[go: up one dir, main page]

WO2015076340A1 - Composition injectable pour l'anesthésie générale et/ou la sédation - Google Patents

Composition injectable pour l'anesthésie générale et/ou la sédation Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
composition
compound
pyridinyl
bromo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2014/080791
Other languages
English (en)
Japanese (ja)
Inventor
加藤　雅也
和彦 ▲高▼畑
誠一 谷川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ono Pharmaceutical Co Ltd
Original Assignee
Ono Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co Ltd filed Critical Ono Pharmaceutical Co Ltd
Publication of WO2015076340A1 publication Critical patent/WO2015076340A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition injectable qui comprend (1) un méthyl 3-[(4S)-8-bromo-1-méthyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazépine-4-yl]propanoate ou un sel de celui-ci en tant que principe actif et (2) un type ou plus d'un additif choisi dans le groupe constitué par dextrane, cyclodextrine et polyvinyle pyrrolidone.
PCT/JP2014/080791 2013-11-21 2014-11-20 Composition injectable pour l'anesthésie générale et/ou la sédation Ceased WO2015076340A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2013-240498 2013-11-21
JP2013240498 2013-11-21

Publications (1)

Publication Number Publication Date
WO2015076340A1 true WO2015076340A1 (fr) 2015-05-28

Family

ID=53179600

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2014/080791 Ceased WO2015076340A1 (fr) 2013-11-21 2014-11-20 Composition injectable pour l'anesthésie générale et/ou la sédation

Country Status (1)

Country Link
WO (1) WO2015076340A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107198691A (zh) * 2016-03-17 2017-09-26 江苏恒瑞医药股份有限公司 一种瑞马唑仑的药物组合物
CN108047229A (zh) * 2017-12-15 2018-05-18 宜昌人福药业有限责任公司 苯并二氮杂*类化合物
JP2020500887A (ja) * 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 ベンゾジアゼピン誘導体の臭化水素酸塩、その調製方法及び使用
CN112462015A (zh) * 2020-11-18 2021-03-09 海南倍特药业有限公司 一种氢溴酸瑞马唑仑细菌内毒素的检测方法
WO2025052259A1 (fr) * 2023-09-05 2025-03-13 Reena Patel Compositions de remimazolam prêtes à l'emploi
CN119700658A (zh) * 2024-11-29 2025-03-28 康诺生物制药股份有限公司 一种盐酸右美托咪定注射液及其制备工艺

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103202815A (zh) * 2013-05-05 2013-07-17 王元青 治疗精神疾病的注射剂
WO2013174883A1 (fr) * 2012-05-22 2013-11-28 Paion Uk Limited Compositions comprenant des benzodiazépines à action rapide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013174883A1 (fr) * 2012-05-22 2013-11-28 Paion Uk Limited Compositions comprenant des benzodiazépines à action rapide
CN103202815A (zh) * 2013-05-05 2013-07-17 王元青 治疗精神疾病的注射剂

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107198691A (zh) * 2016-03-17 2017-09-26 江苏恒瑞医药股份有限公司 一种瑞马唑仑的药物组合物
JP2020500887A (ja) * 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 ベンゾジアゼピン誘導体の臭化水素酸塩、その調製方法及び使用
EP3553059A4 (fr) * 2016-12-09 2020-05-13 Chengdu Brilliant Pharmaceutical Co., Ltd. Bromhydrate de dérivé de benzodiazépine, son procédé de préparation et son utilisation
CN108047229A (zh) * 2017-12-15 2018-05-18 宜昌人福药业有限责任公司 苯并二氮杂*类化合物
CN112462015A (zh) * 2020-11-18 2021-03-09 海南倍特药业有限公司 一种氢溴酸瑞马唑仑细菌内毒素的检测方法
CN112462015B (zh) * 2020-11-18 2022-07-12 海南倍特药业有限公司 一种氢溴酸瑞马唑仑细菌内毒素的检测方法
WO2025052259A1 (fr) * 2023-09-05 2025-03-13 Reena Patel Compositions de remimazolam prêtes à l'emploi
CN119700658A (zh) * 2024-11-29 2025-03-28 康诺生物制药股份有限公司 一种盐酸右美托咪定注射液及其制备工艺
CN119700658B (zh) * 2024-11-29 2025-10-28 康诺生物制药股份有限公司 一种盐酸右美托咪定注射液及其制备工艺

Similar Documents

Publication Publication Date Title
WO2015076340A1 (fr) Composition injectable pour l'anesthésie générale et/ou la sédation
KR101914940B1 (ko) 안과 질환을 치료하기 위한 안드로겐 조성물
TWI806829B (zh) 含有維他命ａ之乳狀點眼液
HUP0301124A2 (hu) Elszíneződésre nem hajlamos. minoxidil-tartalmú kompozíció és eljárás minoxidiltartalmú kompozíció elszíneződésének megakadályozására
Khalid et al. Extemporaneous printing of diclofenac orodispersible films for pediatrics
Singh et al. Solution stability of Captisol-stabilized melphalan (Evomela) versus Propylene glycol-based melphalan hydrochloride injection
JP2015193634A (ja) 水性組成物
EP2735305B1 (fr) Préparations pharmaceutiques liquides stabilisées
WO2023277075A1 (fr) Agent cutané topique contenant un héparinoïde et du loxoprofène ou un sel de celui-ci
TWI406675B (zh) Pharmaceutical composition
JP5593345B2 (ja) イソプロピルウノプロストンの分解抑制方法
AU2013342069B2 (en) Enema composition for treatment of ulcerative colitis having long term stability
TW202128178A (zh) 眼用醫藥組合物
Jia et al. The passive diffusion improvement of Vitamin B12 intestinal absorption by Gelucire that fit for commercialized production
Khattak et al. Photodegradation and stabilization of betamethasone-17 valerate in aqueous/organic solvents and topical formulations
Olivier et al. In situ nasal absorption of midazolam in rats
Spassov et al. Hydrogen sulfide confers lung protection during mechanical ventilation via cyclooxygenase 2, 15-deoxy Δ12, 14-prostaglandin J2, and peroxisome proliferator-activated receptor gamma
Phelan et al. Effect of hepatic and renal impairment on the pharmacokinetics of dalcetrapib: altered distribution of the active thiol?
CN114555054A (zh) 二聚萘酰亚胺制剂
JP2011144123A (ja) 皮膚外用剤
Sautou-Miranda et al. Compatibility of paclitaxel in 5% glucose solution with ECOFLAC® low-density polyethylene containers–stability under different storage conditions
KR20150110773A (ko) 징명한 수성 액제
Gehin et al. Pharmacokinetic interactions between simvastatin and setipiprant, a CRTH2 antagonist
Prohotsky et al. Formulation and stability of an extemporaneously compounded oral solution of chlorpromazine HCl
CN108143717A (zh) 一种薄荷脑纳米乳剂及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14863727

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 12/09/2016)

122 Ep: pct application non-entry in european phase

Ref document number: 14863727

Country of ref document: EP

Kind code of ref document: A1