US20220072012A1 - Ursodeoxycholic acid-containing agent for treating or preventing presbyopia - Google Patents

Ursodeoxycholic acid-containing agent for treating or preventing presbyopia Download PDF

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US20220072012A1
US20220072012A1 US17/414,285 US201917414285A US2022072012A1 US 20220072012 A1 US20220072012 A1 US 20220072012A1 US 201917414285 A US201917414285 A US 201917414285A US 2022072012 A1 US2022072012 A1 US 2022072012A1
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ursodeoxycholic acid
ester
acid
lens
eye
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Masatomo Kato
Tomoko Oda
Kazutaka Kido
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Santen Pharmaceutical Co Ltd
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Santen Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
    • 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
    • A61K47/30—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention relates to an agent for treating or preventing presbyopia, comprising ursodeoxycholic acid or an amide conjugate of ursodeoxycholic acid, or an ester thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Patent Document 1 discloses that lipoic acid derivatives such as lipoic acid choline ester (alias, EV06, UNR844) are useful for the treatment of presbyopia. And an eye drop comprising lipoic acid choline ester is under clinical development in the United States. Clinical developments of the treatment of presbyopia are also underway for an eye drop comprising AGN-199201 and AGN-190584, an eye drop comprising PRX-100, and an eye drop comprising PresbiDrops (CSF-1).
  • the condition of patients with presbyopia is diverse, and an increase in the types of therapeutic agents for eye diseases is still strongly desired so that therapeutic agents can be selected accordingly.
  • Ursodeoxycholic acid is a compound that promotes bile secretion and inhibits cytokine/chemokine production, and is therefore used in the treatment of liver diseases (Non-Patent Document 2).
  • Non-Patent Document 2 there is no literature reporting relationship between ursodeoxycholic acid and presbyopia treatment.
  • Patent Document 1 WO 2010/147957
  • An object of the present application is to provide a new measure for treating or preventing presbyopia, which is a very interesting challenge.
  • ursodeoxycholic acid surprisingly improves lens elasticity, and thereby have reached the present application.
  • the present disclosure provides the following aspects of the invention.
  • the therapeutic or prophylactic agent of the present disclosure can improve the lens elasticity, which is important for lens thickness adjustment, and is therefore useful in the treatment or prevention of eye diseases such as presbyopia etc.
  • ursodiol also called ursodiol and 3 ⁇ ,7 ⁇ -Dihydroxy-5 ⁇ -cholan-24-oic acid, and sometimes abbreviated as UDCA.
  • amide conjugates of ursodeoxycholic acid which may be comprised in the agent of the present invention refer to amide conjugates having a —CO—NH— bond which is formed by dehydration condensation of the carboxyl group of ursodeoxycholic acid with an amino group of an amino compound.
  • amino compound examples include:
  • 2-aminoadipic acid 3-aminoadipic acid, 2-aminobutanoic acid, 4-aminobutanoic acid, 2,4-diaminobutanoic acid, 2-aminohexanoic acid, 6-aminohexanoic acid, 1i-alanine, 2-aminopentanoic acid, 2,3-diaminopropanoic acid, 2-aminopimelic acid, 2,6-diaminopimelic acid, cysteic acid, 2,4-diaminobutanoic acid, 2,6-diaminopimelic acid, 2,3-diaminopropanoic acid, 4-carboxyglutamic acid, homocysteine, homoserine, homoserine lactone, homoserine lactone, 5-hydroxylysine, allohydroxylysine, alloisoleucine, norleucine, norvaline, ornithine, allothreonine, and thyroxine;
  • amino acid analogs e.g., taurine.
  • Examples of the amide conjugates of ursodeoxycholic acid include tauroursodeoxycholic acid and glycoursodeoxycholic acid.
  • esters of ursodeoxycholic acid which may be comprised in the agent of the present invention include esters which are formed by dehydration condensation of the carboxyl group of ursodeoxycholic acid with a monohydric alcohol having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms).
  • esters of the amide conjugates of ursodeoxycholic acid which may be comprised in the agent of the present invention include, for example, when the amino compound part has carboxyl group(s) and/or sulfonic acid group(s), esters which are formed by dehydration condensation of the carboxyl group(s) and/or the sulfonic acid group(s) with monohydric alcohol(s) having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms).
  • esters of ursodeoxycholic acid or the esters of amide conjugates of ursodeoxycholic acid include methyl esters, ethyl esters, n-propyl esters, isopropyl esters, n-butyl esters, isobutyl esters, sec-butyl esters, tert-butyl esters, n-pentyl esters, and n-hexyl esters.
  • Preferred examples of the ester include methyl esters, ethyl esters, n-propyl esters, and isopropyl esters.
  • carboxylic acid esters which are formed by dehydration condensation of at least one hydroxyl group of ursodeoxycholic acid or an amide conjugate of ursodeoxycholic acid with a carboxylic acid having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 2 to 3 carbon atoms).
  • carboxylic acid esters include formate esters, acetate esters, propionate esters, isopropionate esters, butyrate esters, isobutyrate esters, pivalate esters, valerate esters, or isovalerate esters.
  • Preferred examples of the carboxylic acid esters include acetate esters.
  • Examples of pharmaceutically acceptable salts include, inorganic salts such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, phosphates, etc.; organic acid salts such as acetates, trifluoroacetates, benzoates, oxalates, malonates, succinates, maleates, fumarates, tartrates, citrates, methanesulfonates, ethanesulfonates, trifluoromethanesulfonates, benzenesulfonates, p-toluenesulfonates, glutamates, aspartates, etc.; metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts, etc.; inorganic salts such as ammonium salts, etc.; and organic amine salts such as triethylamine salts, guanidine salts, etc.
  • Examples of pharmaceutically acceptable salts include preferably sodium salts and
  • ursodeoxycholic acid or amide conjugates of ursodeoxycholic acid, or esters thereof, or pharmaceutically acceptable salts thereof may be in the form of hydrates or solvates.
  • the amount of ursodeoxycholic acid or an amide conjugate of ursodeoxycholic acid, or an ester thereof, or a pharmaceutically acceptable salt thereof comprised in the agent of the present invention is not particularly limited and may be selected from a wide range depending on dosage forms etc.
  • the amount of ursodeoxycholic acid or an amide conjugate of ursodeoxycholic acid, or an ester thereof, or a pharmaceutically acceptable salt thereof comprised in the agent of the present invention is 0.00001 to 10% (w/v), preferably 0.0001 to 5% (w/v), more preferably 0.001 to 3% (w/v), even more preferably 0.01 to 2% (w/v), particularly preferably 0.15 to 1.5% (w/v).
  • An example of the lower limit of the amount is 0.00001% (w/v), a preferable example is 0.0001% (w/v), a more preferable example is 0.001% (w/v), a further preferable example is 0.01% (w/v), a particularly preferable example is 0.1% (w/v), a further particularly preferable example is 0.15% (w/v).
  • An example of the upper limit of the amount is 10% (w/v), a preferable example is 5% (w/v), a more preferable example is 3% (w/v), a particularly preferable example is 2% (w/v), a further particularly preferable example is 1.5% (w/v).
  • a preferred range of the amount may be indicated by a combination of the above examples of lower and upper limits.
  • the amount of ursodeoxycholic acid or an amide conjugate of ursodeoxycholic acid, or an ester thereof, or a pharmaceutically acceptable salt thereof comprised in the agent of the present invention is 0.00001 to 10% (w/w), preferably 0.0001 to 5% (w/w), more preferably 0.001 to 3% (w/w), even more preferably 0.01 to 2% (w/w), particularly preferably 0.15 to 1.5% (w/w).
  • An example of the lower limit of the amount is 0.00001% (w/w), a preferable example is 0.0001% (w/w), a more preferable example is 0.001% (w/w), a further preferable example is 0.01% (w/w), a particularly preferable example is 0.1% (w/w), and a further preferable example is 0.15% (w/w).
  • An example of the upper limit of the amount is 10% (w/w), a preferable example is 5% (w/w), a more preferable example is 3% (w/w), a particularly preferable example is 2% (w/w), and a particularly preferable example is 1.5% (w/w).
  • a preferred range of the amount may be indicated by a combination of the above examples of lower and upper limits.
  • the amount of ursodeoxycholic acid or an amide conjugate of ursodeoxycholic acid, or an ester thereof, or a pharmaceutically acceptable salt thereof comprised in the agent of the present invention may be 0.3 to 10% (w/w) (e.g., 0.4 to 5% (w/w), 0.5 to 3% (w/w), 0.6 to 1.5% (w/w), 0.8 to 1.3% (w/w)).
  • % (w/v) means the mass (g) of the active ingredient (ursodeoxycholic acid and amide conjugate(s) of ursodeoxycholic acid, and ester(s) thereof, and pharmaceutically acceptable salt(s) thereof) or an additive (surfactant, etc.) comprised in 100 mL of an agent.
  • 0.01% (w/v) of ursodeoxycholic acid means that the amount of ursodeoxycholic acid comprised in 100 mL of an agent is 0.01 g.
  • % (w/w) means the mass (g) of the active ingredient (ursodeoxycholic acid and amide conjugate(s) of ursodeoxycholic acid, and ester(s) thereof, and pharmaceutically acceptable salt(s) thereof) or an additive (surfactant, etc.) comprised in 100 g of an agent.
  • 0.01% (w/w) of ursodeoxycholic acid means that the amount of ursodeoxycholic acid comprised in 100 g of an agent is 0.01 g.
  • the amount of ursodeoxycholic acid or an amide conjugate of ursodeoxycholic acid, or an ester thereof, or a pharmaceutically acceptable salt thereof comprised in the agent may mean the mass of the salt, hydrate, or solvate (including the hydrate or solvate of the salt) added into the agent, or may mean the mass converted as a free form of ursodeoxycholic acid, the amide conjugate of ursodeoxycholic acid or the ester thereof, preferably may mean the mass converted as a free form of ursodeoxycholic acid, the amide conjugate of ursodeoxycholic acid, or the ester thereof.
  • presbyopia means a symptom/disease that is determined to be presbyopia based on general criteria used by a physician or professional.
  • diagnostic criteria for presbyopia include:
  • a binocular daily life visual acuity which is a binocular distant visual acuity measured under the same condition as daily life, is less than 0.4 at 40 cm distance(clinical presbyopia);
  • accommodative amplitude is less than 2.5 Diopters” (medical presbyopia).
  • an eye disease accompanied by a decrease in lens elasticity refers to an eye disease considered in the field of ophthalmology to be accompanied by a decrease in lens elasticity, including, for example, presbyopia (e.g., presbyopia due to aging), and a hardening of the lens induced by drugs and the like.
  • accommodation function of the eye refers to an eye function that automatically focuses on distant and/or near objects.
  • an eye disease accompanied by a decrease in accommodative function of the eye refers to an eye disease considered in the field of ophthalmology to be accompanied by a decrease in accommodative function of the eye, including, for example, presbyopia (e.g., presbyopia due to aging), and a hardening of the lens induced by drugs etc., and decreased accommodation function induced by seeing near objects for a long time.
  • the efficacy of the agent of the present invention may be evaluated, for example, as an increase in “accommodative amplitude of the eye”.
  • the accommodative amplitude of the eye can be measured as a Diopter (D) which can be determined by the following expression 1:
  • Diopter( D ) 1/Near Point Distance( m ) (Expression 1).
  • the accommodative amplitude of the eye is greater than 10 diopters at 10 years, then gradually decreases to about 3 diopters at about 45 years and is almost lost at about 60 years.
  • the accommodative amplitude decreases to about 3 diopters, it becomes difficult to focus on near objects (about 30 cm) in daily life, and subjective symptoms of presbyopia appear.
  • the efficacy of the agent of the present invention may be evaluated, for example, as an improvement in “visual acuity”.
  • the visual acuity can be measured as near visual acuity (uncorrected visual acuity, distance-corrected near visual acuity, corrected visual acuity) and can be measured by using decimal visual acuity, fractional visual acuity, or logMAR.
  • the agent of the present invention may be used to improve near visual acuity (e.g., distance-corrected near visual acuity).
  • the agent of the invention may begin to exhibit an efficacy within one year, preferably within six months, more preferably within one month, more preferably within one week, and most preferably within one day after the administration. Further, once an efficacy is exerted, the efficacy may be exerted continuously until after one day, preferably until after one week, more preferably until after one month, more preferably until after six months, particularly preferably until after one year, and most preferably until after three years.
  • the agent of the present invention may be administered, for example, so as to increase the accommodative amplitude of the eye by at least about 0.5 diopters (preferably at least about 1 diopter, more preferably at least about 1.5 diopters, more preferably at least about 2 diopters, even more preferably at least about 3 diopters, and still more preferably at least about 4 diopters, particularly preferably at least about 5 diopters, and still more preferably at least about 10 diopters).
  • 0.5 diopters preferably at least about 1 diopter, more preferably at least about 1.5 diopters, more preferably at least about 2 diopters, even more preferably at least about 3 diopters, and still more preferably at least about 4 diopters, particularly preferably at least about 5 diopters, and still more preferably at least about 10 diopters.
  • distance-corrected near visual acuity generally refers to near visual acuity measured with distance visual acuity corrected to 0.0 logMAR (decimal visual acuity of 1.0 or more).
  • the agent of the present invention may be administered, for example, so as to restore the accommodative amplitude of the eye to at least about 0.5 diopters (preferably at least about 1 diopter, more preferably at least about 1.5 diopters, more preferably at least about 2 diopters, more preferably at least about 3 diopters, particularly preferably at least about 4 diopters, particularly preferably at least about 5 diopters, and still more preferably at least about 10 diopters).
  • 0.5 diopters preferably at least about 1 diopter, more preferably at least about 1.5 diopters, more preferably at least about 2 diopters, more preferably at least about 3 diopters, particularly preferably at least about 4 diopters, particularly preferably at least about 5 diopters, and still more preferably at least about 10 diopters.
  • the agent of the present invention may be administered orally or parenterally (e.g., ocularly, nasally, transdermally, transmucosally, by injection, etc.).
  • the agent of the present invention may be prepared in the usual manner in the art by mixing the active ingredient with, for example, one or more pharmaceutically acceptable additives, for example, in the form of oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, suspensions, and the like, or parenteral preparations such as eye drops, ophthalmic ointments, injections, suppositories, nasal preparations, and the like.
  • Preferred formulations of the agent of the present invention include eye drops (e.g., ophthalmic suspensions) and eye ointments from the viewpoint of greater efficacy of the agents of the invention.
  • surfactants include cationic surfactants, anionic surfactants, nonionic surfactants and the like.
  • the amount of the surfactant comprised in the agent may be appropriately adjusted depending on the type of the surfactant, etc., and is preferably, for example, 0.01 to 1% (w/v).
  • buffers include phosphoric acid or salts thereof, which may be hydrates or solvates thereof.
  • Examples of the phosphoric acid or salts thereof include phosphoric acid, trisodium phosphate, sodium dihydrogenphosphate, sodium hydrogen phosphate (disodium hydrogenphosphate) and the like, which may be hydrates thereof.
  • the amount of the buffer comprised in the agent may be appropriately adjusted depending on the type of the buffer, etc., but for example, 0.001 to 10% (w/v) is preferable, and 0.01 to 5% (w/v) is more preferable. Two or more kinds of buffers may be used together.
  • tonicity agents examples include ionic tonicity agents and nonionic tonicity agents.
  • examples of the ionic tonicity agents include sodium chloride and the like.
  • the amount of the tonicity agent comprised in the agent may be appropriately adjusted according to the type of the tonicity agent or the like, but for example, 0.001 to 10% (w/v) is preferable, and 0.01% to 5% (w/v) is more preferable.
  • thickeners examples include hydroxypropyl methylcellulose and the like.
  • the amount of the thickener may be appropriately adjusted according to the type of the thickener or the like, but for example, 0.001 to 5% (w/v) is preferable, and 0.01% to 3% (w/v) is more preferable.
  • the agent of the present invention is an aqueous formulation (e.g., eye drops)
  • the pH is preferably 4 to 8 and more preferably 5 to 7.
  • solvents examples include water, physiological saline and the like.
  • Examples of the agent of the present invention which is an aqueous preparation include aqueous preparations comprising ursodeoxycholic acid or an amide conjugate of ursodeoxycholic acid, or an ester thereof, or a pharmaceutically acceptable salt thereof, water, and an additive selected from ethyl pyruvate, sodium dihydrogenphosphate monohydrate (NaH 2 PO 4 H 2 O), disodium hydrogenphosphate (Na 2 HPO 4 ), hydroxypropyl methylcellulose, NaCl, and a mixture thereof.
  • said “a mixture thereof” means any combination of the listed specific additives.
  • an effective amount is the amount of the active ingredient required to provide a patient benefit in the symptoms of a disease.
  • a dosage and administration of the agent of the present invention is not particularly limited as long as the dosage and administration are sufficient to achieve the desired medicinal effect, and may be appropriately selected according to the symptoms of the disease, the age and weight of the patient, the dosage form of the agent, etc.
  • the agent of the present invention have an immediate effect on presbyopia, an eye disease accompanied by a decrease in lens elasticity, or an eye disease accompanied by a decrease in accommodative function of the eye, for example, compared to EV06.
  • the duration of administration of the agent of the present invention may be determined by a physician or professional.
  • the agent of the present invention may be an ophthalmic administration agent such as an eye drop (e.g., a suspension) and an eye ointment, and may be used continuously for at least 2 days, at least 3 days, at least 7 days, at least 10 days.
  • an ophthalmic administration agent such as an eye drop (e.g., a suspension) and an eye ointment, and may be used continuously for at least 2 days, at least 3 days, at least 7 days, at least 10 days.
  • the agent of the present invention may be administered at least once (e.g., at least twice, at least three times) a day.
  • the agent of the present invention when administered to the eye, may be less irritating to the eye while having an effect on presbyopia, an eye disease accompanied by a decrease in lens elasticity, or an eye disease accompanied by a decrease in accommodative function of the eye.
  • a vehicle comprising 0.1% (w/v) of ethyl pyruvate, 0.269% (w/v) of sodium dihydrogenphosphate monohydrate (NaH 2 PO 4 H 2 O), 0.433% (w/v) of disodium hydrogenphosphate (Na 2 HPO 4 ), 0.2% (w/v) of hydroxypropyl methylcellulose, and 0.5% (w/v) of NaCl was prepared.
  • EVO6 was sonicated with the addition of the vehicle to prepare a 5% (w/v) suspension.
  • the resulting 5% (w/v) suspension was diluted with the vehicle to prepare a 1.5% (w/v) solution.
  • the resulting 1.5% (w/v) solution was diluted with the vehicle to prepare a 0.5% (w/v) solution.
  • the total amount of each sample to be used in one day was prepared before use.
  • the mean of the vehicle control group was based on 6 eyes and the mean of each EVO6 sample group was based on 12 eyes.
  • a vehicle comprising 0.1% (w/v) of ethyl pyruvate, 0.269% (w/v) of sodium dihydrogenphosphate monohydrate (NaH 2 PO 4 H 2 O), 0.433% (w/v) of disodium hydrogenphosphate (Na 2 HPO 4 ), 0.2% (w/v) of hydroxypropyl methylcellulose, 0.5% (w/v) of NaCl was prepared.
  • Sodium ursodeoxycholate was sonicated with the addition of the vehicle to prepare a 1.5% (w/v) suspension.
  • the resulting 1.5% (w/v) suspension was diluted with the vehicle to prepare a 0.5% (w/v) suspension.
  • the resulting 0.5% (w/v) suspension was diluted with the vehicle to prepare a 0.15% (w/v) suspension.
  • the total amount of each sample to be used in one day was prepared before use.
  • EVO6 was sonicated with the addition of the vehicle to prepare a 1.5% (w/v) solution. The total amount of the sample to be used in one day was prepared before use.
  • Ursodeoxycholic acid was sonicated with the addition of the vehicle to prepare a 1.5% (w/v) suspension.
  • the resulting 1.5% (w/v) suspension was diluted with the vehicle to prepare a 0.5% (w/v) suspension.
  • the resulting 0.5% (w/v) suspension was diluted with the vehicle to prepare a 0.15% (w/v) suspension.
  • the total amount of each sample to be used in one day was prepared before use.
  • EVO6 was sonicated with the addition of the vehicle to prepare a 1.5% (w/v) solution. The total amount of the sample to be used in one day was prepared before use.
  • Ursodeoxycholic acid was sonicated with the addition of the vehicle to prepare a 3.0% (w/v) suspension.
  • the resulting 3.0% (w/v) suspension was diluted with the vehicle to prepare a 1.0% (w/v) suspension.
  • the resulting 1.0% (w/v) suspension was diluted with the vehicle to prepare a 0.3% (w/v) suspension.
  • the total amount of each sample to be used in one day was prepared before use.
  • Ursodeoxycholic acid was sonicated with the addition of the vehicle to prepare a 1.0% (w/v) suspension. The total amount of the sample to be used in one day was prepared before use.
  • a vehicle comprising 0.1% (w/v) of ethyl pyruvate, 0.269% (w/v) of sodium dihydrogenphosphate monohydrate (NaH 2 PO 4 H 2 O), 0.433% (w/v) of disodium hydrogenphosphate (Na 2 HPO 4 ), 0.2% (w/v) of hydroxypropyl methylcellulose, 0.5% (w/v) of NaCl was prepared.
  • a vehicle comprising 0.1% (w/v) of ethyl pyruvate, 0.269% (w/v) of sodium dihydrogenphosphate monohydrate (NaH 2 PO 4 H 2 O), 0.433% (w/v) of disodium hydrogenphosphate (Na 2 HPO 4 ), 0.2% (w/v) of hydroxypropyl methylcellulose, 0.5% (w/v) of NaCl was prepared.
  • Tauroursodeoxycholic acid was dissolved with the addition of the vehicle to prepare a 1.0% (w/v) solution. The total amount of each sample to be used in one day was prepared before use.
  • a vehicle comprising 0.1% (w/v) of ethyl pyruvate, 0.269% (w/v) of sodium dihydrogenphosphate monohydrate (NaH 2 PO 4 H 2 O), 0.433% (w/v) of disodium hydrogenphosphate (Na 2 HPO 4 ), 0.2% (w/v) of hydroxypropyl methylcellulose, 0.5% (w/v) of NaCl was prepared.
  • the total amount of each sample to be used in one day was prepared before use.
  • a vehicle comprising 0.1% (w/v) of ethyl pyruvate, 0.269% (w/v) of sodium dihydrogenphosphate-monohydrate (NaH 2 PO 4 .H 2 O), 0.433% (w/v) of disodium hydrogenphosphate (Na 2 HPO 4 ), 0.2% (w/v) of hydroxypropyl methylcellulose, 0.5% (w/v) of NaCl was prepared.
  • ursodeoxycholic acid ophthalmic suspensions were prepared in the same manner as in the above pharmacological tests. These ophthalmic suspensions and the vehicle were each instilled into the left eye of Japanese White rabbits at a dose of 50 ⁇ L/eye with pipette twice per day at a 6-hour interval for 2 weeks. One hour after the final instillation, ocular irritation of anterior segment of the eye was evaluated according to the McDonald-Shadduck method, and the lens was observed. The contralateral eye was untreated. The ocular irritation of anterior segment of the eye was scored according to the following criteria: +1: mild; +2: moderate; +3: severe.
  • test results are shown in Table 9. After the 2 week-repeated instillation, no abnormal findings were observed in eyes treated with the ophthalmic suspensions of ursodeoxycholic acid in the observation of ocular irritation of anterior segment of the eye and lens observation. Histopathological examination of the eyes showed no abnormal findings.
  • the agent of the present invention is useful for treating or preventing eye diseases such as presbyopia etc.

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  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
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US17/414,285 2018-12-18 2019-12-17 Ursodeoxycholic acid-containing agent for treating or preventing presbyopia Pending US20220072012A1 (en)

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JP2018236717 2018-12-18
JP2018-236717 2018-12-18
PCT/JP2019/049352 WO2020129964A1 (fr) 2018-12-18 2019-12-17 Agent contenant de l'acide ursodésoxycholique pour traiter ou prévenir la presbytie

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JP (2) JP6771698B1 (fr)
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CN (1) CN113164499A (fr)
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Cited By (2)

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US11419880B2 (en) 2018-12-18 2022-08-23 Santen Pharmaceutical Co., Ltd. Ursodeoxycholic acid-containing agent for treating or preventing presbyopia
WO2022232836A1 (fr) * 2021-04-29 2022-11-03 Baker Hughes Oilfield Operations Llc Ensemble vanne pilote de modulation

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TW202245794A (zh) 2021-02-15 2022-12-01 日商參天製藥股份有限公司 包含熊去氧膽酸或其鹽之水性醫藥組合物
WO2024034592A1 (fr) * 2022-08-09 2024-02-15 参天製薬株式会社 Composition pharmaceutique aqueuse contenant de l'udca ou un sel de celui-ci

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US11419880B2 (en) * 2018-12-18 2022-08-23 Santen Pharmaceutical Co., Ltd. Ursodeoxycholic acid-containing agent for treating or preventing presbyopia

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US11419880B2 (en) * 2018-12-18 2022-08-23 Santen Pharmaceutical Co., Ltd. Ursodeoxycholic acid-containing agent for treating or preventing presbyopia

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11419880B2 (en) 2018-12-18 2022-08-23 Santen Pharmaceutical Co., Ltd. Ursodeoxycholic acid-containing agent for treating or preventing presbyopia
WO2022232836A1 (fr) * 2021-04-29 2022-11-03 Baker Hughes Oilfield Operations Llc Ensemble vanne pilote de modulation

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AU2019407391A1 (en) 2021-07-01
JP6771698B1 (ja) 2020-10-21
CA3123370A1 (fr) 2020-06-25
KR20210105916A (ko) 2021-08-27
EP3900728A1 (fr) 2021-10-27
US20230040386A1 (en) 2023-02-09
JPWO2020129964A1 (ja) 2021-02-15
JP2021006548A (ja) 2021-01-21
US20220096497A1 (en) 2022-03-31
SG11202106216SA (en) 2021-07-29
EP3900728A4 (fr) 2022-08-17
EA202191684A1 (ru) 2021-09-01
CN113164499A (zh) 2021-07-23
MX2021007161A (es) 2021-10-13
IL284004A (en) 2021-08-31
BR112021011653A2 (pt) 2021-09-08
WO2020129964A1 (fr) 2020-06-25
US11419880B2 (en) 2022-08-23

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