅ（バージョン６．００、Ａｄｖａｎｃｅｄ　Ｃｈｅｍｉｓｔｒｙ　Ｄｅｖｅｌｏｐｍｅｎｔ　Ｉｎｃ．社製）、もしくはＣｈｅｍｄｒａｗ　Ｕｌｔｒａ（バージョン１２．０、Ｃａｍｂｒｉｄｇｅ　Ｓｏｆｔ社製）によって命名した。 Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto. The compound name was named by ACD / Name (version 6.00, manufactured by Advanced Chemistry Development Inc.) or Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft).
　クロマトグラフィーによる分離の箇所およびＴＬＣに示されているカッコ内の溶媒は、使用した溶出溶媒または展開溶媒を示し、割合は体積比を表す。ＮＭＲの箇所に示した数値は記載した測定溶媒を用いた時の1Ｈ－ＮＭＲの測定値である。 The point of separation by chromatography and the solvent in parentheses shown in TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio. The numerical value shown in the NMR part is the measured value of 1 H-NMR when using the described measuring solvent.
　実施例１：
メチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート（化合物Ｃ）の製造
Figure JPOXMLDOC01-appb-C000008
 　公知化合物であるメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート（化合物Ａ）（５００ｍｇ）のテトラヒドロフラン（５ｍＬ）溶液に、１，８－ジアザビシクロ［５，４，０］ウンデカ－７－エン（３７４μＬ）を加え、反応混合物を６０℃で４８時間攪拌した。反応混合物を減圧濃縮し、得られた残渣をＢｉｏｔａｇｅ社製中圧分取液体クロマトグラフＳＰ１（メインカラム：ＫＰ－ＳＩＬ　ＦＬＡＳＨ４０Ｓ；インジェクトカラム：ＫＰ－ＳＩＬ　ＦＬＡＳＨ４０　ｓａｍｐｌｅｔ；ヘキサン：酢酸エチル＝１：１～１：２(＋０．５％トリエチルアミン)）によって精製することにより、以下の物性値を有する標題化合物（２０９ｍｇ）を得た。
ＴＬＣ（Ｒｆ値）：０．２９（ヘキサン：酢酸エチル＝１：２）；
ＭＳ（ＥＳＩ，Ｐｏｓ．，２０Ｖ）：４４１（Ｍ＋Ｈ）+；
1Ｈ－ＮＭＲ（ＣＤ3ＯＤ）：δ　2.48 (d, J=0.92Hz, 3H), 2.76 (t, J=6.87Hz, 2H), 2.98 (dtd, J=17.76, 6.96, 1.65Hz, 1H), 3.54 (dtd, J=17.76, 6.96, 1.47Hz, 1H), 3.56 (s, 3H), 5.37 (s, 1H), 6.73 (dd, J=2.11, 0.64Hz, 1H), 7.10 (d, J=0.92Hz, 1H), 7.19 (d, J=8.42Hz, 1H), 7.33 (dddd, J=7.58, 4.83, 1.24, 0.46Hz, 1H), 7.47 (ddd, J=8.61, 2.20, 0.37Hz, 1H), 7.92 (ddd, J=7.69, 1.83Hz, 1H), 8.28 (ddd, J=7.83, 1.79, 1.01Hz, 1H), 8.62 (ddd, J=4.76, 1.83, 0.92Hz, 1H)；
ＩＲ（ＫＢｒ）：505, 621, 649, 706, 725, 757, 784, 827, 880, 900, 930, 961, 993, 1013, 1046, 1086, 1119, 1167, 1216, 1242, 1300, 1367, 1413, 1436, 1469, 1487, 1549, 1571, 1589, 1631, 1736, 2948, 3058, 3447 (cm-1)。 Example 1:
Preparation of methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate (Compound C)
Figure JPOXMLDOC01-appb-C000008
 Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate, a known compound 1,8-Diazabicyclo [5,4,0] undec-7-ene (374 μL) was added to a solution of (Compound A) (500 mg) in tetrahydrofuran (5 mL), and the reaction mixture was stirred at 60 ° C. for 48 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to medium pressure preparative liquid chromatograph SP1 (main column: KP-SIL FLASH40S; injection column: KP-SIL FLASH40 sample; hexane: ethyl acetate = 1: 1). Purification by ˜1: 2 (+ 0.5% triethylamine)) gave the title compound (209 mg) having the following physical properties.
TLC (Rf value): 0.29 (hexane: ethyl acetate = 1: 2);
MS (ESI, Pos., 20V): 441 (M + H) + ;
1 H-NMR (CD 3 OD): δ 2.48 (d, J = 0.92Hz, 3H), 2.76 (t, J = 6.87Hz, 2H), 2.98 (dtd, J = 17.76, 6.96, 1.65Hz, 1H) , 3.54 (dtd, J = 17.76, 6.96, 1.47Hz, 1H), 3.56 (s, 3H), 5.37 (s, 1H), 6.73 (dd, J = 2.11, 0.64Hz, 1H), 7.10 (d, J = 0.92Hz, 1H), 7.19 (d, J = 8.42Hz, 1H), 7.33 (dddd, J = 7.58, 4.83, 1.24, 0.46Hz, 1H), 7.47 (ddd, J = 8.61, 2.20, 0.37Hz, 1H), 7.92 (ddd, J = 7.69, 1.83Hz, 1H), 8.28 (ddd, J = 7.83, 1.79, 1.01Hz, 1H), 8.62 (ddd, J = 4.76, 1.83, 0.92Hz, 1H);
IR (KBr): 505, 621, 649, 706, 725, 757, 784, 827, 880, 900, 930, 961, 993, 1013, 1046, 1086, 1119, 1167, 1216, 1242, 1300, 1367, 1413 , 1436, 1469, 1487, 1549, 1571, 1589, 1631, 1736, 2948, 3058, 3447 (cm -1 ).
　実施例２：
メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩（化合物Ｂ）含有凍結乾燥組成物の保存下における類縁物質の生成に及ぼすｐＨの影響の検討 Example 2:
Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate Examination of effect of pH on formation of related substances under storage of freeze-dried composition containing (compound B)
＜評価用サンプルの製造＞
　化合物Ｂ、マルトース、リン酸二水素ナトリウム、ポリソルベート８０およびｐＨ調節剤（塩酸／水酸化ナトリウム）を用いて、以下の各処方の水溶液を調製し、バイアルに充填後、凍結乾燥に付して評価用サンプルを製造した。
Figure JPOXMLDOC01-appb-T000009
 <Manufacture of evaluation samples>
Using Compound B, maltose, sodium dihydrogen phosphate, polysorbate 80 and a pH adjuster (hydrochloric acid / sodium hydroxide), aqueous solutions of the following formulations were prepared, filled into vials, and subjected to lyophilization for evaluation. Samples were manufactured.
Figure JPOXMLDOC01-appb-T000009
＜保存試験＞
　各評価用サンプルにつき、６０℃、２週間の保存試験を実施した。 <Storage test>
Each evaluation sample was subjected to a storage test at 60 ° C. for 2 weeks.
＜類縁物質の分析＞
　保存試験に付した前記サンプルを水／アセトニトリル混液で再溶解後、以下の試験条件にて高速液体クロマトグラフィー分析し、類縁物質の量について製造直後のサンプル（Initial）との比較を行った。なお、類縁物質のうち、化合物Ｃに相当するピークは、前述の実施例１で製造した化合物を標品として用いた高速液体クロマトグラフィー、ＭＳおよびＮＭＲにより同定されたものである。 <Analysis of related substances>
The sample subjected to the storage test was redissolved with a water / acetonitrile mixture, and then subjected to high performance liquid chromatography analysis under the following test conditions, and the amount of the related substance was compared with that of the sample immediately after production (Initial). Of the related substances, the peak corresponding to compound C is identified by high performance liquid chromatography, MS and NMR using the compound prepared in Example 1 as a standard.
試験条件
検出器：紫外吸光光度計（測定波長：２３０ｎｍ）；
カラム：内径４．６ｍｍ、長さ１５ｃｍのステンレス管に３μｍの液体クロマトグラフィー用オクタデシルシリル化シリカゲルを充填したもの；
カラム温度：４０℃付近の一定温度；
移動相Ａ：１０ｍｍｏｌ／Ｌリン酸二水素カリウム溶液；
移動相Ｂ：メタノール；
移動相の送液：移動相Ａと移動相Ｂの混合比変化による濃度勾配制御（移動相Ａと移動相Ｂとを混合し、移動相Ａの混合比率が３０％乃至５０％の範囲内となるように濃度勾配制御した。）；
流量：毎分１．０ｍＬ。 Test conditions Detector: UV absorption photometer (measurement wavelength: 230 nm);
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm packed with 3 μm of octadecylsilylated silica gel for liquid chromatography;
Column temperature: constant temperature around 40 ° C;
Mobile phase A: 10 mmol / L potassium dihydrogen phosphate solution;
Mobile phase B: methanol;
Mobile phase feeding: concentration gradient control by changing the mixing ratio of mobile phase A and mobile phase B (mixing mobile phase A and mobile phase B, and the mixing ratio of mobile phase A is in the range of 30% to 50%) The concentration gradient was controlled so that
Flow rate: 1.0 mL per minute.
＜結果＞
　保存試験下で生成する類縁物質のうち、ｐＨの影響で生成量が変動したものは下記式：
Figure JPOXMLDOC01-appb-C000010
 で示される、３－［（４Ｓ）－８－ブロモ－１－メチル－６－２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパン酸（化合物Ａの加水分解体）と、化合物Ｃであった。保存に伴って生成する化合物Ｃの量を面積百分率にて算出した結果を以下に示す。この条件において、保存に伴う化合物Ｃの生成量は、ｐＨが３付近になると急激に、約１００倍程度（加水分解体ではせいぜい１０倍程度）まで増加することが判明した。
（M3301）Initial：　０．０６％　；　保存後：　５．８１％
（M3302）Initial：　０．０７％　；　保存後：　２．３７％
（M3303）Initial：　０．０７％　；　保存後：　２．２７％
（M3304）Initial：検出限界以下　；　保存後：　２．０７％ <Result>
Among the related substances generated under the storage test, those whose production amount fluctuated due to the influence of pH are represented by the following formula:
Figure JPOXMLDOC01-appb-C000010
 3-[(4S) -8-bromo-1-methyl-6-2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoic acid represented by Compound A hydrolyzate) and Compound C. The results of calculating the amount of compound C produced during storage as an area percentage are shown below. Under these conditions, it was found that the amount of compound C produced during storage suddenly increased to about 100 times (at most about 10 times in the hydrolyzate) when the pH reached around 3.
(M3301) Initial: 0.06%; After storage: 5.81%
(M3302) Initial: 0.07%; After storage: 2.37%
(M3303) Initial: 0.07%; After storage: 2.27%
(M3304) Initial: Below detection limit; After storage: 2.07%
　実施例３：
メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩（化合物Ｂ）含有凍結乾燥組成物の保存下におけるメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート（化合物Ｃ）の生成を抑制する添加剤の探索 Example 3:
Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate Methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepine- under storage of the (compound B) -containing lyophilized composition 4-Il] Search for Additives that Suppress the Formation of Propanoate (Compound C)
＜評価用サンプルの製造＞
　化合物Ｂ、マルトース、およびｐＨ調節剤（塩酸／水酸化ナトリウム）と、各種添加剤を用いて、以下の各処方の水溶液を調製し、バイアルに充填後、凍結乾燥に付して評価用サンプルを製造した。
Figure JPOXMLDOC01-appb-T000011
 　使用した各種添加剤とそのサンプル番号の対応を以下に示す。
（M3101）デキストラン４０（ＤＸ４０）
（M3102）ポリソルベート８０(ＰＳ８０)
（M3103）ＨＣＯ－６０
（M3104）α－シクロデキストリン（α－ＣＤ）
（M3105）ヒドロキシプロピル－β－シクロデキストリン（ＨＰ－β－ＣＤ）
（M3106）マクロゴール４０００
（M3107）ポリビニルピロリドンＫ１２（ＰＶＰ－Ｋ１２）
（M3108）マンニトール
（M3109）スクロース
（M3110）トレハロース
（M3111）デキストラン７０（ＤＸ７０） <Manufacture of evaluation samples>
Prepare compound B, maltose, and pH adjuster (hydrochloric acid / sodium hydroxide) and various additives, prepare aqueous solutions of the following formulas, fill vials, freeze-dry, and prepare samples for evaluation. Manufactured.
Figure JPOXMLDOC01-appb-T000011
 The correspondence between the various additives used and their sample numbers is shown below.
(M3101) Dextran 40 (DX40)
(M3102) Polysorbate 80 (PS80)
(M3103) HCO-60
(M3104) α-Cyclodextrin (α-CD)
(M3105) Hydroxypropyl-β-cyclodextrin (HP-β-CD)
(M3106) Macrogol 4000
(M3107) Polyvinylpyrrolidone K12 (PVP-K12)
(M3108) Mannitol (M3109) Sucrose (M3110) Trehalose (M3111) Dextran 70 (DX70)
＜保存試験＞
　各評価用サンプルにつき、６０℃、１ヶ月間の保存試験を実施した。 <Storage test>
Each sample for evaluation was subjected to a storage test at 60 ° C. for one month.
＜分析＞
　保存試験に付した前記サンプルを水／アセトニトリル混液で再溶解後、実施例２に記載の試験条件にて高速液体クロマトグラフィー分析し、類縁物質の量について製造直後のサンプル（Initial）との比較を行った。また、凍結乾燥サンプルの色調および外観を目視で観察後、生理食塩液にて再溶解を行い、再溶解速度の指標として再溶解時間を測定するとともに、再溶解液の色差を色差計により測定した。 <Analysis>
The sample subjected to the storage test was redissolved in a water / acetonitrile mixture and then analyzed by high performance liquid chromatography under the test conditions described in Example 2 to compare the amount of the related substance with that of the sample immediately after production (Initial). went. In addition, after visually observing the color tone and appearance of the freeze-dried sample, it was redissolved in physiological saline, and the re-dissolution time was measured as an indicator of the re-dissolution rate, and the color difference of the redissolved solution was measured with a color difference meter. .
＜結果＞
・類縁物質
　保存試験に伴って生成する化合物Ｃの量を面積百分率にて算出した結果を以下に示す。
（M3101）Initial：検出限界以下　；　保存後：　０．０７％
（M3102）Initial：　０．０２％　；　保存後：　１．０７％
（M3103）Initial：検出限界以下　；　保存後：　０．５０％
（M3104）Initial：検出限界以下　；　保存後：　０．０５％
（M3105）Initial：検出限界以下　；　保存後：　０．０３％
（M3106）Initial：検出限界以下　；　保存後：　５．２９％
（M3107）Initial：検出限界以下　；　保存後：　０．０５％
（M3108）Initial：検出限界以下　；　保存後：　０．０９％
（M3109）Initial：検出限界以下　；　保存後：　０．０７％
（M3110）Initial：検出限界以下　；　保存後：　０．０５％
（M3111）Initial：検出限界以下　；　保存後：　０．０６％ <Result>
-Related substance The result of having calculated the amount of the compound C produced | generated with a preservation | save test in area percentage is shown below.
(M3101) Initial: Below detection limit; After storage: 0.07%
(M3102) Initial: 0.02%; After storage: 1.07%
(M3103) Initial: Below detection limit; After storage: 0.50%
(M3104) Initial: Below detection limit; After storage: 0.05%
(M3105) Initial: Below detection limit; After storage: 0.03%
(M3106) Initial: Below detection limit; After storage: 5.29%
(M3107) Initial: Below detection limit; After storage: 0.05%
(M3108) Initial: Below detection limit; After storage: 0.09%
(M3109) Initial: Below detection limit; After storage: 0.07%
(M3110) Initial: Below detection limit; After storage: 0.05%
(M3111) Initial: Below detection limit; After storage: 0.06%
・再溶解速度
　再溶解速度は、再溶解に要した時間（再溶解時間）を指標として判断した。再溶解時間の測定は、各評価用サンプルにつき３検体ずつ、それぞれの検体に生理食塩液１０ｍＬを添加したときに再溶解するまでの時間を測定することで行った。なお、再溶解に要した時間の測定は６０秒から３００秒の間に行い、６０秒の時点で既に溶解しているものについては６０秒以内、３００秒の時点でまだ溶解していないものについては、３００秒以上と判定した。その平均値を以下に示す。
（M3101）Initial：　６５秒　　　；　保存後：　６０秒以内
（M3102）Initial：　７５秒　　　；　保存後：　６０秒以内
（M3103）Initial：３００秒以上　；　保存後：３００秒以上
（M3104）Initial：　６０秒以内　；　保存後：　６０秒以内
（M3105）Initial：　６０秒以内　；　保存後：　６０秒以内
（M3106）Initial：　８５秒　　　；　保存後：　９５秒
（M3107）Initial：　６０秒以内　；　保存後：　６０秒以内
（M3108）Initial：３００秒以上　；　保存後：３００秒以上
（M3109）Initial：１７５秒　　　；　保存後：１２０秒
（M3110）Initial：３００秒以上　；　保存後：２５５秒
（M3111）Initial：　６０秒以内　；　保存後：　６０秒以内 -Re-dissolution rate The re-dissolution rate was judged using the time required for re-dissolution (re-dissolution time) as an index. The re-dissolution time was measured by measuring three specimens for each evaluation sample and measuring the time until redissolution when 10 mL of physiological saline was added to each specimen. The time required for re-dissolution is measured between 60 seconds and 300 seconds. For those that have already dissolved at the time of 60 seconds, within 60 seconds, those that have not yet dissolved at the time of 300 seconds. Was determined to be 300 seconds or more. The average value is shown below.
(M3101) Initial: 65 seconds; After saving: Within 60 seconds (M3102) Initial: 75 seconds; After saving: Within 60 seconds (M3103) Initial: 300 seconds or more; After saving: 300 seconds or more (M3104) Initial: 60 seconds After saving: Within 60 seconds (M3105) Initial: Within 60 seconds; After saving: Within 60 seconds (M3106) Initial: 85 seconds; After saving: 95 seconds (M3107) Initial: Within 60 seconds; After saving: 60 seconds Within (M3108) Initial: 300 seconds or more; After saving: 300 seconds or more (M3109) Initial: 175 seconds; After saving: 120 seconds (M3110) Initial: 300 seconds or more; After saving: 255 seconds (M3111) Initial: 60 seconds Within; After saving: Within 60 seconds
・再溶解液の色差（ΔＥ）
　再溶解液の色差（ΔＥ）は、製造直後のサンプル（Initial）と保存試験後のサンプルとで、最も変色の程度が小さかったサンプル（M3101）の、製造直後のサンプルの再溶解液を比較対照として測定した。なお、色差測定には、色彩色差計（コニカミノルタセンシング社製）を使用した。測定値を以下に示す。
（M3101）Initial：　　比較対照　；　保存後：　　０．１６
（M3102）Initial：　　０．３９　；　保存後：　８１．８３
（M3103）Initial：　　４．０４　；　保存後：　５５．４２
（M3104）Initial：　　０．７７　；　保存後：　　０．４４
（M3105）Initial：　　０．２４　；　保存後：　　０．０５
（M3106）Initial：　　０．０９　；　保存後：１０７．９３
（M3107）Initial：　　０．１６　；　保存後：　　０．５４
（M3108）Initial：　　０．１１　；　保存後：　　３．７１
（M3109）Initial：　　０．１６　；　保存後：　　２．５２
（M3110）Initial：　　０．０９　；　保存後：　　０．１８
（M3111）Initial：　　０．０７　；　保存後：　　０．３０ -Color difference of redissolved solution (ΔE)
The color difference (ΔE) of the re-dissolved solution is the control of the re-dissolved solution of the sample immediately after manufacture of the sample (M3101) with the smallest color change between the sample immediately after manufacture (Initial) and the sample after storage test. As measured. A color difference meter (manufactured by Konica Minolta Sensing) was used for color difference measurement. The measured values are shown below.
(M3101) Initial: Comparative control; After storage: 0.16
(M3102) Initial: 0.39; After storage: 81.83
(M3103) Initial: 4.04; After storage: 55.42
(M3104) Initial: 0.77; After storage: 0.44
(M3105) Initial: 0.24; After storage: 0.05
(M3106) Initial: 0.09; After storage: 107.93
(M3107) Initial: 0.16; After storage: 0.54
(M3108) Initial: 0.11; After storage: 3.71
(M3109) Initial: 0.16; After storage: 2.52
(M3110) Initial: 0.09; After storage: 0.18
(M3111) Initial: 0.07; After saving: 0.30
　前記で得られた類縁物質、再溶解速度、および再溶解液の色差（ΔＥ）の結果を表４にまとめた。再溶解液の色差（ΔＥ）については、０．８を超えたものを変色と判断し、凍結乾燥ケーキの外観変化に関する記載を含めて「性状（色調・外観）」の項目に記載した。なお、表中で類縁物質の「異性体」の記載は化合物Ｃを表し、再溶解速度の「遅い」の記載は、再溶解時間の平均が７５秒を超えるものを「遅い」と判断した。
Figure JPOXMLDOC01-appb-T000012
 Table 4 summarizes the results of the related substances obtained above, the redissolution rate, and the color difference (ΔE) of the redissolved solution. Regarding the color difference (ΔE) of the redissolved solution, a color difference exceeding 0.8 was judged to be discolored, and was described in the item of “property (color tone / appearance)” including a description of the appearance change of the freeze-dried cake. In the table, the description of the “isomer” of the related substance represents Compound C, and the description of “slow” of the re-dissolution rate was judged as “slow” when the average re-dissolution time exceeded 75 seconds.
Figure JPOXMLDOC01-appb-T000012
　表４の記載より、性状（色調・外観）、再溶解速度、および類縁物質の項目に関し、デキストラン４０（M3101）、α－シクロデキストリン（M3104）、ヒドロキシプロピル－β－シクロデキストリン（M3105）、ポリビニルピロリドンＫ１２（M3107）、およびデキストラン７０（M3111）が良好な結果を示したことがわかった。 From the description in Table 4, regarding properties (color tone / appearance), re-dissolution rate, and related substances, dextran 40 (M3101), α-cyclodextrin (M3104), hydroxypropyl-β-cyclodextrin (M3105), polyvinyl It was found that pyrrolidone K12 (M3107) and dextran 70 (M3111) showed good results.
　実施例４：
メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩（化合物Ｂ）含有凍結乾燥組成物の保存下におけるメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート（化合物Ｃ）の生成に対するデキストラン４０の効果の検討（１） Example 4:
Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate Methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepine- under storage of the (compound B) -containing lyophilized composition Study of the effect of dextran 40 on the formation of 4-yl] propanoate (compound C) (1)
＜評価用サンプルの製造＞
　化合物Ｂ、マルトース、およびｐＨ調節剤（塩酸／水酸化ナトリウム）と、各種添加量のデキストラン４０（ＤＸ４０）を用いて、以下の各処方の水溶液を調製し、バイアルに充填後、凍結乾燥に付して評価用サンプルを製造した。
Figure JPOXMLDOC01-appb-T000013
 <Manufacture of evaluation samples>
Using Compound B, maltose, and a pH regulator (hydrochloric acid / sodium hydroxide) and various addition amounts of dextran 40 (DX40), aqueous solutions of the following formulations are prepared, filled into vials, and then subjected to lyophilization. Thus, a sample for evaluation was manufactured.
Figure JPOXMLDOC01-appb-T000013
　デキストラン４０の含有量とそのサンプル番号の対応を以下に示す。
（DX020）２０ｍｇ
（DX040）４０ｍｇ
（DX080）８０ｍｇ
（DX160）１６０ｍｇ
（DX320）３２０ｍｇ
（DX640）６４０ｍｇ The correspondence between the content of dextran 40 and its sample number is shown below.
(DX020) 20mg
(DX040) 40mg
(DX080) 80mg
(DX160) 160mg
(DX320) 320mg
(DX640) 640mg
＜保存試験＞
　各評価用サンプルにつき、６０℃、１ヶ月間の保存試験を実施した。 <Storage test>
Each sample for evaluation was subjected to a storage test at 60 ° C. for one month.
＜分析＞
　保存試験に付した前記サンプルを水／アセトニトリル混液で再溶解後、実施例２に記載の試験条件にて高速液体クロマトグラフィー分析し、類縁物質の量について製造直後のサンプル（Initial）との比較を行った。また、凍結乾燥サンプルの色調および外観を目視で観察後、生理食塩液にて再溶解を行い、再溶解速度の指標として再溶解時間を測定した。 <Analysis>
The sample subjected to the storage test was redissolved in a water / acetonitrile mixture and then analyzed by high performance liquid chromatography under the test conditions described in Example 2 to compare the amount of the related substance with that of the sample immediately after production (Initial). went. Moreover, after visually observing the color tone and appearance of the freeze-dried sample, the sample was redissolved with physiological saline, and the re-dissolution time was measured as an index of the rate of re-dissolution.
＜結果＞
・類縁物質
　保存試験に伴って生成する化合物Ｃの量を面積百分率にて算出した結果を以下に示す。
（DX020）Initial：検出限界以下　；　保存後：　０．０７％
（DX040）Initial：検出限界以下　；　保存後：　０．０６％
（DX080）Initial：検出限界以下　；　保存後：　０．０７％
（DX160）Initial：検出限界以下　；　保存後：　０．０６％
（DX320）Initial：検出限界以下　；　保存後：　０．０５％
（DX640）Initial：検出限界以下　；　保存後：　０．０５％ <Result>
-Related substance The result of having calculated the amount of the compound C produced | generated with a preservation | save test in area percentage is shown below.
(DX020) Initial: Below detection limit; After storage: 0.07%
(DX040) Initial: Below detection limit; After storage: 0.06%
(DX080) Initial: Below detection limit; After storage: 0.07%
(DX160) Initial: Below detection limit; After storage: 0.06%
(DX320) Initial: Below detection limit; After storage: 0.05%
(DX640) Initial: Below detection limit; After storage: 0.05%
・色調および外観
　製造直後のサンプル（Initial）において、各サンプル間で色調および外観に差は認められなかった。保存後のサンプルにおいても同様であり、製造直後のサンプル（Initial）と比較しても、収縮や変色などの変化は認められなかった。 -Color tone and appearance In the sample immediately after production (Initial), there was no difference in color tone and appearance between the samples. The same applies to the sample after storage, and no change such as shrinkage or discoloration was observed even when compared with the sample immediately after production (Initial).
・再溶解速度
　再溶解速度は、再溶解に要した時間（再溶解時間）を指標として判断した。再溶解時間の測定は、各評価用サンプルにつき３検体ずつ、それぞれの検体に生理食塩液１０ｍＬを添加したときに再溶解するまでの時間を測定することで行った。なお、再溶解に要した時間の測定は６０秒から３００秒の間に行い、６０秒の時点で既に溶解しているものについては６０秒以内、３００秒の時点でまだ溶解していないものについては、３００秒以上と判定した。その平均値を以下に示す。
（DX020）Initial：　６０秒以内　；　保存後：　６０秒以内
（DX040）Initial：　６０秒以内　；　保存後：　６０秒以内
（DX080）Initial：　６５秒　　　；　保存後：　６０秒以内
（DX160）Initial：　６０秒以内　；　保存後：　６０秒以内
（DX320）Initial：　８５秒　　　；　保存後：　９５秒
（DX640）Initial：１５０秒　　　；　保存後：１９０秒 -Re-dissolution rate The re-dissolution rate was judged using the time required for re-dissolution (re-dissolution time) as an index. The re-dissolution time was measured by measuring three specimens for each evaluation sample and measuring the time until redissolution when 10 mL of physiological saline was added to each specimen. The time required for re-dissolution is measured between 60 seconds and 300 seconds. For those that have already dissolved at the time of 60 seconds, within 60 seconds, those that have not yet dissolved at the time of 300 seconds. Was determined to be 300 seconds or more. The average value is shown below.
(DX020) Initial: within 60 seconds; After saving: within 60 seconds (DX040) Initial: within 60 seconds; After saving: within 60 seconds (DX080) Initial: 65 seconds; After saving: within 60 seconds (DX160) Initial: 60 Within seconds; After saving: Within 60 seconds (DX320) Initial: 85 seconds; After saving: 95 seconds (DX640) Initial: 150 seconds; After saving: 190 seconds
　前記で得られた結果より、化合物Ｃの生成、ならびに色調および外観の点で、デキストラン４０は２０ｍｇ～６４０ｍｇの添加量の範囲で良好な結果を示した。また、再溶解速度の点で、デキストラン４０は２０ｍｇ～１６０ｍｇの添加量の範囲で良好な結果を示した。３２０ｍｇを超えるデキストラン４０の添加量では、再溶解速度は遅くなる傾向にあった。 From the results obtained above, dextran 40 showed good results in the range of 20 mg to 640 mg in terms of the formation of compound C, color tone and appearance. In terms of the re-dissolution rate, dextran 40 showed good results in the range of 20 mg to 160 mg. When the amount of dextran 40 added exceeds 320 mg, the re-dissolution rate tends to be slow.
　実施例５：
メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩（化合物Ｂ）含有凍結乾燥組成物の保存下におけるメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート（化合物Ｃ）の生成に対するデキストラン４０の効果の検討（２） Example 5:
Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate Methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepine- under storage of the (compound B) -containing lyophilized composition Study of the effect of dextran 40 on the formation of 4-yl] propanoate (compound C) (2)
＜評価用サンプルの製造＞
　化合物Ｂ、マルトース、ポリソルベート８０（ＰＳ８０）およびｐＨ調節剤（塩酸／水酸化ナトリウム）と、各種添加量のデキストラン４０（ＤＸ４０）を用いて、以下の各処方の水溶液を調製し、バイアルに充填後、凍結乾燥に付して評価用サンプルを製造した。
Figure JPOXMLDOC01-appb-T000014
 <Manufacture of evaluation samples>
Using Compound B, Maltose, Polysorbate 80 (PS80) and pH adjuster (hydrochloric acid / sodium hydroxide) and various addition amounts of dextran 40 (DX40), prepare aqueous solutions of the following formulations, and fill the vials The sample for evaluation was manufactured by freeze-drying.
Figure JPOXMLDOC01-appb-T000014
　デキストラン４０の含有量とそのサンプル番号の対応を以下に示す。
（M1307）２．５ｍｇ
（M1308）５ｍｇ
（M1309）１０ｍｇ
（M1310）２０ｍｇ
（M1403）３０ｍｇ
（M1404）４０ｍｇ
（M1311）５０ｍｇ
（M1405）６０ｍｇ
（M1803）７５ｍｇ
（M1804）１００ｍｇ
（M1805）１２５ｍｇ The correspondence between the content of dextran 40 and its sample number is shown below.
(M1307) 2.5mg
(M1308) 5mg
(M1309) 10mg
(M1310) 20mg
(M1403) 30mg
(M1404) 40mg
(M1311) 50mg
(M1405) 60mg
(M1803) 75mg
(M1804) 100mg
(M1805) 125mg
＜保存試験＞
　各評価用サンプルにつき、６０℃、１ヶ月間の保存試験を実施した。 <Storage test>
Each sample for evaluation was subjected to a storage test at 60 ° C. for one month.
＜分析＞
　保存試験に付した前記サンプルを水／アセトニトリル混液で再溶解後、以下の試験条件にて高速液体クロマトグラフィー分析し、類縁物質の量について製造直後のサンプル（Initial）との比較を行った。なお、類縁物質のうち、化合物Ｃに相当するピークは、前述の実施例１で製造した化合物を標品として用いた高速液体クロマトグラフィー、ＭＳおよびＮＭＲにより同定されたものである。また、凍結乾燥サンプルの色調および外観を目視で観察後、生理食塩液にて再溶解を行い、再溶解速度の指標として再溶解時間を測定した。 <Analysis>
The sample subjected to the storage test was redissolved with a water / acetonitrile mixture, and then subjected to high performance liquid chromatography analysis under the following test conditions, and the amount of the related substance was compared with that of the sample immediately after production (Initial). Of the related substances, the peak corresponding to compound C is identified by high performance liquid chromatography, MS and NMR using the compound prepared in Example 1 as a standard. Moreover, after visually observing the color tone and appearance of the freeze-dried sample, the sample was redissolved with physiological saline, and the re-dissolution time was measured as an index of the rate of re-dissolution.
試験条件
検出器：紫外吸光光度計（測定波長：２３０ｎｍ）；
カラム：内径４．６ｍｍ、長さ１５ｃｍのステンレス管に３μｍの液体クロマトグラフィー用オクタデシルシリル化シリカゲルを充填したもの；
カラム温度：４０℃付近の一定温度；
移動相Ａ：１０ｍｍｏｌ／Ｌリン酸二水素カリウム溶液；
移動相Ｂ：メタノール；
移動相の送液：移動相Ａと移動相Ｂの混合比変化による濃度勾配制御（移動相Ａと移動相Ｂとを混合し、移動相Ａの混合比率が３５％乃至５０％の範囲内となるように濃度勾配制御した。）；
流量：毎分１．０ｍＬ。 Test conditions Detector: UV absorption photometer (measurement wavelength: 230 nm);
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm packed with 3 μm of octadecylsilylated silica gel for liquid chromatography;
Column temperature: constant temperature around 40 ° C;
Mobile phase A: 10 mmol / L potassium dihydrogen phosphate solution;
Mobile phase B: methanol;
Mobile phase liquid feeding: concentration gradient control by changing the mixing ratio of mobile phase A and mobile phase B (mixing mobile phase A and mobile phase B, and the mixing ratio of mobile phase A is in the range of 35% to 50%) The concentration gradient was controlled so that
Flow rate: 1.0 mL per minute.
＜結果＞
・類縁物質
　保存試験に伴って生成する化合物Ｃの量を面積百分率にて算出した結果を以下に示す。なお、デキストラン４０を添加しない場合における化合物Ｃの量は、Initialでは検出限界以下、保存後は０．５６％であった。
（M1307）Initial：検出限界以下　；　保存後：　０．５７％
（M1308）Initial：検出限界以下　；　保存後：　０．５２％
（M1309）Initial：検出限界以下　；　保存後：　０．４８％
（M1310）Initial：検出限界以下　；　保存後：　０．４１％
（M1403）Initial：検出限界以下　；　保存後：　０．４２％
（M1404）Initial：検出限界以下　；　保存後：　０．３９％
（M1311）Initial：検出限界以下　；　保存後：　０．３６％
（M1405）Initial：検出限界以下　；　保存後：　０．３５％
（M1803）Initial：検出限界以下　；　保存後：　０．３４％
（M1804）Initial：検出限界以下　；　保存後：　０．３０％
（M1805）Initial：検出限界以下　；　保存後：　０．３０％ <Result>
-Related substance The result of having calculated the amount of the compound C produced | generated with a preservation | save test in area percentage is shown below. The amount of Compound C in the case where dextran 40 was not added was not more than the detection limit for Initial, and was 0.56% after storage.
(M1307) Initial: Below detection limit; After storage: 0.57%
(M1308) Initial: Below detection limit; After storage: 0.52%
(M1309) Initial: Below detection limit; After storage: 0.48%
(M1310) Initial: Below detection limit; After storage: 0.41%
(M1403) Initial: Below detection limit; After storage: 0.42%
(M1404) Initial: Below detection limit; After storage: 0.39%
(M1311) Initial: Below detection limit; After storage: 0.36%
(M1405) Initial: Below detection limit; After storage: 0.35%
(M1803) Initial: Below detection limit; After storage: 0.34%
(M1804) Initial: Below detection limit; After storage: 0.30%
(M1805) Initial: Below detection limit; After storage: 0.30%
・色調および外観
　製造直後のサンプル（Initial）において、各サンプル間で色調および外観に差は認められなかった。一方、保存後のサンプルにおいては、デキストラン４０の添加量が少ないサンプルほど強い変色（橙色）が認められ、デキストラン４０の添加量を増やすにつれて変色の程度は軽微となった。また、デキストラン４０の添加量が７５ｍｇ以上のサンプル（M1803、M1804、M1805）では、デキストラン４０による変色抑制効果はほぼプラトーに達した。 -Color tone and appearance In the sample immediately after production (Initial), there was no difference in color tone and appearance between the samples. On the other hand, in the sample after storage, the sample having a smaller amount of dextran 40 was observed to have a strong color change (orange), and the degree of color change became lighter as the amount of dextran 40 added was increased. Further, in the samples (M1803, M1804, M1805) in which the amount of dextran 40 added was 75 mg or more, the discoloration suppressing effect by dextran 40 almost reached a plateau.
・再溶解速度
　再溶解速度は、再溶解に要した時間（再溶解時間）を指標として判断した。再溶解時間の測定は、各評価用サンプルにつき２検体ずつ、それぞれの検体に生理食塩液１０ｍＬを添加したときに再溶解するまでの時間を測定することで行った。なお、再溶解に要した時間の測定は６０秒から３００秒の間に行い、６０秒の時点で既に溶解しているものについては６０秒以内、３００秒の時点でまだ溶解していないものについては、３００秒以上と判定した。その平均値を以下に示す。
（M1307）Initial：１７２．５秒　；　保存後：　８２．５秒
（M1308）Initial：１５０　　秒　；　保存後：　７５　　秒
（M1309）Initial：１３５　　秒　；　保存後：　７５　　秒
（M1310）Initial：１５０　　秒　；　保存後：　７５　　秒
（M1403）Initial：１２０　　秒　；　保存後：　７５　　秒
（M1404）Initial：１３５　　秒　；　保存後：　９０　　秒
（M1311）Initial：１４２．５秒　；　保存後：　７５　　秒
（M1405）Initial：１５０　　秒　；　保存後：　７５　　秒
（M1803）Initial：　６０　　秒　；　保存後：　６０　　秒
（M1804）Initial：　６０　　秒　；　保存後：　６０　　秒
（M1805）Initial：　６０　　秒　；　保存後：　６０　　秒 -Re-dissolution rate The re-dissolution rate was judged using the time required for re-dissolution (re-dissolution time) as an index. The re-dissolution time was measured by measuring two specimens for each evaluation sample and measuring the time until redissolution when 10 mL of physiological saline was added to each specimen. The time required for re-dissolution is measured between 60 seconds and 300 seconds. For those that have already dissolved at the time of 60 seconds, within 60 seconds, those that have not yet dissolved at the time of 300 seconds. Was determined to be 300 seconds or more. The average value is shown below.
(M1307) Initial: 172.5 seconds; After saving: 82.5 seconds (M1308) Initial: 150 seconds; After saving: 75 seconds (M1309) Initial: 135 seconds; After saving: 75 seconds (M1310) Initial: 150 seconds After saving: 75 seconds (M1403) Initial: 120 seconds; After saving: 75 seconds (M1404) Initial: 135 seconds; After saving: 90 seconds (M1311) Initial: 142.5 seconds; After saving: 75 seconds (M1405) After saving: 75 seconds (M1803) Initial: 60 seconds; After saving: 60 seconds (M1804) Initial: 60 seconds; After saving: 60 seconds (M1805) Initial: 60 seconds; After saving: 60 seconds
　前記で得られた結果より、「組成物の変色」を抑制する効果は、デキストラン４０の添加量が７５ｍｇ以上である場合に顕著であることが判明した。「化合物Ａの分解」を抑制する効果については、デキストラン４０の添加量を増やすにつれて強くなる傾向が認められた。一方、再溶解速度については、可溶化剤であるポリソルベート８０共存下での試験であるため、デキストラン４０の効果は確認できなかった。 From the results obtained above, it was found that the effect of suppressing “discoloration of the composition” is significant when the amount of dextran 40 added is 75 mg or more. About the effect which suppresses "decomposition | disassembly of the compound A", the tendency which became strong as the addition amount of the dextran 40 was increased was recognized. On the other hand, since the re-dissolution rate is a test in the presence of polysorbate 80, which is a solubilizing agent, the effect of dextran 40 could not be confirmed.
　本発明で開示する、有効成分としてメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩を含有してなる注射用組成物は、保存下においても安定で、分解物であるメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの生成を抑え、また組成物自体の変色を抑えた注射用組成物であるため、品質の劣化なく、安全に臨床現場に提供することができる。 As an active ingredient disclosed in the present invention, methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine- An injectable composition comprising 4-yl] propanoate or a salt thereof is stable under storage and is a decomposition product of methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl)- 6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate is an injectable composition that suppresses discoloration of the composition itself, and is therefore safe without quality deterioration. Can be provided to clinical sites.

Claims (23)

  1. 　（１）有効成分であるメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩と、（２）デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤とを含有してなる注射用組成物。 (1) Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine-4- Il] propanoate or a salt thereof and (2) one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone.
  2. 　添加剤が、デキストラン４０、デキストラン７０、α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリンまたはポリビニルピロリドンＫ１２である、請求項１記載の注射用組成物。 The injectable composition according to claim 1, wherein the additive is dextran 40, dextran 70, α-cyclodextrin, hydroxypropyl-β-cyclodextrin or polyvinylpyrrolidone K12.
  3. 　添加剤が、デキストラン４０である、請求項１記載の注射用組成物。 The composition for injection according to claim 1, wherein the additive is dextran 40.
  4. 　デキストラン４０の含有量が、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート１重量部あたり約０．４重量部乃至約１２．８重量部である、請求項３記載の注射用組成物。 The content of dextran 40 is methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine-4- The composition for injection according to claim 3, which is about 0.4 to about 12.8 parts by weight per 1 part by weight of yl] propanoate.
  5. 　有効成分がメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩である、請求項１乃至４のいずれか一項に記載の注射用組成物。 The active ingredient is methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzene The injectable composition according to any one of claims 1 to 4, which is a sulfonate.
  6. 　組成物の保存に伴う、（ａ）メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの分解、（ｂ）メチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの生成、および／または（ｃ）組成物の変色を抑制した、請求項１乃至５のいずれか一項に記載の注射用組成物。 (A) Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine accompanying storage of the composition -4-yl] propanoate decomposition, (b) methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepine-4 The composition for injection according to any one of claims 1 to 5, wherein the production of -yl] propanoate and / or (c) discoloration of the composition is suppressed.
  7. 　保存条件が、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間である、請求項６に記載の注射用組成物。 7. Storage conditions according to claim 6, wherein the storage conditions are (1) a temperature of 60 ° C. for 1 month, (2) a temperature of 40 ° C. and a relative humidity of 75% for 6 months, and / or (3) room temperature for 3 years. Injectable composition.
  8. 　凍結乾燥組成物である、請求項１に記載の注射用組成物。 The injectable composition according to claim 1, which is a lyophilized composition.
  9. 　組成物１単位形態あたり、有効成分である約６８ｍｇのメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩と、約４０ｍｇ乃至約１６０ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物。 About 68 mg of methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1] as an active ingredient per unit form of the composition , 4] benzodiazepin-4-yl] propanoate benzenesulfonate and about 40 mg to about 160 mg of dextran 40.
  10. 　組成物１単位形態あたり、有効成分である約２７．２ｍｇのメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩と、約１６ｍｇ乃至約６４ｍｇのデキストラン４０とを含有してなる凍結乾燥組成物。 Approximately 27.2 mg of methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] as an active ingredient per unit form of the composition [1,4] Benzodiazepin-4-yl] propanoate A lyophilized composition comprising benzenesulfonate and about 16 mg to about 64 mg of dextran 40.
  11. 　メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩、デキストラン４０、マルトースおよびｐＨ調節剤を含有するｐＨ２．５乃至３．５の注射用組成物。 Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate An injectable composition having a pH of 2.5 to 3.5, containing dextran 40, maltose and a pH regulator.
  12. 　メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩、デキストラン４０、マルトースおよびｐＨ調節剤を含有するｐＨ２．５乃至３．５の注射用組成物であり、かつ、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間の保存後において、メチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートが実質的に生成されないか、またはメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの生成量が０．２％未満である注射用組成物。 Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate , Dextran 40, maltose and a pH regulator, and an injectable composition having a pH of 2.5 to 3.5, and (1) a temperature of 60 ° C. for one month, (2) a temperature of 40 ° C. and a relative humidity of 75 % For 3 months and / or after storage for 3 years at room temperature methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a ], [1,4] benzodiazepin-4-yl] propanoate is not substantially formed or methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2- a] 1,4] benzodiazepin-4-yl] Injectable compositions the amount of propanoate is less than 0.2%.
  13. 　ｐＨ調節剤が塩酸および／または水酸化ナトリウムである、請求項１１または１２のいずれか一項に記載の注射用組成物。 The injectable composition according to any one of claims 11 and 12, wherein the pH adjuster is hydrochloric acid and / or sodium hydroxide.
  14. 　凍結乾燥組成物である、請求項１１乃至１３のいずれか一項に記載の注射用組成物。 The injectable composition according to any one of claims 11 to 13, which is a lyophilized composition.
  15. 　有効成分としてメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩を含有する安定な凍結乾燥組成物であって、組成物１単位形態あたり、（ａ）約６８ｍｇのメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩、（ｂ）約８０ｍｇのデキストラン４０、（ｃ）約３６０ｍｇのマルトース、および（ｄ）ｐＨ調節剤を含有し、かつ、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間の保存後において、メチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートが実質的に生成されないか、またはメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの生成量が０．２％未満である、ｐＨ２．５乃至３．５の凍結乾燥組成物。 Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzene as an active ingredient A stable lyophilized composition containing a sulfonate salt, wherein (a) about 68 mg of methyl 3-[(4S) -8-bromo-1-methyl-6- (2- Pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate, (b) about 80 mg dextran 40, (c) about 360 mg maltose, and (d ) Containing a pH regulator and (1) for 1 month at 60 ° C., (2) for 6 months at 40 ° C. and 75% relative humidity, and / or (3) after 3 years storage at room temperature In this case, methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate is substantially formed. Or the amount of methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate produced A lyophilized composition having a pH of 2.5 to 3.5 that is less than 0.2%.
  16. 　有効成分としてメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩を含有する安定な凍結乾燥組成物であって、組成物１単位形態あたり、（ａ）約２７．２ｍｇのメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアート　ベンゼンスルホン酸塩、（ｂ）約３２ｍｇのデキストラン４０、（ｃ）約１４５ｍｇのマルトース、および（ｄ）ｐＨ調節剤を含有し、かつ、（１）温度６０℃で１ヶ月間、（２）温度４０℃、相対湿度７５％で６ヶ月間、および／または（３）室温で３年間の保存後において、メチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートが実質的に生成されないか、またはメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの生成量が０．２％未満である、ｐＨ２．５乃至３．５の凍結乾燥組成物。 Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzene as an active ingredient A stable lyophilized composition containing a sulfonate salt, wherein (a) about 27.2 mg of methyl 3-[(4S) -8-bromo-1-methyl-6- ( 2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate benzenesulfonate, (b) about 32 mg dextran 40, (c) about 145 mg maltose, and (D) containing a pH regulator and (1) for 1 month at 60 ° C., (2) for 6 months at 40 ° C. and 75% relative humidity, and / or (3) for 3 years at room temperature. Protection Later, methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate is substantially formed. Or the amount of methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate produced A lyophilized composition having a pH of 2.5 to 3.5 that is less than 0.2%.
  17. 　デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤を注射用組成物中に含有せしめることを特徴とする、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩を含有する安定な注射用組成物の製造方法。 One or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone are contained in the injectable composition, and methyl 3-[(4S) -8-bromo-1-methyl A process for producing a stable injectable composition comprising -6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate or a salt thereof.
  18. 　（１）有効成分であるメチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩とデキストラン４０とを含有してなる注射用組成物と、（２）容器と、（３）前記組成物が全身麻酔および／または鎮静のために使用することができる旨を示す、指示書、説明書、添付文書、または製品ラベルとを含む、製品。 (1) Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine-4- Ill] propanoate or a salt thereof and dextran 40, (2) a container, and (3) that the composition can be used for general anesthesia and / or sedation. Product, including instructions, instructions, package inserts, or product labels to indicate.
  19. 　メチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩。 Methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate or a salt thereof.
  20. 　メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩もしくはそれらを有効成分として含有する医薬組成物の安全性および／または安定性の評価のためのメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩。 Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate or a salt thereof Methyl 3- [8-bromo-1-methyl-6- (2-pyridinyl) -6H-imidazo [1,2] for evaluation of safety and / or stability of pharmaceutical compositions containing them as active ingredients -A] [1,4] benzodiazepin-4-yl] propanoate or a salt thereof.
  21. 　デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤を用いることを特徴とする、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩の安定化方法。 Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) characterized by using one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone ) A method for stabilizing 4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate or a salt thereof.
  22. 　メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩の安定化のための、デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤の使用。 Of methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate or a salt thereof Use of one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone for stabilization.
  23. 　デキストラン、シクロデキストリンおよびポリビニルピロリドンからなる群より選択される１種以上の添加剤を用いることを特徴とする、メチル　３－［（４Ｓ）－８－ブロモ－１－メチル－６－（２－ピリジニル）－４Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートまたはその塩を含有してなる注射用組成物の保存に伴うメチル　３－［８－ブロモ－１－メチル－６－（２－ピリジニル）－６Ｈ－イミダゾ［１，２－ａ］［１，４］ベンゾジアゼピン－４－イル］プロパノアートの生成抑制方法。 Methyl 3-[(4S) -8-bromo-1-methyl-6- (2-pyridinyl) characterized by using one or more additives selected from the group consisting of dextran, cyclodextrin and polyvinylpyrrolidone ) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate or its salt accompanying the storage of an injectable composition methyl 3- [8-bromo-1- A method for inhibiting the production of methyl-6- (2-pyridinyl) -6H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] propanoate.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107198691A (en) * 2016-03-17 2017-09-26 江苏恒瑞医药股份有限公司 A kind of pharmaceutical composition of auspicious horse azoles logical sequence
CN108047229A (en) * 2017-12-15 2018-05-18 宜昌人福药业有限责任公司 Benzodiazepine * class compounds
JP2020500887A (en) * 2016-12-09 2020-01-16 チョントゥー ブリリアント ファーマシューティカル カンパニー，リミティド Hydrobromide salts of benzodiazepine derivatives, their preparation and use
CN112462015A (en) * 2020-11-18 2021-03-09 海南倍特药业有限公司 Method for detecting Remazolam hydrobromide bacterial endotoxin

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103202815A (en) * 2013-05-05 2013-07-17 王元青 Injection for treating mental disease
WO2013174883A1 (en) * 2012-05-22 2013-11-28 Paion Uk Limited Compositions comprising short-acting benzodiazepines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013174883A1 (en) * 2012-05-22 2013-11-28 Paion Uk Limited Compositions comprising short-acting benzodiazepines
CN103202815A (en) * 2013-05-05 2013-07-17 王元青 Injection for treating mental disease

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107198691A (en) * 2016-03-17 2017-09-26 江苏恒瑞医药股份有限公司 A kind of pharmaceutical composition of auspicious horse azoles logical sequence
JP2020500887A (en) * 2016-12-09 2020-01-16 チョントゥー ブリリアント ファーマシューティカル カンパニー，リミティド Hydrobromide salts of benzodiazepine derivatives, their preparation and use
EP3553059A4 (en) * 2016-12-09 2020-05-13 Chengdu Brilliant Pharmaceutical Co., Ltd. Hydrobromate of benzodiazepine derivative, preparation method and use thereof
CN108047229A (en) * 2017-12-15 2018-05-18 宜昌人福药业有限责任公司 Benzodiazepine * class compounds
CN112462015A (en) * 2020-11-18 2021-03-09 海南倍特药业有限公司 Method for detecting Remazolam hydrobromide bacterial endotoxin
CN112462015B (en) * 2020-11-18 2022-07-12 海南倍特药业有限公司 Method for detecting bacterial endotoxin of remazolam hydrobromide

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