Classifications

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  • A61P27/02—Ophthalmic agents
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  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
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  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
  • A61K31/728—Hyaluronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
  • A61K38/13—Cyclosporins
• • 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
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • 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
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • 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
  • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present disclosure relates to the fields of medicine, healthcare, biology, and biotechnology.
• the present disclosure relates to a technology for improving the redispersibility of a suspension containing a heterocyclideneacetamide derivative, and a formulation technology based thereon.
• the number of dry eye patients in Japan is estimated at at least 8 million, and the number is estimated to be about 22 million if potential patients who use over-the-counter eye drops without visiting a doctor's office are included, and it is said that there are more than 1 billion people with dry eye worldwide.
• the use of televisions, computers, mobile devices, etc. increases the number of times people stare at screens, reducing the number of times they blink, and the use of air conditioners, etc., dries the air, which is known to result in increased evaporation of tears and cause dry eyes.
• refractive surgery and the use of contact lenses can result in dry eyes. Symptoms associated with dry eyes include discomfort, dryness, a burning sensation, and irritation on the surface of the eye.
• Patent document 1 International Publication No. 2021/066144 Brochure
• the present disclosure provides an aqueous suspension having excellent redispersibility, which contains as a first component (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, which is a heterocyclideneacetamide derivative, or a pharma- ceutically acceptable salt or solvate thereof, and as a second component at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and a pharma-ceutically acceptable salt or solvate thereof.
• an aqueous suspension comprising a first component and a second component
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof
• An aqueous suspension, wherein the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma- ceutically acceptable salts or solvates thereof.
• (Item 2) The aqueous suspension according to the preceding paragraph, further comprising a non-ionic surfactant.
• (Item 3) 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, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil.
• (Item 4) 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 40 monostearate, and polyoxyethylene hydrogenated castor oil 60.
• (Item 5) Item 11.
• Item 6 Item 2. 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 1 w/v %.
• Item 7 The aqueous suspension according to any one of the preceding items, wherein the concentration of the first component in the aqueous suspension is from about 0.01 w/v% to about 5 w/v%.
• the concentration of the diquafosol, or a pharma- ceutically acceptable salt or solvate thereof, in the aqueous suspension is about 0.3 w/v % to about 10 w/v %; the concentration of said cyclosporine, or a pharma- ceutically acceptable salt or solvate thereof, in said aqueous suspension is from about 0.005% w/v to about 0.5% w/v; the concentration of the hyaluronic acid, or a pharma- ceutically acceptable salt or solvate thereof, in the aqueous suspension is from about 0.01% w/v to about 1% w/v; the concentration of the loteprednol etabonate, or a pharma- ceutically acceptable salt or solvate thereof, in the aqueous suspension is about 0.025% w/v to about 2.5% w/v; the concentration of said bromfenac, or a pharma- ceutically acceptable salt or solvate thereof, in
• An aqueous suspension comprising a first component, a second component, and a non-ionic surfactant
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma- ceutically acceptable salts or solvates thereof
• An aqueous suspension, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil.
• An aqueous suspension comprising a first component, a second component, and a non-ionic surfactant
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma- ceutically acceptable salts or solvates thereof
• the aqueous suspension, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate, and polyoxyethylene hydrogenated castor oil 60.
• An aqueous suspension comprising a first component, a second component, and a non-ionic surfactant
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma- ceutically acceptable salts or solvates thereof
• the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate, and polyoxyethylene hydrogenated castor oil 60
• the concentration of the first component in the aqueous suspension is
• An aqueous suspension comprising a first component, a second component, and a non-ionic surfactant
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma- ceutically acceptable salts or solvates thereof
• the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate, and polyoxyethylene hydrogenated castor oil 60
• the concentration of the first component in the aqueous suspension is
• An aqueous suspension comprising a first component, a second component, and a non-ionic surfactant
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma- ceutically acceptable salts or solvates thereof
• the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate, and polyoxyethylene hydrogenated castor oil 60
• the concentration of the first component in the aqueous suspension is
• An aqueous suspension comprising a first component, a second component, a nonionic surfactant, and boric acid
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma- ceutically acceptable salts or solvates thereof
• the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate, and polyoxyethylene hydrogenated castor oil 60;
• a method for producing an aqueous suspension comprising the steps of: The method includes the step of preparing an aqueous suspension by mixing a first component, a second component, and a non-ionic surfactant;
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof;
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma- ceutically acceptable salts or solvates thereof;
• the method, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate,
• a method for improving the redispersibility of an aqueous suspension comprising the steps of: The method includes the step of preparing an aqueous suspension by mixing a first component, a second component, and a non-ionic surfactant;
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof;
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma- ceutically acceptable salts or solvates thereof;
• the method, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glyco
• This disclosure makes it possible to provide an aqueous suspension with excellent redispersibility.
• the present disclosure suppresses the phenomenon in which suspended particles are not uniformly dispersed, enabling the required amount of active ingredient to be administered stably, and achieving a stable and sufficient pharmacological effect. This contributes to improving patient adherence and convenience.
• FIG. 1 shows the transmittance at each wavelength of the body of the bottle of each container used in the examples.
• aqueous suspension is used in the same sense as the term is usually used in this field, and refers to a liquid agent containing at least a portion of water, in which the components to be mixed are in a suspended state and solid particles are present in the liquid.
• the first component (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, has extremely low solubility in water, so in the aqueous suspension of the present disclosure, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof, becomes suspended particles, but some of them are in a dissolved state. In addition to the first component, the second component may also become suspended particles.
• pharmaceutically acceptable salts refers to relatively non-toxic, inorganic or organic acid addition salts, or inorganic or organic base addition salts, of the compounds disclosed herein.
• solvate refers to a group formed by interaction between the compound of the present disclosure or a pharma- ceutically acceptable salt thereof and any solvent, and includes, for example, solvates with organic solvents (e.g., solvates with alcohols (e.g., ethanol)), hydrates, etc. When forming a hydrate, it may be coordinated with any number of water molecules. Examples of hydrates include monohydrates, dihydrates, etc.
• redispersibility refers to the ease with which particles that have settled in the solvent of a liquid containing particles (in the case of a suspension, they are also called “suspended particles", such as a suspension, can be dispersed again uniformly throughout the liquid by storing the liquid for a certain period of time.
• “redispersibility” is evaluated by a test using a shaking or inversion procedure.
• the term “shaking operation” refers to the action of holding a container filled with an “aqueous suspension” in the hand and shaking it up and down.
• the “shaking operation” involves shaking the container up and down in a range of 10 to 15 cm, then shaking it up and back to the original position, counting as one shake, and shaking five times at a speed of 1.1 seconds per set.
• Tests of redispersibility using the "shaking operation” are performed on 3 to 6 specimens per formulation, and the average number of sets is calculated from the number of sets required for redispersion for each specimen, and this number is used as the number of shakes converted.
• inversion refers to the action of holding a container filled with an “aqueous suspension” in one hand and turning it upside down.
• a redispersibility test using “inversion” is performed on 3 to 6 samples per formulation, and one inversion is defined as the operation of inverting the container 180° upside down at a speed of 1 second, then inverting it 180° again to return it to the upright position.
• improved redispersibility refers to the fact that particles that have settled in a liquid containing particles, such as a suspension, become easier to disperse again. In comparing any formulation, if the number of "shaking operations” or “tipping operations” described above is reduced, it can be said that redispersibility has been improved.
• the "average particle size of suspended particles” refers to the median particle size (D50) of particles of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen- 1 -yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and is a value measured using a laser diffraction particle size distribution measuring device.
• nonionic surfactant is also referred to as a nonionic surfactant, and refers to a surfactant in which the hydrophilic group portion is nonionic. Whether or not a surfactant is nonionic can be easily determined by a person skilled in the art, and can be determined 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 40 monostearate (MYS-40), polyethylene glycol 400 monostearate, 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.).
• the present disclosure may provide an aqueous suspension comprising a first component and a second component, wherein the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and the second component is at least one selected from the group consisting of other active ingredients, and pharma- ceutically acceptable salts or solvates thereof.
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of other active ingredients, and pharma- ceutically acceptable salts or solvates thereof.
• the present disclosure provides an aqueous suspension preparation comprising a first component and a second component, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and the second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and a pharma-ceutically acceptable salt or solvate thereof.
• an aqueous suspension preparation comprising a first component, a second component, and a non-ionic surfactant
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof
• the non-ionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil.
• an aqueous suspension preparation comprising a first component, a second component, and a non-ionic surfactant
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof
• the non-ionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate, and polyoxyethylene hydrogenated castor oil 60.
• an aqueous suspension preparation comprising a first component, a second component, a nonionic surfactant, and boric acid
• the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof
• the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof
• the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate, and polyoxyethylene hydrogenated castor oil 60.
• an aqueous suspension preparation comprising a first component and a second component, wherein the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and the second component is at least one selected from the group consisting of rebamipide, olodaterol, delcocitinib, and a pharma-ceutically acceptable salt or solvate thereof; or an aqueous suspension preparation comprising a first component, a second component, a nonionic surfactant, and boric acid, wherein the first component is (E )-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen
• a method for producing an aqueous suspension comprising the step of mixing a first component and a second component to prepare an aqueous suspension, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and the second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and a pharma-ceutically acceptable salt or solvate thereof.
• a method for producing an aqueous suspension comprising the step of preparing an aqueous suspension by mixing a first component, a second component, and a nonionic surfactant, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof, the second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof, and the nonionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil
• a method for producing an aqueous suspension comprising the step of preparing an aqueous suspension by mixing a first component, a second component, and a nonionic surfactant, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof, the second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof, and the nonionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate, and polyoxyethylene hydrogenated cast
• a method for producing an aqueous suspension comprising the step of preparing an aqueous suspension by mixing a first component, a second component, a nonionic surfactant, and boric acid, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof, the second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof, and the nonionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate
• a method for improving the redispersibility of an aqueous suspension comprising the step of preparing an aqueous suspension by mixing a first component and a second component, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof, and the second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof.
• a method for improving the redispersibility of an aqueous suspension comprising the step of preparing an aqueous suspension by mixing a first component, a second component, and a nonionic surfactant, in which the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof, the second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof, and the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate, and poly
• a method for improving the redispersibility of an aqueous suspension comprising the step of preparing an aqueous suspension by mixing a first component, a second component, and a nonionic surfactant, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof, the second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof, and the nonionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol 40 monostearate, and
• a method for improving the redispersibility of an aqueous suspension comprising the step of preparing an aqueous suspension by mixing a first component, a second component, a nonionic surfactant, and boric acid, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof, the second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharma-ceutically acceptable salts or solvates thereof, and the nonionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycosulfate, and the nonionic
• (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), the S-form (CAS. No. 920332-29-2), or the racemic form (CAS. No. 920332-27-0), but more preferably the R-form ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (also referred to as compound (1) in this disclosure).
• Compound (1) that can be used in this disclosure may be provided in any form, for example, it may be a sterilized compound (1), but it may also be a non-sterilized compound (1).
• Sterilization methods include dry heat sterilization, high-pressure steam sterilization, filtration sterilization, electron beam sterilization, gamma rays, ethylene oxide gas sterilization, and hydrogen peroxide gas sterilization, with dry heat sterilization being preferred.
• the processing temperature for dry heat sterilization is not particularly limited, and is usually about 100 to about 175°C, preferably about 100 to about 170°C, and more preferably about 150 to about 170°C.
• diquafosol is a compound whose salt form is incorporated in Diquafosol ophthalmic solution as an active ingredient (IUPAC: Tetrasodium P 1 ,P 4 -bis(5'-uridul)tetraphosphate/CAS. No. 211427-08-6).
• IUPAC Tetrasodium P 1 ,P 4 -bis(5'-uridul)tetraphosphate/CAS. No. 211427-08-6.
• diquafosol or a pharma- ceutically acceptable salt or solvate thereof a commercially available compound, a compound produced by a method known in the literature, or a pharma- ceutically acceptable salt or solvate thereof can be used.
• cyclosporine is a compound that is incorporated in RESTASIS ophthalmic solution as the active ingredient (IUPAC: cyclo ⁇ -[(2S, 3R, 4R, 6E)-3-Hydroxy-4-methyl-2-methylaminooct-6-enoyl]-L-2-aminobutanoyl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl- ⁇ /CAS. No. 59865-13-3).
• cyclosporine or a pharma-ceutically acceptable salt or solvate thereof a commercially available compound, a compound produced by a method known in the literature, or a pharma-ceutically acceptable salt or solvate thereof can be used.
• hyaluronic acid is a compound whose salt form is incorporated in hyalein eye drops as an active ingredient (IUPAC: [ ⁇ 3)-2-Acetamido-2-deoxy- ⁇ -D-glucopyranosyl-(1 ⁇ 4)- ⁇ -D-glucopyranosyluronic acid-(1 ⁇ ] n /CAS. No. 9067-32-7).
• the weight-average molecular weight of hyaluronic acid, or its pharma- ceutically acceptable salt or solvate is usually 500,000 to 1,200,000, preferably 600,000 to 1,200,000.
• hyaluronic acid, or its pharma-ceutically acceptable salt or solvate a commercially available compound, a compound produced by a method known in the literature, or its pharma-ceutically acceptable salt or solvate can be used.
• loteprednol etabonate is a compound contained in EYSUVIS ophthalmic solution as an active ingredient (IUPAC: Chloromethyl 17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylate/CAS. No. 82034-46-6).
• loteprednol etabonate or its pharma- ceutically acceptable salt or solvate a commercially available compound, a compound produced by a method known in the literature, or its pharma-ceutically acceptable salt or solvate can be used.
• bromfenac refers to a compound whose salt form is incorporated in Bronac ophthalmic solution as the active ingredient (Sodium 2-[2-amino-3-(4-bromobenzoyl)phenyl acetate sesquihydrate/CAS. No. 120638-55-3).
• bromfenac or its pharma- ceutically acceptable salt or solvate a commercially available compound, a compound produced by a method known in the literature, or its pharma-ceutically acceptable salt or solvate can be used.
• fluorometholone is a compound contained in flumetholone ophthalmic solution as an active ingredient (IUPAC: 9-Fluoro-11 ⁇ ,17-dihydroxy-6 ⁇ -methylpregna-1,4-diene-3,20-dione/CAS. No. 426-13-1).
• fluorometholone or its pharma-ceutically acceptable salt or solvate a commercially available compound, a compound produced by a method known in the literature, or its pharma-ceutically acceptable salt or solvate can be used.
• rebamipide is a compound contained in Mucosta ophthalmic solution as an active ingredient (IUPAC: (2RS)-2-(4-Chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid/CAS. No. 90098-04-7).
• IUPAC (2RS)-2-(4-Chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid/CAS. No. 90098-04-7.
• rebamipide or its pharma- ceutically acceptable salt or solvate a commercially available compound, a compound produced by a method known in the literature, or its pharma-ceutically acceptable salt or solvate can be used.
• olodaterol is a compound whose salt form is incorporated as the active ingredient (6-hydroxy-8-((1R)-1-hydroxy-2- ⁇ [1-(4-methoxyphenyl)-2-methylpropane-2-yl]amino ⁇ ethyl)-2H-1,4-benzooxazine-3(4H)-one ⁇ hydrochloride/CAS. No. 869477-96-3) in Spiolto Respimat 28 inhalant.
• olodaterol or its pharma- ceutically acceptable salt or solvate a commercially available compound, a compound produced by a method known in the literature, or a pharma-ceutically acceptable salt or solvate thereof can be used.
• delcocitinib is a compound known as a Janus kinase (JAK) inhibitor (IUPAC: 3-[(3S,4R)-3-Methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile/CAS. No. 869477-96-3).
• delcocitinib or a pharmaceutically acceptable salt or solvate thereof may be a commercially available compound, a compound produced by a method known in the literature, or a pharmaceutically acceptable salt or solvate thereof.
• the pharma- ceutically acceptable salts of the first and second components of the present disclosure are not particularly limited as long as they are each independently pharma- ceutically acceptable salts, but specific examples include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, 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; aromatic monocarboxylic acids such as benzoic acid and salicylic acid; aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, and tartaric acid; Examples of such salts include organic carboxylic acids such as aliphatic tricarboxylic acids such as
• salts can be obtained by a conventional method, for example, by mixing a solution containing an equivalent amount of the compound of the present disclosure and the desired acid or base, and collecting the desired salt by filtration or by distilling off the solvent.
• the compound of the present disclosure or its salt can also form a solvate with a solvent such as water or ethanol.
• TRPV1 Transient Receptor Potential Vanilloid 1
• VR1 Transient Receptor Potential Vanilloid 1
• the R-isomer (compound (1)), S-isomer, or racemic form of ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide is described in WO 2007/010383, JP 4754566, JP 6230743, WO 2018/221543, JP 6830569, WO 2021/038889, and WO 2021/039023.
• the R-isomer (compound (1)), S-isomer, or racemic form can be produced by the production method described in the publication. The contents of the publication are incorporated herein in their entirety by reference.
• TRPV1 was cloned from the dorsal root ganglion (DRG) as a cation channel that responds to capsaicin, and is also sensitive to heat above 43°C and protons; it is a TRP channel that has been studied as a key molecule in nociception (Biochemistry, Vol. 85, No. 7: 561-565). It is known that TRPV1 activity increases during inflammation and tissue damage, causing hyperalgesia. For this reason, TRPV1 has attracted attention as a potential drug target that can be used to treat pain.
• DRG dorsal root ganglion
• TRPV1 antagonists have been reported to be effective against various pain models, including inflammatory pain, neuropathic pain, and osteoarthritis pain (Biochemistry, Vol. 85, No. 7: 561-565).
• (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof is mixed with at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and a pharma-ceutically acceptable salt or solvate thereof to prepare an aqueous suspension, thereby improving the redispersibility of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof.
• a composition for improving the redispersibility of an aqueous suspension containing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof can be provided, the composition including at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and a pharma-ceutically acceptable salt or solvate thereof.
• a composition for improving the redispersibility of an aqueous suspension containing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof can be provided, the composition comprising at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and a pharma-ceutically acceptable salt or solvate thereof, and a nonionic surfactant.
• a composition for improving the redispersibility of an aqueous suspension containing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof can be provided, the composition comprising at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and a pharma-ceutically acceptable salt or solvate thereof, a nonionic surfactant, and boric acid.
• (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof can be present in the aqueous suspension of the present disclosure at a concentration of typically 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 about 1.5 w/v%, and even more preferably about 0.3 w/v% to about 1.0 w/v%.
• the R-isomer of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or its pharma- ceutically acceptable salt or solvate when used, it can be present in the aqueous suspension formulation of the present disclosure at a concentration of typically 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 about 1.5 w/v%, and even more preferably about 0.3 w/v% to about 1.0 w/v%.
• the nonionic surfactant is not particularly limited as long as it is pharma- ceutically acceptable, but examples thereof include tyloxapol, polyoxyl stearates (polyethylene glycol monostearate, polyethylene glycol 40 monostearate (MYS-40), polyethylene glycol 400 monostearate, 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 alone or in combination of two or more.
• the nonionic surfactant is preferably tyloxapol, polysorbate 80, polyethylene glycol monostearate, or polyoxyethylene hydrogenated castor oil 60, more preferably tyloxapol, polysorbate 80, or polyethylene glycol monostearate, and even more preferably tyloxapol.
• the nonionic surfactant can be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.0001 w/v% to about 1 w/v%, preferably about 0.0005 w/v% to about 0.5 w/v%, more preferably about 0.001 w/v% to about 0.5 w/v%, particularly preferably about 0.005 w/v% to about 0.1 w/v%, and even more preferably about 0.01 w/v% to about 0.05 w/v%.
• tyloxapol when used as the nonionic surfactant, it can be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.0001 w/v% to about 1 w/v%, preferably about 0.0005 w/v% to about 0.5 w/v%, more preferably about 0.001 w/v% to about 0.5 w/v%, particularly preferably about 0.005 w/v% to about 0.1 w/v%, and even more preferably about 0.01 w/v% to about 0.05 w/v%.
• the second component can be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.005% w/v to about 12% w/v, preferably about 0.005% w/v to about 10% w/v.
• diquafosol or a pharma- ceutically acceptable salt or solvate thereof, may be present in the aqueous suspension of the present disclosure at a concentration of about 0.3 w/v% to about 12 w/v%, preferably about 0.3 w/v% to about 10 w/v%, and more preferably about 3 w/v% to about 5 w/v%.
• diquafosol can be mixed with (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, to improve the redispersibility of the aqueous suspension.
• concentration of diquafosol, or a pharma- ceutically acceptable salt or solvate thereof is the concentration converted to diquafosol sodium, unless otherwise specified.
• cyclosporine, or a pharma- ceutically acceptable salt or solvate thereof may be present in the aqueous suspension of the present disclosure at a concentration of about 0.005% w/v to about 1% w/v, preferably about 0.005% w/v to about 0.5% w/v, and more preferably about 0.05% w/v to about 0.1% w/v.
• concentration of cyclosporine, or a pharma- ceutically acceptable salt or solvate thereof, as used herein is the concentration converted to cyclosporine (free form) unless otherwise specified.
• hyaluronic acid or a pharma- ceutically acceptable salt or solvate thereof, may be present in the aqueous suspension of the present disclosure at a concentration of about 0.01% w/v to about 2% w/v, preferably about 0.01% w/v to about 1% w/v, and more preferably about 0.1% w/v to about 0.5% w/v.
• concentration of hyaluronic acid, or a pharma- ceutically acceptable salt or solvate thereof, as used herein is the concentration converted to sodium hyaluronate, unless otherwise specified.
• loteprednol etabonate, or a pharma- ceutically acceptable salt or solvate thereof may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.025% w/v to about 3% w/v, preferably about 0.025% w/v to about 2.5% w/v, and more preferably about 0.25% w/v to about 1% w/v.
• concentration of loteprednol etabonate, or a pharma- ceutically acceptable salt or solvate thereof, as used herein is the concentration converted to loteprednol etabonate (free form) unless otherwise specified.
• bromfenac or a pharma- ceutically acceptable salt or solvate thereof, may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.01% w/v to about 2% w/v, preferably about 0.01% w/v to about 1% w/v, and more preferably about 0.1% w/v to about 0.5% w/v.
• concentration of bromfenac, or a pharma- ceutically acceptable salt or solvate thereof is the concentration converted to bromfenac sodium sesquihydrate, unless otherwise specified.
• fluorometholone or a pharma- ceutically acceptable salt or solvate thereof, may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.01% w/v to about 2% w/v, preferably about 0.01% w/v to about 1% w/v, and more preferably about 0.1% w/v to about 0.5% w/v.
• concentration of fluorometholone, or a pharma- ceutically acceptable salt or solvate thereof is the concentration converted to fluorometholone (free form) unless otherwise specified.
• the aqueous suspension of the present disclosure may contain, in addition to the first and second components, any additional active ingredient.
• an aqueous suspension having improved redispersibility can be provided by incorporating any amount of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and a pharma- ceutically acceptable salt or solvate thereof in the presence of a nonionic surfactant as a dispersant.
• an aqueous suspension with improved redispersibility can be provided by combining (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, with at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and a pharma-ceutically acceptable salt or solvate thereof.
• the measurement using the falling operation can be said to reproduce the evaluation when used by patients whose hands have weakened due to some kind of disability or condition and who have difficulty redispersing by shaking, so it can also be said to evaluate the redispersibility when used by such patients and elderly people.
• the redispersibility can be determined to be improved when the number of inversion operations required for the redispersion described above is usually about 44 times or less, preferably about 40 times or less, more preferably about 35 times or less, particularly preferably about 30 times or less, even more preferably about 25 times or less, and most preferably about 20 times or less.
• redispersibility can be evaluated by any means, for example, by filling a container with the aqueous suspension of the present disclosure and measuring the number of times the container is shaken at any speed and/or amplitude, or inverted, until the suspended particles are redispersed.
• the average particle size (D 50 ) of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen- 1 -yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension of the present disclosure is not particularly limited, but can usually be about 0.1 ⁇ m to about 50 ⁇ m, preferably about 0.5 ⁇ m to about 10 ⁇ m, particularly preferably about 1 ⁇ m to about 10 ⁇ m, and further preferably about 1 ⁇ m to about 5 ⁇ m.
• redispersibility can be improved.
• the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension of the present disclosure can be used in a crystalline form, and the crystalline form is not particularly limited as long as it does not affect redispersibility.
• type I crystals, type II crystals, type III crystals, or mixtures thereof of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide disclosed in WO 2018/221543, Japanese Patent No. 6230743, etc. can be used.
• the type I crystals are used.
• the aqueous suspension is an ophthalmic suspension, which may be provided as an ophthalmic injection solution, an eye drop, or an ophthalmic irrigation solution.
• the ophthalmic suspension may be provided in the form of a suspension in which the active ingredient is suspended in an aqueous solvent (e.g., phosphate buffered saline), or in the form of a solution in which the active ingredient is dissolved.
• an aqueous solvent e.g., phosphate buffered saline
• the aqueous suspension may be an eye drop 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 treatment drugs are generally set to be administered frequently, there is a strong demand for formulations that are easy for patients to adhere to and convenient to use.
• redispersibility is a major issue in eye drops for treating dry eye, and the provision of an aqueous suspension with excellent redispersibility as disclosed herein is of great value.
• aqueous suspensions of the present disclosure may be administered by any suitable route as determined by one of skill in the art, and may be formulated to be suitable for administration by a route selected from, but not limited to, ocular injection, topical application (including application to the eye), eye drops, intravenous injection, infusion, oral, parenteral, transdermal, etc.
• Aqueous suspensions of the present disclosure may contain any pharma- ceutically acceptable additives and/or excipients known in the art, including, but not limited to, viscosity agents, stabilizers, pH adjusting agents, buffers, and preservatives.
• Thickening agents are not particularly limited as long as they are pharma- ceutically acceptable, but examples include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; and cellulose-based polymers such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. These thickening agents may be used alone or in combination of two or more. From the viewpoint of redispersibility, cellulose-based polymers are preferred, and methyl cellulose is particularly preferred.
• the stabilizer is not particularly limited as long as it is pharma- ceutically acceptable, but examples include polyvinylpyrrolidone, monoethanolamine, cyclodextrin, dextran, ascorbic acid, tocopherol, dibutylhydroxytoluene, sulfites, etc., and the content is preferably about 0.001 w/v% to about 1 w/v% of the total composition.
• the pH adjuster is not particularly limited as long as it is pharma- ceutically acceptable, but examples include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid; and alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, and sodium carbonate.
• the content of the pH adjuster is, for example, 0 to about 20 w/v % of the total amount of the aqueous suspension.
• the aqueous suspension of the present disclosure can be mixed with a pH adjuster as described above as necessary to adjust the pH to generally about 4 to about 8, preferably about 5.0 to about 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 buffer used in the aqueous suspension of the present disclosure is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include borate buffer, phosphate buffer, Tris buffer, citrate buffer, tartrate buffer, acetate buffer, amino acid buffer, etc., but from the viewpoint of redispersibility or stability of the aqueous suspension, borate buffer or phosphate buffer is preferred, and borate buffer is particularly preferred.
• the concentration of the buffering agent may be set appropriately within a range that can impart the desired buffering ability to the aqueous liquid preparation, and may be, for example, about 0.1 w/v% to about 10 w/v%, and from the viewpoint of improving redispersibility or stability, preferably about 1 w/v% to about 5 w/v%, and more preferably about 1 w/v% to about 3 w/v%.
• the boric acid buffer is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include boric acid and/or its salts.
• the boric acid is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include orthoboric acid, metaboric acid, tetraboric acid, etc.
• the salts of boric acid are not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and aluminum salt; and organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. Boric acid or its salts may be used alone or in combination of two or more.
• a preferred embodiment of the boric acid buffer is a combination of boric acid and borax.
• the ratio of boric acid to borax is not particularly limited, but for example, 10 to 300 parts by mass of borax per 100 parts by mass of boric acid, preferably 10 to 250 parts by mass, more preferably 30 to 100 parts by mass, and particularly preferably 40 to 60 parts by mass, can be mentioned.
• phosphate buffers include phosphoric acid and/or its salts.
• Phosphate salts are not particularly limited as long as they are pharma- ceutically acceptable, but include, for example, dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate.
• Phosphate salts may be in the form of solvates such as hydrates, for example, dodecahydrate in the case of disodium hydrogen phosphate, and dihydrate in the case of sodium dihydrogen phosphate.
• Phosphate buffers may be one of phosphoric acid and its salts, and may be used alone or in combination of two or more.
• phosphoric acid and its salts preferred are phosphates, more preferably at least one of dialkali metal hydrogen phosphate and alkali metal dihydrogen phosphate, and particularly preferably at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.
• Tris buffers include Tris (also known as trishydroxymethylaminomethane) and/or salts thereof. There is no particular limitation on the Tris salts as long as they are pharmaceutically acceptable, and examples of such salts include acetate, hydrochloride, maleate, and sulfonate.
• the Tris acid buffer may be one selected from Tris and its salts and used alone, or two or more may be used in combination.
• the Tris buffer specifically includes trometamol and/or salts thereof.
• the salts of trometamol so long as they are pharmaceutically acceptable, and examples of such salts include organic acid salts such as acetate; and inorganic acid salts such as hydrochloride and sulfonate.
• the Tris acid buffer may be one selected from trometamol and its salts and used alone, or two or more may be used in combination. Among trometamol and its salts, trometamol is preferred.
• citrate buffers include citric acid and/or its salts.
• the salts of citric acid are not particularly limited as long as they are pharma- ceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; and alkaline earth metal salts such as calcium salts and magnesium salts.
• the salts of citric acid may also be in the form of solvates such as hydrates.
• a citrate buffer one type may be selected from citric acid and its salts and used alone, or two or more types may be used in combination.
• citric acid and its salts preferred are salts of citric acid, more preferred are alkali metal salts of citric acid, and particularly preferred is sodium citrate.
• tartaric acid buffers include tartaric acid and/or its salts.
• Salts of tartaric acid are not particularly limited as long as they are pharma- ceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; and alkaline earth metal salts such as calcium salts and magnesium salts.
• the salts of tartaric acid may be in the form of solvates such as hydrates.
• a tartaric acid buffer one of tartaric acid and its salts may be selected and used alone, or two or more of them may be used in combination.
• acetate buffers include acetic acid and/or its salts.
• Salts of acetic acid are not particularly limited as long as they are pharma- ceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts. Salts of acetic acid may also be in the form of solvates such as hydrates.
• one of acetic acid and its salts may be selected and used alone, or two or more of them may be used in combination.
• amino acid buffers include acidic amino acids and/or their salts.
• acidic amino acids include aspartic acid and glutamic acid.
• salts of acidic amino acids include alkali metal salts such as sodium salts and potassium salts, but are not particularly limited as long as they are pharma- ceutical acceptable.
• an amino acid buffer one of the acidic amino acids and its salts may be selected and used alone, or two or more of them may be used in combination.
• the preservative is not particularly limited as long as it is pharma- ceutically acceptable, but examples include sorbic acid, potassium sorbate, paraoxybenzoic acid esters such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate, chlorhexidine gluconate, quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, alkyl polyaminoethyl glycine, chlorobutanol, polyquad, polyhexamethylene biguanide, and chlorhexidine, and the content can be varied appropriately depending on the type, but may be, for example, about 0.0001 w/v% to about 0.2 w/v% based on the total amount of the aqueous suspension.
• the desired components can be dissolved or suspended in an aqueous solvent such as sterilized purified water, physiological saline, or a buffer solution (e.g., phosphate buffer, citrate buffer, or acetate buffer), or in a non-aqueous solvent such as a vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil, and the osmotic pressure is adjusted to a predetermined level, followed by sterilization such as filtration sterilization.
• an aqueous solvent such as sterilized purified water, physiological saline, or a buffer solution (e.g., phosphate buffer, citrate buffer, or acetate buffer), or in a non-aqueous solvent such as a vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil, and the osmotic pressure is adjusted to a predetermined level, followed by sterilization such as filtration sterilization.
• an aqueous solvent such as sterilized purified water, physiological saline
• the container for containing the aqueous suspension of the present disclosure is not particularly limited, and may be, for example, a glass container or a plastic container.
• the plastic container may be made of any material, such as polyester (polyethylene terephthalate, polyarylate), polycarbonate, polyethylene, polypropylene, a mixture thereof, or a mixture of these and other materials.
• the container used in the present disclosure may be one used in the medical field or may be other than those.
• the container may be made of any material that meets the "Standard for Plastic Containers for Eye Drops" in Japan or other equivalent standards.
• the shape of the container used may be any shape, and generally any shape suitable for eye drops can be used.
• the aqueous suspension formulation of the present disclosure can be filled into any eye drop container commonly used in the medical field, for example, a polyethylene (preferably low density polyethylene) or polypropylene, preferably a colorless polypropylene container.
• a polyethylene preferably low density polyethylene
• polypropylene preferably a colorless polypropylene container.
• Short Protocols in Molecular Biology A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Ausubel, FM(1995).Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub.
• the prepared suspension was stirred with a stirrer and 5 mL of each was dispensed into an eye dropper.
• the eye dropper was a colorless polyethylene container (the same container used for GatiFlo ophthalmic solution 0.3% (manufactured and sold by Senju Pharmaceutical Co., Ltd.)).
• Redispersibility evaluation (tipping operation) It was confirmed that the suspended particles in the suspension filled in the eye drop container had completely settled.
• the inversion operation (the action of holding the container in the hand and turning it upside down) was repeated until the precipitate disappeared from the bottom and walls of the eye drop container and was redispersed.
• the number of inversion operations required to redisperse was counted.
• the operation of inverting the container 180° upside down at a speed of 1 second and then inverting it 180° again to the upright state was counted as one inversion.
• the test was performed on 3 to 6 samples per formulation, and the average number of inversion operations was calculated.
• Results The results are shown in Tables 1 to 7.
• the aqueous suspension containing compound (1) showed good redispersibility with a reduced number of inversion operations by incorporating diquafosol sodium, cyclosporine, sodium hyaluronate, loteprednol etabonate, bromfenac sodium, or fluorometholone.
• Example 1 was evaluated by shaking operation, the number of shaking operations was 10.0.
• Eye drops can be manufactured by preparing aqueous suspensions having the compositions shown in Tables 8 and 9. The formulation amounts of compound (1) and each additive are expressed as "g/100 mL".
• Tyloxapol (cloud point: 90-100°C) manufactured by AMRI Rensselaer (Curia Global, Inc.), methylcellulose manufactured by Shin-Etsu Chemical Co., Ltd. as Metrose SM-15, hydroxypropyl methylcellulose (HPMC) manufactured by Shin-Etsu Chemical Co., Ltd. as 60SH-4000, carboxymethylcellulose (CMC) manufactured by Daiichi Kogyo Seiyaku Co., Ltd. as Cellogen PR-S, and lifitegrast manufactured by Shanghai Sumway Pharmaceutical Technology Co., Ltd. are used.
• Compound (1) is type I crystal.
• Each container is composed of a bottle (colorless PE, colorless PP or brown PP), a nozzle (PE) and a cap (PP).
• the appearance, brightness, chromaticity, saturation and transmittance at each wavelength of the body of the bottle of each container are as shown in Table 10 and Figure 1.
• Each container is shrink-wrapped as a product label.
• the dimensions of the bottle are approximately 23 mm x 17 mm x 50 mm, and the resin weight is approximately 3 g.
• the shape is the same as that of the bottle of Softia (registered trademark) ophthalmic solution 0.02% (manufactured and sold by Senju Pharmaceutical Co., Ltd.).
• the polyethylene bottle material is low-density polyethylene.
• Polypropylene is a propylene-ethylene copolymer with a propylene/ethylene ratio of 50/50 to 99.9/0.1, and is the same as the bottle material of Softia (registered trademark) eye drops 0.02% (manufactured and sold by Senju Pharmaceutical Co., Ltd.).
• Measurement method for lightness, chroma, and transmittance of bottle body The lightness ( L* value) and chromaticity (a * value, b * value) of the side portion (wider side portion, 1.0 cm x 2.0 to 3.0 cm) cut from the body of the bottle are measured using a spectrophotometer (CM-5, manufactured by Konica Minolta, Inc.).
• the chroma (c * value) is calculated according to the formula: ((a * value) 2 + (b * value) 2 ) 1/2 .
• the transmittance (%) of light in the 200 to 800 nm region of this side portion is measured using an ultraviolet-visible spectrophotometer ("UV-2450 type", manufactured by Shimadzu Corporation).
• Bottle sterilization method EB electron beam radiation sterilization: Eye drop bottles are sterilized by irradiating them with electron beams at 10 to 60 kGy.
• EOG ethylene oxide gas sterilization: Eye drop bottles are sterilized under the following conditions: ethylene oxide concentration 400-700 mg/L, temperature 40-50°C, relative humidity 45-85%, and processing time 3 hours or more.
• VHP Vapor Hydrogen Peroxide: Eye drop bottles are sterilized by spraying 3% VHP at a temperature of 20-50° C., a relative humidity of 30-90%, and for approximately 1 hour.
• Gamma rays (gamma sterilization): Bottles are sterilized by exposure to gamma rays at 20-60 kGy.
• 50L scale manufacturing method for eye drops Purified water and a specified amount of boric acid, borax, sodium chloride, and zinc chloride are added to a 30L stainless steel container and stirred. A specified amount of tyloxapol aqueous solution is prepared in a 1L stainless steel container and this aqueous solution is added to the 30L stainless steel container. A specified amount of methylcellulose is dispersed with hot water (50-90°C) in another 1L stainless steel container, cooled, and this methylcellulose aqueous solution is added to the 30L stainless steel container. After confirming that all additives have dissolved in the 30L stainless steel container, purified water is added to make a 1.5-fold concentrated base solution and the weight is increased to a measuring tape.
• This base solution is sterilized by filtration, and the weight is increased to a measuring tape with purified water (including washing in) to prepare a specified amount of base solution.
• Compound (1) as the first component and second component diquafosol sodium, cyclosporine, sodium hyaluronate, loteprednol etabonate, bromfenac sodium, fluorometholone, rebamipide, olodaterol hydrochloride, or delcocitinib
• the suspension is gently stirred to defoam. Then, 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 a nozzle and a cap are attached to the bottle.
• This disclosure can be used in the fields of medicine, pharmaceuticals, healthcare, biology, biochemistry, etc.

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