WO2022210784A1 - ヘテロシクリデンアセトアミド誘導体含有懸濁液 - Google Patents

ヘテロシクリデンアセトアミド誘導体含有懸濁液 Download PDF

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WO2022210784A1
WO2022210784A1 PCT/JP2022/015691 JP2022015691W WO2022210784A1 WO 2022210784 A1 WO2022210784 A1 WO 2022210784A1 JP 2022015691 W JP2022015691 W JP 2022015691W WO 2022210784 A1 WO2022210784 A1 WO 2022210784A1
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Prior art keywords
aqueous suspension
trifluoromethylchroman
ylidene
acetamide
hydroxy
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PCT/JP2022/015691
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English (en)
French (fr)
Japanese (ja)
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有希 山下
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Senju Pharmaceutical Co Ltd
Mochida Pharmaceutical Co Ltd
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Senju Pharmaceutical Co Ltd
Mochida Pharmaceutical Co Ltd
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Priority to MX2023011649A priority Critical patent/MX2023011649A/es
Priority to US18/553,141 priority patent/US12564553B2/en
Priority to AU2022250028A priority patent/AU2022250028A1/en
Priority to BR112023019820A priority patent/BR112023019820A2/pt
Priority to EP22780995.1A priority patent/EP4316485A4/en
Priority to KR1020237037161A priority patent/KR20230163502A/ko
Priority to JP2022546133A priority patent/JP7175431B1/ja
Priority to CN202280026310.3A priority patent/CN117120048A/zh
Application filed by Senju Pharmaceutical Co Ltd, Mochida Pharmaceutical Co Ltd filed Critical Senju Pharmaceutical Co Ltd
Priority to CA3215750A priority patent/CA3215750A1/en
Publication of WO2022210784A1 publication Critical patent/WO2022210784A1/ja
Priority to JP2022178888A priority patent/JP7273235B2/ja
Anticipated expiration legal-status Critical
Priority to US19/009,331 priority patent/US12527740B2/en
Ceased legal-status Critical Current

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    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • This disclosure relates to fields such as medicine, healthcare, biology and biotechnology.
  • the present disclosure relates, inter alia, to techniques for improving the redispersibility of suspensions containing heterocyclideneacetamide derivatives, and formulation techniques based thereon.
  • the population of dry eye patients in Japan is at least about 8 million, and it is estimated that there are about 22 million people including potential patients who use over-the-counter eye drops without going to the hospital, and there are more than 1 billion people in the world.
  • the use of televisions, computers, mobile terminals, etc. increases the number of times we stare at the screen and the number of times we blink decreases.
  • the use of air conditioners, etc. dries the air, resulting in accelerated evaporation of tears. , is widely known to cause dry eye.
  • refractive surgery and contact lens use result in dry eyes. Symptoms associated with dry eye include ocular discomfort, dryness, burning and irritation of the ocular surface.
  • the present disclosure describes one heterocyclideneacetamide derivative, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydro
  • An aqueous suspension containing naphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof and having excellent redispersibility is provided.
  • the present disclosure provides: (Item 1) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable thereof an aqueous suspension comprising a salt or solvate, a cellulosic polymer, and a nonionic surfactant. (Item 2) The aqueous suspension according to the preceding items, wherein the concentration of the cellulosic polymer in the aqueous suspension is about 0.00007 w/v% to about 0.01 w/v%.
  • aqueous suspension according to any one of the preceding items wherein the concentration of the nonionic surfactant in the aqueous suspension is from about 0.01 w/v% to about 0.05 w/v%.
  • the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil. Turbidity agent.
  • aqueous suspension comprising a salt or solvate, a cellulosic polymer, and a nonionic surfactant, the concentration of the cellulosic polymer in the aqueous suspension is about 0.0001 w/v% to about 0.005 w/v%;
  • the cellulosic polymer is at least one selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose, the concentration of the nonionic surfactant in the aqueous suspension is from about 0.01 w/v% to about 0.05 w/v%; wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, and polyethylene glycol monostearate
  • aqueous suspension comprising a salt or solvate, a cellulosic polymer, and a nonionic surfactant, the concentration of the cellulosic polymer in the aqueous suspension is about 0.0001 w/v% to about 0.005 w/v%;
  • the cellulosic polymer is at least one selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose, the concentration of the nonionic surfactant in the aqueous suspension is from about 0.01 w/v% to about 0.05 w/v%; wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, and polyethylene glycol monostearate
  • aqueous suspension comprising a salt or solvate, a cellulosic polymer, and a nonionic surfactant, the concentration of the cellulosic polymer in the aqueous suspension is about 0.0001 w/v% to about 0.005 w/v%; the cellulosic polymer is methyl cellulose, the concentration of the nonionic surfactant in the aqueous suspension is from about 0.01 w/v% to about 0.05 w/v%; the nonionic surfactant is tyloxapol; Additionally containing zinc chloride, and borate buffer, the concentration of the zinc chloride in the aqueous suspension is from about 0.0005% w/v to about 0.01% w/v; the a salt or solvate, a cellulosic polymer, and a nonionic surfactant, the concentration of the cellulosic polymer in the aqueous suspension is about 0.0001 w/v% to about 0.005 w/v%;
  • aqueous suspension comprising a salt or solvate, a cellulosic polymer, and a nonionic surfactant, the concentration of the cellulosic polymer in the aqueous suspension is about 0.0005 w/v% to about 0.003 w/v%; the cellulosic polymer is methyl cellulose, the concentration of the nonionic surfactant in the aqueous suspension is from about 0.01 w/v% to about 0.03 w/v%; the nonionic surfactant is tyloxapol; Additionally containing zinc chloride, and borate buffer, the concentration of the zinc chloride in the aqueous suspension is from about 0.001% w/v to about 0.005% w/v; the a salt or solvate, a cellulosic polymer, and a nonionic surfactant, the concentration of the cellulosic polymer in the aqueous suspension is about 0.0005 w/v% to about 0.003 w/v%;
  • (Item B2) An aqueous suspension according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is from about 0.0001 w/v% to about 0.5 w/v%.
  • (Item B2a) The aqueous suspension according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is from about 0.0001 w/v% to about 0.1 w/v%.
  • (Item B3) An aqueous suspension according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is from about 0.01 w/v% to about 0.05 w/v%.
  • (Item B4) The aqueous suspension according to any one of the preceding items, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil. Turbidity agent.
  • (Item B11) The aqueous suspension according to any one of the above items, wherein the cellulosic polymer is at least one selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose.
  • (Item B12) The (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide is (E)-2 Any one of the preceding items which is -(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide Aqueous suspension agent according to item.
  • (Item D2) The method according to the preceding items, wherein the concentration of the cellulosic polymer in the aqueous suspension is from about 0.00007 w/v% to about 0.01 w/v%.
  • (Item D2a) The method according to the preceding items, wherein the concentration of the cellulosic polymer in the aqueous suspension is from about 0.00007 w/v% to about 0.007 w/v%.
  • (Item D3) A method according to any one of the preceding items, wherein the concentration of the cellulosic polymer in the aqueous suspension is from about 0.0001 w/v % to about 0.008 w/v %.
  • (Item D3a) A method according to any one of the preceding items, wherein the concentration of the cellulosic polymer in the aqueous suspension is from about 0.0001 w/v % to about 0.005 w/v %.
  • (Item D4) The method according to any one of the above items, wherein the cellulosic polymer is at least one selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose.
  • (Item D5) A method according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is from about 0.0001% w/v to about 0.5% w/v.
  • (Item D6) A method according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is from about 0.0001% w/v to about 0.1% w/v.
  • (Item D6a) A method according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is from about 0.01 w/v % to about 0.05 w/v %.
  • the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil.
  • (Item D10) A method according to any one of the preceding items, wherein the concentration of the zinc or silver salt in the aqueous suspension is from about 0.0001 w/v % to about 0.05 w/v %.
  • (Item D11) A method according to any one of the preceding items, wherein the zinc salt is zinc chloride or zinc sulfate.
  • (Item D11a) A method according to any one of the preceding items, wherein the silver salt is silver nitrate.
  • (Item G1) (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable thereof
  • a method for improving the stability of an aqueous suspension comprising a salt or solvate comprising: (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable thereof mixing a salt or solvate of tyloxapol with tyloxapol to prepare an aqueous suspension.
  • an aqueous suspension having excellent redispersibility can be provided.
  • the present disclosure suppresses the phenomenon that the suspended particles are not uniformly dispersed, enables stable administration of the required amount of the active ingredient, and stably and sufficiently exerts the pharmacological effect. Realize to do. It contributes to improvement of patient adherence and convenience.
  • FIG. 1 is a graph showing the transmittance of each bottle (colorless PE, colorless PP, brown PE) at each wavelength.
  • aqueous suspension is used in the same sense as the term used in this field, and is a liquid agent containing at least a portion of water, in which the components to be mixed are suspended. It is a state in which solid particles are present in a liquid.
  • pharmaceutically acceptable salts refer to relatively non-toxic, inorganic or organic acid addition salts or inorganic or organic base addition salts of the compounds of the present disclosure.
  • solvate refers to a compound of the present disclosure or a pharmaceutically acceptable salt thereof and any solvent that forms a single group by interaction, for example, with an organic solvent Solvates (for example, alcohol (ethanol etc.) hydrates), hydrates and the like are included. When forming a hydrate, it may be coordinated with any number of water molecules. Examples of hydrates include monohydrates and dihydrates.
  • the term “redispersibility” refers to the fact that a liquid containing particles such as a suspension (in the case of a suspension, it is also referred to as “suspended particles”) is stored for a certain period of time so that the solvent of the liquid It refers to the easiness of dispersion when the particles that have sedimented therein are uniformly redispersed throughout the liquid.
  • "redispersibility” is evaluated by a test using a shaking operation or an inversion operation.
  • the term “shaking operation” refers to the action of holding a container filled with an “aqueous suspension” and shaking it up and down.
  • the container In the “shaking operation", the container is shaken vertically 10 to 15 cm wide, and shaken once until it returns to the original position after being shaken up.
  • the redispersibility test by "shaking operation” is performed with 3 to 5 samples per formulation, the average number of sets is calculated from the number of sets required for redispersion of each sample, and the number of times converted to the number of shakings is used.
  • turning operation refers to the action of holding a container filled with an “aqueous suspension” and turning it upside down.
  • the redispersibility test by “inversion operation” is performed with 3 to 5 samples per formulation, and the container is inverted 180 ° up and down at a speed of 1 second / time, and then inverted 180 ° again to make it upright. The operation is set to one overturn.
  • the term "improved redispersibility” means that particles that have sedimented in a liquid containing particles such as a suspension are easily dispersed again. It can be said that the redispersibility was improved when the number of times of "shaking operation” or "overturning operation” decreased.
  • Stability refers to (E)-2-(7-trifluoromethylchroman-4-ylidene) dissolved and/or suspended in an aqueous suspension by storage for a certain period of time.
  • “stability” as used herein means (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6 ,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, of (E)-2- in an aqueous suspension stored for a period of time after preparation (7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.
  • the content maintenance rate which is the ratio of the content of, is typically evaluated by dissolving (E)-2-(7-trifluoromethylchroman-4-ylidene) in an aqueous suspension.
  • improved stability means that the stability is improved when the content maintenance rate is high in comparison of arbitrary formulations.
  • the "average particle size of suspended particles” means (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8- Refers to the median particle size (D 50 ) of the particles of tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, measured using a laser diffraction particle size distribution analyzer. is the value to be
  • cellulose-based polymer is a type of water-soluble polymer, and refers to a cellulose derivative in which the hydroxyl groups of cellulose are partially converted to other substituents.
  • cellulosic polymers include methyl cellulose (hereinafter sometimes referred to as "MC”), hydroxypropylmethyl cellulose, carboxymethyl cellulose (hereinafter sometimes referred to as "CMC”), ethyl cellulose, propyl cellulose, hydroxy Examples include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and sulfonated cellulose derivatives.
  • nonionic surfactant is also referred to as a nonionic surfactant, and refers to a surfactant in which the portion of the hydrophilic group is nonionic. Whether or not it is a nonionic surfactant can be easily determined by those skilled in the art by confirming that it does not ionize (does not exhibit ionicity) when dissolved in water.
  • nonionic surfactants include tyloxapol, polyoxyl stearates (polyethylene glycol monostearate, polyethylene glycol monostearate 40 (MYS-40), polyethylene glycol monostearate 400, etc.), polyoxyethylene sorbitan fatty acid esters.
  • polyoxyethylene sorbitan monooleate polysorbate 80
  • polyoxyethylene sorbitan tristearate polyoxyethylene sorbitan tristearate
  • polyoxy Ethylene hydrogenated castor oils polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 (HCO-60), etc.
  • zinc salt refers to a salt containing zinc ion (Zn 2+ ) as a constituent ion (a compound of zinc and an organic acid or an inorganic acid) or an oxide of zinc.
  • zinc halides such as zinc chloride, zinc bromide or zinc fluoride, zinc sulfate, zinc acetate, zinc phosphate, zinc carbonate, zinc hydroxide, zinc citrate, zinc lactate, zinc gluconate, zinc oxide, or and hydrates thereof.
  • silver salt refers to a salt containing silver ions (Ag + ) as constituent ions (a compound of silver and an organic acid or an inorganic acid) or an oxide of silver. Examples include silver nitrate, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, silver protein, and hydrates thereof.
  • Aqueous suspensions comprising a pharmaceutically acceptable salt or solvate and a nonionic surfactant may be provided.
  • aqueous suspension comprising a pharmaceutically acceptable salt or solvate, a cellulosic polymer, and a nonionic surfactant.
  • aqueous suspension comprising a pharmaceutically acceptable salt or solvate, a nonionic surfactant, and a zinc or silver salt.
  • aqueous suspension comprising a pharmaceutically acceptable salt or solvate, a cellulosic polymer, a nonionic surfactant, and a zinc or silver salt.
  • a method may be provided comprising the step of preparing a liquid formulation.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or A method for improving the redispersibility of suspended particles of a pharmaceutically acceptable salt or solvate thereof comprising: (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-( 7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, a cellulosic polymer, and a nonionic surfactant mixed to prepare an aqueous suspension.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or A method for improving the redispersibility of suspended particles of a pharmaceutically acceptable salt or solvate thereof comprising: (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-( 7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, a nonionic surfactant, and a zinc salt or silver salt
  • a method may be provided comprising mixing to form an aqueous suspension.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or A method for improving the redispersibility of suspended particles of a pharmaceutically acceptable salt or solvate thereof comprising: (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-( 7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, a cellulosic polymer, a nonionic surfactant, and zinc
  • a method may be provided comprising the step of mixing with a salt or silver salt to prepare an aqueous suspension.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl) A method for improving the redispersibility of an aqueous suspension containing acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene )-N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, containing a cellulose-based high A method may be provided comprising adding a molecule.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl) A method for improving the redispersibility of an aqueous suspension containing acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene )-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to an aqueous suspension containing a nonionic interface
  • a method may be provided comprising adding an active agent.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl) A method for improving the redispersibility of an aqueous suspension containing acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene )-N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, containing a cellulose-based high
  • a method may be provided comprising adding a molecule and a non-ionic surfactant.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl) A method for improving the redispersibility of an aqueous suspension containing acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene )-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, to an aqueous suspension containing a nonionic interface
  • a method may be provided comprising adding an active agent and a zinc or silver salt.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl) A method for improving the redispersibility of an aqueous suspension containing acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene )-N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, containing a cellulose-based high
  • a method may be provided comprising adding a molecule and a zinc or silver salt.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl) A method for improving the redispersibility of an aqueous suspension containing acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene )-N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, containing a cellulose-based high
  • a method may be provided comprising adding a molecule, a nonionic surfactant, and a zinc or silver salt.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide includes the R-form (CAS. No.920332-28-1), S form (CAS.No.920332-29-2), or racemic form (CAS.No.920332-27-0), but more preferably R form (( E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (compound in the present disclosure Also referred to as (1))).
  • a pharmaceutically acceptable salt of the compound of the present disclosure is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • Specific examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, Mineral acids such as nitric acid and phosphoric acid; aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid and mandelic acid , benzoic acid, salicylic acid and other aromatic monocarboxylic acids, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid and other aliphatic dicarboxylic acids, and citric acid and other aliphatic tricarboxylic acids.
  • Carboxylic acids such as aliphatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid, and aromatic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid.
  • organic sulfonic acids such as aliphatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid
  • aromatic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid.
  • inorganic base addition salts with metals such as alkali metals or alkaline earth metals such as sodium, potassium, magnesium, and calcium
  • organic base addition salts such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, ornithine, etc. is mentioned
  • salts can be obtained by a conventional method, for example, by mixing an equivalent amount of the compound of the present disclosure with a solution containing the desired acid or base and collecting the desired salt by filtration or distilling off the solvent. sell.
  • Compounds of the present disclosure or salts thereof may also form solvates with water or solvents such as ethanol.
  • TRPV1 transient receptor potential vanilloid 1
  • VR1 transient receptor potential vanilloid 1
  • TRPV1 is a TRP channel that was cloned from the dorsal root ganglion (DRG) as a cation channel that responds to capsaicin. Chemistry Vol. 85, No. 7: 561-565). TRPV1 is known to increase its activity during inflammation or tissue damage and induce hyperalgesia. Therefore, TRPV1 is of interest as a potential drug target for pain therapy.
  • DRG dorsal root ganglion
  • TRPV1 antagonists are effective against various pain models such as inflammatory pain, neuropathic pain and osteoarthritis (Seikagaku Vol. 85, No. 7: 561- 565).
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide By mixing a pharmaceutically acceptable salt or solvate with a cellulosic polymer and a nonionic surfactant to form an aqueous suspension, (E)-2-(7-trifluoromethylchroman -4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, improves redispersibility be able to.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide , or a pharmaceutically acceptable salt or solvate thereof, for improving the redispersibility of an aqueous suspension, the composition comprising a nonionic surfactant. can do.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide , or a pharmaceutically acceptable salt or solvate thereof, for improving the redispersibility of an aqueous suspension the composition providing a composition comprising a cellulosic polymer be able to.
  • composition comprising a cellulosic polymer and a nonionic surfactant
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide , or a pharmaceutically acceptable salt or solvate thereof, comprising a cellulosic polymer and a zinc or silver salt for improving the redispersibility of an aqueous suspension of A composition comprising:
  • a composition comprising a salt can be provided.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide , or a pharmaceutically acceptable salt or solvate thereof, in the aqueous suspensions of the present disclosure is generally about 0.01% w/v to about 5% w/v, preferably about 0.1% w/v v% to about 3% w/v%, more preferably about 0.2% w/v% to about 2% w/v%, particularly preferably about 0.2% w/v% to about 1.5% It can be present at a concentration of w/v %, more preferably from about 0.3% w/v % to about 1.0% w/v %.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide , or a pharmaceutically acceptable salt or solvate thereof, in the aqueous suspension of the present disclosure usually about 0.01 w/v% to about 5 w/v%, preferably about 0 .1% w/v% to about 3% w/v%, more preferably about 0.2% w/v% to about 2% w/v%, particularly preferably about 0.2% w/v% to It can be present at a concentration of about 1.5% w/v%, more preferably from about 0.3% w/v% to about 1.0% w/v%.
  • the cellulosic polymer is not particularly limited as long as it is pharmaceutically acceptable, but methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, ethylcellulose, propylcellulose, hydroxymethylcellulose , hydroxyethyl cellulose, hydroxypropyl cellulose, sulfonated cellulose derivatives, or pharmaceutically acceptable salts thereof, and the like. Moreover, these cellulose-based polymer compounds may be used singly or in combination of two or more. Cellulosic polymers are preferably methylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose from the viewpoint of redispersibility of aqueous suspensions.
  • Cellulose-based polymers are linear water-soluble polymers with glucose as the basic unit.
  • a cellulosic polymer is added to an aqueous suspension containing compound (1), the cellulosic polymer is appropriately distributed around the suspended particles in the presence of the nonionic surfactant.
  • cellulose-based polymers form a sheet structure between cellulose particles. maintains an appropriate distance and contributes to the formation of a bulky sedimentation layer.
  • the cellulosic polymer acts as an appropriate steric hindrance by adjusting the cellulosic polymer to an arbitrary concentration relative to the suspended particles.
  • aqueous suspension that forms a bulky sedimentation layer and has good redispersibility can be prepared. Therefore, in one embodiment of the present disclosure, the use of a cellulosic polymer can be expected to prepare an aqueous suspension having excellent redispersibility.
  • carboxyvinyl polymer and polyvinylpyrrolidone have acrylic acid and N-vinyl-2-pyrrolidone main chain structures, respectively, and are water-soluble polymers that do not have a three-dimensional structure like a sheet structure.
  • these water-soluble polymers are distributed around suspended particles, the effect of maintaining the distance between suspended particles is considered to be weaker than that of cellulosic polymers.
  • the methyl cellulose used is not particularly limited, but any methyl cellulose having different methoxy group substitution rates, molecular weights, viscosities, etc. may be used, and these may be used alone or Two or more kinds can be used in combination.
  • the degree of substitution of methoxy groups in methylcellulose is usually in the range of about 20 to about 40%, preferably in the range of 26 to 33%.
  • the viscosity of methyl cellulose (20 ° C., 2 wt% aqueous solution) is usually 1 to 10000 mPa s, preferably 3 to 3000 mPa s, more preferably 4 to 1500 mPa s, particularly preferably 3 to 50 mPa.
  • ⁇ s more preferably 10 to 20 mPa ⁇ s.
  • Examples of commercially available products include METOLOSE SM-4, METOLOSE SM-15, METOLOSE SM-25, SM-100, SM-400, METOLOSE SM-1500, SM-4000 (Shin-Etsu Chemical Co., Ltd.) and the like.
  • the cellulosic polymer is generally about 0.00007 w/v% to about 0.01 w/v%, preferably about 0.0001 w/v%, in the aqueous suspension of the present disclosure. to about 0.008 w/v%, more preferably about 0.0005 w/v% to about 0.005 w/v%, particularly preferably about 0.0006 w/v% to about 0.003 w/v%, more preferably It can be present at a concentration of about 0.0007 w/v % to about 0.002 w/v %, most preferably about 0.0008 w/v % to about 0.001 w/v %.
  • the cellulosic polymer is typically about 0.00007 w/v% to about 0.007 w/v%, preferably about 0.0001 w/v, in the aqueous suspension of the present disclosure. % to about 0.005 w/v%, more preferably about 0.0003 w/v% to about 0.004 w/v%, particularly preferably about 0.0005 w/v% to about 0.003 w/v%, even more preferably can be present at a concentration of about 0.0007 w/v % to about 0.001 w/v %, most preferably about 0.001 w/v %.
  • methyl cellulose when used as the cellulosic polymer, it is generally about 0.00007 w/v % to about 0.007 w/v %, preferably about 0.007 w/v %, in the aqueous suspension of the present disclosure.
  • the nonionic surfactant is not particularly limited as long as it is pharmaceutically acceptable.
  • Tyloxapol polyoxyls stearate (polyethylene glycol monostearate, monostearate polyethylene glycol 40 (MYS-40), polyethylene glycol monostearate 400, etc.), polyoxyethylene sorbitan fatty acid esters (polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, etc.), polyoxyethylene hydrogenated castor oils (polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 (HCO-60), etc.).
  • Nonionic surfactants may be used singly or in combination of two or more.
  • Nonionic surfactants are preferably tyloxapol, polysorbate 80, polyethylene glycol monostearate, polyoxyethylene hydrogenated castor oil 60, tyloxapol, polysorbate 80, monostearin from the viewpoint of redispersibility or stability of aqueous suspensions. Acid polyethylene glycol is more preferred, and tyloxapol is even more preferred.
  • the nonionic surfactant is from about 0.0001 w/v% to about 0.5 w/v%, preferably about 0.0001 w/v%, in the aqueous suspension of the present disclosure. It can be present at a concentration of from to about 0.1 w/v %, more preferably from about 0.01 w/v % to about 0.005 w/v %.
  • the nonionic surfactant is from about 0.0001 w/v % to about 0.5 w/v %, preferably about 0.005 w/v, in the aqueous suspensions of the present disclosure. % to about 0.1 w/v %, more preferably about 0.01 w/v % to about 0.05 w/v %, particularly preferably about 0.01 w/v % to about 0.03 w/v % can exist.
  • the amount in the aqueous suspension of the present disclosure is from about 0.0001 w/v % to about 0.5 w/v %, preferably about 0.5 w/v %. 005 w/v% to about 0.1 w/v%, more preferably about 0.01 w/v% to about 0.05 w/v%, particularly preferably about 0.01 w/v% to about 0.03 w/v% can be present in concentrations of
  • zinc halides such as zinc chloride, zinc bromide or zinc fluoride, zinc sulfate, zinc acetate, zinc phosphate, zinc carbonate, zinc hydroxide, zinc citrate, zinc lactate, zinc gluconate, zinc oxide, or hydrates thereof;
  • the zinc salt is present in the aqueous suspension of the present disclosure from about 0.0001 w/v% to about 0.05 w/v%, more preferably from about 0.0005 w/v% to about It can be present in a concentration of 0.01 w/v %, particularly preferably from about 0.001 w/v % to about 0.005 w/v %.
  • w/v % when zinc chloride is used as the zinc salt, about 0.0001 w/v % to about 0.05 w/v %, more preferably about 0.0005 w/v %, is used in the aqueous suspension of the present disclosure. /v % to about 0.01 w/v %, particularly preferably from about 0.001 w/v % to about 0.005 w/v %.
  • silver salts that can be added to the aqueous suspension of the present disclosure include silver nitrate, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, and silver phosphate. , silver oxalate, silver thiosulfate, silver protein, or hydrates thereof.
  • the silver salt is present in the aqueous suspension of the present disclosure from about 0.0001 w/v% to about 0.05 w/v%, more preferably from about 0.0005 w/v% to about It can be present in a concentration of 0.01 w/v %, particularly preferably from about 0.001 w/v % to about 0.005 w/v %.
  • the number of times of shaking required for redispersion described above is usually about 15 times or less, preferably about 13 times or less, more preferably about 12 times or less, particularly preferably about 11 times or less, further preferably about 10 times. It can be judged that the redispersibility is improved when the following conditions are satisfied.
  • the measurement by falling operation reproduces the evaluation when used by patients who have weak hand strength due to some disorder or symptom and who have difficulty redispersing by shaking. It can be said that the redispersibility at the time of use is evaluated.
  • the number of tumbling operations required for redispersion described above is usually about 40 times or less, preferably about 35 times or less, more preferably about 30 times or less, particularly preferably about 25 times or less, further preferably about 20 times. It can be judged that the redispersibility is improved when the number is less than or equal to the number of times.
  • redispersibility can be assessed by any means, for example, by filling a container with an aqueous suspension of the present disclosure and subjecting the container to It can also be evaluated by counting the number of times until the suspended particles are redispersed by shaking or turning.
  • the average particle size (D 50 ) of 1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is not particularly limited, but is usually about 0.1 ⁇ m to about 50 ⁇ m, preferably about 0.1 ⁇ m to about 50 ⁇ m. .5 ⁇ m to about 10 ⁇ m, particularly preferably about 1 ⁇ m to about 10 ⁇ m, more preferably about 1 ⁇ m to about 5 ⁇ m.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene in the aqueous suspension of the disclosure -1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof can be used as a crystal form, and the crystal form is not particularly limited as long as it does not affect redispersibility.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R )-7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide type I crystals, type II crystals, type III crystals or mixtures thereof can be used.
  • the type I crystal is preferably used.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide , or a pharmaceutically acceptable salt or solvate thereof can be suspended in an aqueous solution containing tyloxapol to form (E)-2-(7-trifluoromethylchroman-4-ylidene)-N in aqueous solution.
  • a composition for improving the stability of tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, said composition comprising tyloxapol. be able to.
  • (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1 in an aqueous suspension -yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof comprising: (E)-2-(7-trifluoromethylchroman-4-ylidene)-N- (7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and tyloxapol are mixed to prepare an aqueous suspension
  • a method is provided that includes steps.
  • the stability is determined by storing (E)-2-(7-trifluoromethylchroman-4-ylidene) dissolved and/or suspended in an aqueous suspension over a period of time.
  • -N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or its pharmaceutically acceptable salt or solvate content retention rate (residual rate) can be evaluated.
  • the aqueous suspension is an ophthalmic suspension and can be provided as an eye injection, eye drops or eye irrigation solution.
  • ophthalmic suspensions can be provided in the form of suspensions or solutions in which the active ingredient is suspended in an aqueous solvent (eg, phosphate-buffered saline).
  • the aqueous suspension can be eye drops for treating dry eye.
  • Dry eye is a disease accompanied by subjective symptoms such as eye discomfort, and requires long-term and regular treatment.
  • dry eye therapeutic drugs are generally administered in a large number of doses, there is a strong demand for formulations with good patient adherence and convenience.
  • suspension with poor redispersibility there is concern that the suspended particles will not be uniformly dispersed, the desired active ingredient will not be administered, and the pharmacological effect will not be sufficiently exhibited. From these points of view as well, redispersibility is a major issue in eye drops for treating dry eye, and the provision of an aqueous suspension having excellent redispersibility according to the present disclosure is highly valuable.
  • aqueous suspensions of the present disclosure can be administered by any suitable route determined by those of ordinary skill in the art, including but not limited to ocular injection, topical application (including application to the eye), It can be formulated to be suitable for administration by an administration route selected from eye drop, intravenous injection, drip, oral, parenteral, transdermal and the like.
  • Aqueous suspensions of the present disclosure may contain any pharmaceutically acceptable additives and/or excipients known in the art.
  • Additives include, but are not limited to, stabilizers, pH adjusters, buffers, and preservatives (preservatives).
  • the stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and examples include polyvinylpyrrolidone, monoethanolamine, cyclodextrin, dextran, ascorbic acid, tocopherol, dibutylhydroxytoluene, sulfites, and the like. , the content is preferably about 0.001 w/v% to about 1 w/v% of the total amount of the composition.
  • the pH adjuster is not particularly limited as long as it is pharmaceutically acceptable.
  • examples include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide. , borax, triethanolamine, monoethanolamine, sodium hydrogen carbonate, alkalis such as sodium carbonate, etc., and the content thereof is, for example, 0 to about 20 w/v% with respect to the total amount of the aqueous suspension agent. .
  • the aqueous suspension of the present disclosure is adjusted to a pH of generally about 4 to about 8, preferably about 5.0 to about 8, by mixing a pH adjuster as described above, if necessary. 8.0, more preferably about 6.0 to about 8.0, particularly preferably about 7.0 to about 8.0, and even more preferably about 7.2 to about 7.8.
  • the buffering agent used in the aqueous suspension of the present disclosure is not particularly limited as long as it is pharmaceutically acceptable.
  • borate buffer, phosphate buffer, Tris buffer, citrate buffer , tartaric acid buffers, acetic acid buffers, amino acid buffers, etc. but from the viewpoint of redispersibility or stability of the aqueous suspension, boric acid buffers or phosphate buffers are preferred, and boric acid buffers agents are particularly preferred.
  • the concentration of the buffering agent may be appropriately set within a range in which the desired buffering capacity can be imparted to the aqueous solution. is preferably about 1 w/v% to about 5 w/v%, more preferably about 1 w/v% to about 3 w/v%.
  • the borate buffer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include boric acid and/or salts thereof.
  • Boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, tetraboric acid and the like.
  • the salt of boric acid is not particularly limited as long as it is pharmaceutically acceptable.
  • Metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt; triethylamine, triethanolamine , morpholine, piperazine, pyrrolidine and other organic amine salts. Boric acid or a salt thereof may be used singly or in combination of two or more.
  • a preferred embodiment of the borate buffer is a combination of boric acid and borax.
  • the ratio of boric acid and borax is not particularly limited. , more preferably 30 to 100 parts by mass, and particularly preferably 40 to 60 parts by mass.
  • phosphate buffers include phosphoric acid and/or salts thereof.
  • the salt of phosphoric acid is not particularly limited as long as it is pharmaceutically acceptable.
  • dialkali metal salts of hydrogen phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate
  • alkali metal dihydrogen phosphate such as potassium dihydrogen phosphate
  • tri-alkali metal phosphate such as tri-sodium phosphate and tripotassium phosphate.
  • the salt of phosphoric acid may be in the form of a solvate such as a hydrate.
  • disodium hydrogen phosphate the form of dodecahydrate, In some cases, it may be in the form of a dihydrate or the like.
  • the phosphate buffer one of phosphoric acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination.
  • phosphoric acid and salts thereof phosphates are preferred, more preferably at least one of dialkali metal hydrogen phosphate and alkali metal dihydrogen phosphate, particularly preferably disodium hydrogen phosphate and dihydrogen phosphate At least one of sodium is included.
  • Tris buffers include Tris (also known as trishydroxymethylaminomethane) and/or salts thereof.
  • the tris salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include salts such as acetate, hydrochloride, maleate and sulfonate.
  • the Tris acid buffer one selected from Tris and salts thereof may be used alone, or two or more thereof may be used in combination.
  • the Tris buffer specifically includes trometamol and/or salts thereof.
  • the salt of trometamol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as acetate; inorganic acid salts such as hydrochloride and sulfonate.
  • the tris acid buffer one selected from trometamol and salts thereof may be used alone, or two or more thereof may be used in combination. Among trometamol and salts thereof, trometamol is preferred.
  • Citric acid buffers specifically include citric acid and/or salts thereof.
  • the salt of citric acid is not particularly limited as long as it is pharmaceutically acceptable. Examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; be done.
  • the citric acid salt may be in the form of a solvate such as a hydrate.
  • the citric acid buffer one of citric acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination. Among citric acid and salts thereof, citric acid salts are preferred, alkali metal citric acid salts are more preferred, and sodium citrate is particularly preferred.
  • tartaric acid buffers include tartaric acid and/or salts thereof.
  • Salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; .
  • the salt of tartaric acid may be in the form of a solvate such as a hydrate.
  • the tartaric acid buffer one of tartaric acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination.
  • acetate buffers include acetic acid and/or salts thereof.
  • the salt of acetic acid is not particularly limited as long as it is pharmaceutically acceptable. Examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts, etc. are mentioned.
  • the acetic acid salt may be in the form of a solvate such as a hydrate.
  • the acetate buffer one of acetic acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination.
  • amino acid buffers include acidic amino acids and/or salts thereof.
  • acidic amino acids include aspartic acid and glutamic acid.
  • Salts of acidic amino acids are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts.
  • the amino acid buffer one selected from acidic amino acids and salts thereof may be used alone, or two or more thereof may be used in combination.
  • Preservatives are not particularly limited as long as they are pharmaceutically acceptable. Examples include sorbic acid, potassium sorbate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate. paraoxybenzoic acid ester, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, quaternary ammonium salts such as cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylenebiguanide, chlorhexidine, etc. The content thereof can be appropriately changed depending on the type thereof, and is, for example, about 0.0001 w/v% to about 0.2 w/v% of the total amount of the aqueous suspension.
  • aqueous solvent such as sterilized purified water, physiological saline, a buffer (e.g., phosphate buffer, citrate buffer, acetate buffer, etc.), or cottonseed oil. , soybean oil, sesame oil, peanut oil, and other vegetable oils.
  • a buffer e.g., phosphate buffer, citrate buffer, acetate buffer, etc.
  • cottonseed oil e.g., soybean oil, sesame oil, peanut oil, and other vegetable oils.
  • the container for containing the aqueous suspension of the present disclosure is not particularly limited, and examples thereof include glass containers and plastic containers.
  • the plastic container may be made of any material such as polyester (polyethylene terephthalate, polyarylate), polycarbonate, polyethylene or polypropylene, mixtures thereof, and mixtures thereof.
  • the containers used in the present disclosure may be those used in the medical field or otherwise. In one embodiment, it can be made of any material that can meet the "standard for plastic containers for eye drops" in Japan or other equivalent standards.
  • the shape of the container used may be arbitrary, and any shape can be used as long as it is a shape for eye drops.
  • the aqueous suspension of the present disclosure can be filled into any eye drop container commonly used in the medical field, such as polyethylene (preferably low density polyethylene) or polypropylene, preferably colorless polypropylene container. can do.
  • polyethylene preferably low density polyethylene
  • polypropylene preferably colorless polypropylene container. can do.
  • Table 1 shows the test results .
  • the number of times of shaking was 15 times or less.
  • the number of times of shaking was the least, 8.3 times.
  • the surface tension of a separately prepared base (formulation excluding compound (1) and tyloxapol) was 54.6 mN/m, and there was no correlation between redispersibility and surface tension.
  • Test Example 2 Comparative study of cellulose derivatives
  • HPMC Hydroxypropyl methylcellulose
  • CMC carboxymethyl cellulose
  • 60SH-4000 was used as hydroxypropylmethylcellulose
  • Celogen PR-S was used as carboxymethylcellulose.
  • the above type I crystal was used.
  • Table 2 shows the test results .
  • Test Example 3 Comparative study of nonionic surfactants
  • a suspension having the composition shown in Table 3 was prepared, and the number of times of shaking required for redispersion was determined in the same manner as in Test Example 1.
  • Polysorbate 80 was manufactured by NOF, and polyethylene glycol monostearate 40 (MYS-40) was manufactured by Nippon Surfactant Kogyo.
  • MYS-40 polyethylene glycol monostearate 40
  • Table 3 shows the test results . Suspensions containing tyloxapol, polysorbate 80 and MYS-40 were shaken 15 times or less.
  • Test Example 4 Comparative examination of water-soluble polymers other than cellulose
  • a suspension having the composition shown in Table 4 was prepared, and the number of times of shaking required for redispersion was obtained in the same manner as in Test Example 1.
  • Polyvinylpyrrolidone (PVP) from BASF Japan, xanthan gum from DSP Gokyo Food & Chemical, and carboxyvinyl polymer (CVP) from Lubrizol were used.
  • Kollidon 30 was used as polyvinylpyrrolidone
  • 974P was used as carboxyvinyl polymer.
  • the above type I crystal was used.
  • Table 4 shows the test results .
  • the suspension containing PVP, xanthan gum, and CVP was shaken 15 times or more.
  • Table 5 shows the test results .
  • the number of inversion operations increased from 47.3 to 24.7.
  • zinc chloride was added to Formula 28, the number of tipping operations was 32.3.
  • the number of inversion operations was 16.0.
  • the aqueous solution was stored at 25° C. for 1 month (1M), and the content of compound (1) in the solution was measured using a liquid chromatography device (manufactured by Shimadzu Corporation) under the following conditions.
  • the content retention rate was determined as the ratio (%) of the measured content after storage to the amount of compound (1) used for preparation.
  • Table 6 shows the measurement results .
  • the content retention rate of compound (1) after 1M storage at 25° C. was 100%, and compound (1) was stable in an aqueous solution containing tyloxapol.
  • Test Example 7 Change in redispersibility due to addition of each metal
  • Suspensions having the compositions shown in Tables 7 to 9 were prepared, and the number of inversion operations required for redispersion was determined in the same manner as in Test Example 5.
  • Zinc sulfate was manufactured by Merck KGaA
  • silver nitrate was manufactured by Fujifilm Wako Pure Chemical Industries
  • sodium chloride manufactured by Manac was manufactured by Fujifilm Wako Pure Chemical Industries
  • potassium chloride manufactured by Manac calcium chloride manufactured by Fujifilm Wako Pure Chemical Industries
  • magnesium chloride manufactured by Nacalai Tesque for compound (1), the above type I crystal was used.
  • Test Example 8 Change in redispersibility of 0.3 w/v% compound (1)
  • a suspension having the composition shown in Table 10 was prepared, and the number of times of shaking required for redispersion was determined in the same manner as in Test Example 1.
  • the number of times of shaking was 15 times or less.
  • the number of times of shaking was the least, 6.7 times.
  • the redispersibility by inversion operation was evaluated. Good redispersibility was also confirmed by the number of operations.
  • Test Example 9 Change in redispersibility due to addition of zinc chloride
  • a suspension having the composition shown in Table 11 was prepared, and the number of inversion operations required for redispersion was determined in the same manner as in Test Example 5.
  • High-quality eye drops can be produced by preparing aqueous suspensions having the compositions shown in Tables 12 to 14.
  • the prescription amount of compound (1) and each additive is described as "g/100 mL.”
  • Tyloxapol (cloud point: 90 to 100 ° C.) is manufactured by AMRI Rensselaer (Curia Global, Inc.), methyl cellulose is Metrose SM-15 manufactured by Shin-Etsu Chemical, hydroxypropylmethyl cellulose (HPMC) is 60SH-4000 manufactured by Shin-Etsu Chemical, Carboxymethyl cellulose (CMC) is Celogen PR-S manufactured by Dai-ichi Kogyo Seiyaku, and Lifitegrast is manufactured by Shanghai Sumway Pharmaceutical Technology.
  • Compound (1) uses type I crystals.
  • each container consists of a bottle (colorless PE, colorless PP or brown PP), a nozzle (PE) and a cap (PP).
  • the appearance, brightness, chromaticity, chroma, and transmittance at each wavelength of the bottle body of each container are as specified in Table 15 and FIG.
  • each container is shrink-wrapped as a product label.
  • the dimensions of the bottle-shaped bottle are about 23m x about 17mm x about 50mm, and the resin weight is about 3g. Its shape is similar to the bottle of Softia (registered trademark) ophthalmic solution 0.02% (manufactured and sold by Senju Pharmaceutical Co., Ltd.).
  • Bottle material polyethylene is low density polyethylene.
  • Polypropylene is a propylene-ethylene copolymer having a propylene component/ethylene component ratio of 50/50 to 99.9/0.1. Senju Pharmaceutical Co., Ltd.) bottle material.
  • a spectrophotometer (manufactured by Konica Minolta, Inc.) is used to measure lightness (L * value) and chromaticity (a * value, b * value). Also, the chroma (c * value) was calculated according to the formula: ((a * value) 2 +(b * value) 2 ) 1/2 .
  • the transmittance (%) of light in the range of 200 to 800 nm is measured for this side portion using an ultraviolet-visible spectrophotometer ("UV-2450", manufactured by Shimadzu Corporation).
  • Bottle Sterilization Method EB Eye drop bottles are sterilized by electron beam irradiation of 10 to 60 kGy.
  • EOG Ethylene Oxide Gas Sterilization
  • Eye drop bottles are sterilized under the conditions of ethylene oxide concentration of 400-700 mg/L, temperature of 40-50° C., relative humidity of 45-85%, and treatment time of 3 hours or longer.
  • VHP Vapor Hydrogen Peroxide
  • An eye drop bottle is sterilized under conditions of 3% VHP spray, temperature of 20-50° C., relative humidity of 30-90%, and treatment time of about 1 hour.
  • ⁇ -ray ⁇ -ray sterilization
  • Bottles are sterilized by irradiation with 20-60 kGy of ⁇ -ray.
  • Method for producing 50 L scale eye drops (No. 11) Purified water and predetermined amounts of boric acid, borax, sodium chloride and zinc chloride are put into a 30 L stainless container and stirred. A predetermined amount of tyloxapol aqueous solution is prepared in a 1 L stainless container, and this aqueous solution is put into a 30 L stainless container. Furthermore, after dispersing a predetermined amount of methyl cellulose with hot water (50 to 90° C.) in another 1 L stainless steel container, it is cooled, and this methyl cellulose aqueous solution is put into a 30 L stainless steel container.
  • purified water is added so as to obtain a base solution having a concentration of 1.5 times, and the weight is adjusted to a volume.
  • This base solution is sterilized by filtration, and weighted up with purified water (including washing) to prepare a predetermined amount of base solution.
  • Compound (1) is added to this base solution and dispersed by stirring to prepare a suspension. After confirming that the compound (1) is dispersed in the liquid, the suspension is gently stirred for defoaming. After that, the suspension is roughly filtered through a filter with a pore size of 75 ⁇ m, and the suspension is filled into a bottle while being stirred, and then the bottle is fitted with a nozzle and a cap.
  • the present disclosure can be used in fields such as medicine, pharmaceuticals, healthcare, biology, and biochemistry.

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WO2025206172A1 (ja) * 2024-03-28 2025-10-02 千寿製薬株式会社 電子線滅菌処理したヘテロシクリデンアセトアミド誘導体含有組成物

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WO2024019118A1 (ja) 2022-07-20 2024-01-25 旭化成株式会社 ヒアルロン酸誘導体医薬品組成物及び医薬品組成物
WO2025206172A1 (ja) * 2024-03-28 2025-10-02 千寿製薬株式会社 電子線滅菌処理したヘテロシクリデンアセトアミド誘導体含有組成物

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