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WO2024096629A1 - Cftr 조절제 화합물을 포함하는 점안용 조성물 - Google Patents

Cftr 조절제 화합물을 포함하는 점안용 조성물 Download PDF

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WO2024096629A1
WO2024096629A1 PCT/KR2023/017412 KR2023017412W WO2024096629A1 WO 2024096629 A1 WO2024096629 A1 WO 2024096629A1 KR 2023017412 W KR2023017412 W KR 2023017412W WO 2024096629 A1 WO2024096629 A1 WO 2024096629A1
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eye
composition
active ingredient
compound
formula
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PCT/KR2023/017412
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English (en)
French (fr)
Korean (ko)
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오창목
이설희
임다미
정일지
윤홍철
박준태
안경미
이정우
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일동제약 주식회사
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Publication of WO2024096629A1 publication Critical patent/WO2024096629A1/ko

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P27/04—Artificial tears; Irrigation solutions

Definitions

  • the present invention relates to an ophthalmic composition, and more particularly, to an ophthalmic composition containing a cystic fibrosis transmembrane conductance regulator (CFTR) regulator.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Dry eye syndrome is a disease of the tear film that causes irritation to the eyes due to a lack of tears. It is an eye disease in which the components are unbalanced, damaging the ocular surface and causing irritating symptoms such as eye irritation, foreign body sensation, and dryness. says There are various causes of dry eye, including decreased tear secretion, excessive evaporation of tears, inflammation of the tear-producing organ, and systemic diseases such as Sjögren's syndrome, Steven Johnson syndrome, and pemphigoid. It is one of the most widespread eye diseases. However, treatment options are limited. The most common treatments include artificial tear drops, which occlude the lacrimal punctum to reduce the amount of tears released, reduce ocular surface inflammation, or enhance tear/mucin secretion.
  • cystic fibrosis transmembrane conductance regulator a major chloride ion channel that stimulates fluid secretion from the ocular surface
  • CFTR refers to the membrane protein and chloride ion (Cl - ) channel encoded by the CFTR gene.
  • the CFTR is a protein located in the cell membrane that acts as a channel for chlorine ions, and induces fluid secretion from the ocular surface through chloride ion transport.
  • CFTR can treat many diseases caused by loss or deterioration of CFTR function by activating CFTR present in the cell membrane. For example, substances that activate CFTR can correct the abnormal tear film that occurs in dry eye syndrome by activating chlorine ion (Cl - ) channels and increasing tear volume.
  • the inventors of the present invention studied dry eye syndrome treatment using CFTR modulators and completed the present invention.
  • the problem to be solved by the present invention is to provide an ophthalmic composition containing a compound of formula 1 that can act as a cystic fibrosis transmembrane conductance regulator (CFTR) regulator, preferably a CFTR activator. It is done.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • another problem that the present invention aims to solve is to provide a preferable usage amount, usage method, prescription amount, etc. of the eye drop of the present invention.
  • One embodiment of the present invention is effective in significantly suppressing the decrease in tear secretion, keratoconjunctivitis, and changes in corneal shape caused by dry eye syndrome, restoring damaged corneas, and increasing tear secretion, making it safe and effective for dry eye syndrome.
  • it provides preferred usage amounts, usage methods, prescription amounts, etc. of ophthalmic compositions that can be used in the development of treatments for diseases related to dry eye syndrome.
  • the scope of the present invention is not limited by this effect.
  • One aspect of the present invention includes a compound represented by the following formula (1) at a concentration of 0.01 to 0.3% (w/v), or a pharmaceutically acceptable salt, solvate, hydrate, prodrug or stereoisomer thereof as an active ingredient, Provides an ophthalmic composition for the treatment, prevention or improvement of dry eye syndrome or dry eye-related diseases, which is characterized in that 1-3 drops per eye are instilled 1-7 times a day.
  • Another aspect of the present invention is a method for treating or improving dry eye syndrome or a dry eye-related disease in an individual, comprising administering to an individual in need a compound represented by the following formula (1) at a concentration of 0.01 to 0.3% (w/v), or It includes the step of administering a pharmaceutically acceptable salt, solvate, hydrate, prodrug, or stereoisomer thereof as an active ingredient, wherein the administration is administered by instilling 1-3 drops per eye at a time, 1-7 times a day. do.
  • Another aspect of the present invention is a compound represented by Formula 1 at a concentration of 0.01 to 0.3% (w/v) for use in a treatment for the treatment, prevention, or improvement of dry eye or dry eye-related diseases, or a pharmaceutically acceptable compound thereof.
  • the use of salts, solvates, hydrates, prodrugs, or stereoisomers is provided, and the active ingredient in the treatment is administered 1-3 drops per eye at a time, 1-7 times a day.
  • One aspect of the present invention provides an ophthalmic composition
  • a compound of formula 1 below which can act as a CFTR activator.
  • the IUPAC name of Formula 1 is (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine- 2-1) It is methanone. These compounds can be obtained by the method disclosed in International Patent Application Publication WO 2022/084741 A1.
  • the compound of Formula 1 is a pyrazolo[1,5- ⁇ ]pyrimidine derivative compound, and the pyrazolo[1,5- ⁇ ]pyrimidine derivative compound contains a pyrazolo[1,5-a]pyrimidine core.
  • aryl optionally substituted (C1-C10)alkyl and optionally substituted (C1-C10)alkoxy substituents, and by substitution at position 7 of the core structure by optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocycle. You can get it.
  • the compounds described herein may include crystalline, powdered, and amorphous forms of these compounds, including polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), and conformational forms. It can exist in a variety of forms, including pharmaceutically acceptable salts, including polymorphic and amorphous forms of the compound, as well as mixtures thereof.
  • the compounds described herein may exist as solvates, especially hydrates, and, unless otherwise specified, all such solvates and hydrates are intended to be included. Hydrates may form during the manufacture of the compound or composition comprising the compound, or hydrates may form over time due to the hygroscopic nature of the compound.
  • the compounds of the present technology may also exist as organic solvates, including DMF, ether and alcohol solvates, among others. Identification and preparation of any particular solvate is within the skill of those of ordinary skill in the fields of synthetic organic chemistry or medicinal chemistry.
  • the compounds described herein exist in solvate form.
  • the compounds described herein exist in hydrate form when the solvent component of the solvate is water.
  • Compounds of the invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, such as diastereomers, enantiomers, and racemic mixtures, are considered to form part of the invention.
  • “pharmaceutically acceptable salts” refer to salts commonly used in the pharmaceutical industry, examples of which include inorganic ionic salts made of calcium, potassium, sodium, magnesium, etc.; Inorganic acid salts made from hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid.
  • organic acid salts made from aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc., and sulfonates made from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid.
  • amino acid salts made from glycine, arginine, lysine, etc.; and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but are not limited thereto.
  • water solubility is one of the key factors affecting ocular bioavailability and ophthalmic formulations.
  • ROx rule of thumb
  • the optimal calculated solubility for an effective ophthalmic drug should be greater than 1 ⁇ M.
  • the inventors of the present invention completed the present invention as a result of research to provide an excellent eye drop by improving the solubility while maintaining the efficacy of CFTR.
  • the inventors of the present invention conducted research to provide an optimal eye drop method that can provide effects such as increasing tear secretion, improving corneal erosion, and suppressing inflammation, and can be well distributed to target tissues, including the cornea and conjunctiva. did.
  • the present invention was completed by confirming the preferred eye drop method and the dosage of the eye drop solution.
  • the compound of Formula 1 was confirmed to have an effect of improving tear volume in a tear volume reduction model, and had excellent solubility, an effect of improving corneal erosion, and an effect of reducing the expression of various pro-inflammatory cytokines present in the cornea and conjunctiva.
  • the compound of Formula 1 can be used to treat, prevent, or improve dry eye syndrome or dry eye disease-related diseases.
  • Diseases related to dry eye syndrome may include diseases caused or worsened by decreased tear volume, or eye diseases prevented or improved by increased tear volume. Examples may include conjunctivitis, meibomian gland dysfunction, ocular surface damage (preferably corneal damage) due to dry eye, burning, itching, foreign body sensation, or rough sensation.
  • the cause of the dry eye syndrome is not particularly limited.
  • composition of the present invention may contain an active ingredient at a concentration of 0.01 to 0.3% (w/v) in order to achieve the desired effect of the present invention or to achieve stable solubility in the formulation.
  • an administration method suitable for administering the active ingredient at the above concentration with 1-3 drops per eye once, 1-7 times a day.
  • one aspect of the present invention is to effectively use a compound represented by the following formula (1) at a concentration of 0.01 to 0.3% (w/v), or a pharmaceutically acceptable salt, solvate, hydrate, prodrug or stereoisomer thereof.
  • a compound represented by the following formula (1) at a concentration of 0.01 to 0.3% (w/v), or a pharmaceutically acceptable salt, solvate, hydrate, prodrug or stereoisomer thereof.
  • % (w/v) means the mass (g) of the target component contained in 100 mL of the eye drop or eye drop composition of the present invention.
  • the value is the content of the salt of the compound.
  • the compound of Formula 1 or its salt is blended in the form of a hydrate or solvate, the value is the content of the hydrate or solvate of the compound of Formula 1 or its salt.
  • the pharmaceutical composition of the present invention may contain 0.5% (w/v) or less of a CFTR activator based on the total composition as an active ingredient.
  • the compound of Formula 1 is used in an amount of 0.01 to 0.3% (w/v), 0.04 to 0.25% (w/v), 0.05 to 0.2% (w/v), or 0.01 to 0.25% (w) based on the total composition.
  • the pharmaceutical composition may contain the active ingredient at a concentration of 0.4-3 mg/ml.
  • the composition of the present invention may include the active ingredient at a concentration of 0.45-2.5 mg/ml or 0.43-2.3 mg/ml.
  • the amount of active ingredient instilled per eye is about 3 mg or less, about 2.5 mg or less, about 2.2 mg or less, about 2 mg or less, about 0.01 to about 3 mg, about 0.015. to about 2.8 mg, from about 0.018 to about 2.5 mg, from about 0.02 to about 2.4 mg, from about 0.05 to about 2.3 mg, from about 0.08 to about 2.28 mg, from about 0.09 to about 2.25 mg, from about 0.095 to about 2.2 mg, from about 0.01 to about 0.01 mg.
  • mg, about 0.095 to about 1.1 mg, about 0.01 to about 1 mg, about 0.015 to about 0.8 mg, about 0.018 to about 0.5 mg, about 0.02 to about 0.4 mg, about 0.05 to about 0.3 mg, about 0.08 to about 0.28 mg, About 0.09 to about 0.25 mg, about 0.095 to about 0.2 mg, about 0.095 to about 0.15 mg can be instilled, for example, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2mg, 0.225mg, 0.25mg, 0.3mg, 0.35 mg, 0.375mg, 0.4mg, 0.45mg, 0.5mg, 0.525 mg, 0.6mg, 0.7 mg, 0.75mg, 0.8mg, 0.9mg, 1.0mg, 1.05 mg , 1.2 mg, 1.4 mg, 1.5 mg, 1.8 mg, 2.0 mg, or 2.1 mg of the active ingredient can be instilled.
  • the eye drop of the present invention can be administered 1 to 7 times per day, 1 to 3 drops per eye.
  • the interval between drops of the eye drops of the present invention may be at least 1 hour.
  • One drop is usually about 10 to 100 ⁇ l, 20 to 80 ⁇ l, 30 to 70 ⁇ l, 40 to 60 ⁇ l, and may be, for example, 50 ⁇ l.
  • the active ingredient in the above content is administered by eye drop in the amount of 1 to 5 drops, 1 to 4 drops, or 1 to 3 drops at a time to achieve the purpose or effect of the present invention, such as the stability of the formulation, the degree of distribution on the ocular surface, and the effect of reducing corneal erosion. can do.
  • the usage of the composition may be applied once to several times a day, for example, 1 to 7 times a day, 1 to 6 times a day, 1 to 5 times a day, 1 to 4 times a day, 1 It may be applied 1-3 times a day, 1-2 times a day, once a day, or occasionally or irregularly as needed.
  • treatment or amelioration comprises daily administration of a therapeutic agent for at least two consecutive weeks.
  • the eye drop composition may be administered more than once per day, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day.
  • the treatment regimen may comprise daily administration of a therapeutic agent for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more consecutive weeks. You can.
  • the content, concentration, or amount of the active ingredient contained in the eye drop of the present invention is Surprisingly, the active ingredient adhered to the corneal surface, enabling stable drug efficacy. In addition, the active ingredient was able to achieve the effect on the target area, the ocular surface.
  • the active ingredient having the above content or concentration range makes it possible to provide an eye drop composition with excellent solubility.
  • composition according to the present invention When the composition according to the present invention is applied to treat dry eye or dry eye-related diseases at a defined dosage and/or administration regimen, it surprisingly exhibits effects such as the degree of distribution on the ocular surface, reduction of corneal erosion, and reduction of eye inflammation. It was confirmed that it can be achieved.
  • the composition of the present invention may further include pharmaceutically acceptable excipients.
  • the eye drop composition may be a liquid composition or a semi-solid composition.
  • the eye drop composition may be in the form of an eye drop solution, ointment, gel, cream, lotion, emulsion, suspension, or spray.
  • the ophthalmic composition of the present invention may be formulated to be compatible with the eye and/or other tissues to be treated with the composition.
  • the compositions of the present invention may generally be formulated as sterile aqueous compositions (e.g., suspensions, solutions, emulsions, etc.), which may typically include purified water, e.g.
  • Ophthalmic compositions are intended for direct application to the corneal surface of the eye and can typically be formulated to have a pH and isotonicity that are compatible with the eye.
  • the composition typically has a pH of 4 to 9, preferably 5.5 to 8.5 and most preferably 5.5 to 8.0. It can have a range.
  • the pH range is 6.0 to 7.8 and more specifically 6.4 to 7.6.
  • the eye drop composition may be in the form of eye drops or eye ointment, for example.
  • the eye drops according to one embodiment have the great advantage of being easy and convenient to use for subjects.
  • the eye drops may be dissolved eye drops or suspension type eye drops. Additionally, the composition may also be provided in the form of artificial tears or eyewash.
  • the compositions can be delivered in a pharmaceutically acceptable ophthalmic vehicle such that they remain in contact with the ocular surface for a period of time sufficient to penetrate the cornea, conjunctiva or interior areas of the eye.
  • the eye drop composition according to one embodiment may be prepared according to methods well known in the art. Appropriate excipients and/or carriers and their amounts can be easily determined by those skilled in the art depending on the type of formulation being prepared.
  • the eye drop composition can be stored in containers made of various materials. For example, it may be a container made of polyethylene, polypropylene, etc. containing low-density polyethylene (LDPE), etc., or a glass container. If the composition is an eye drop, it may be contained in an eye drop container, and more specifically, a multi-dose eye drop container or a unit dose. Can be accommodated in a type eye drop container.
  • LDPE low-density polyethylene
  • a multi-dose eye drop container is an eye drop container equipped with a container body and a cap that can be attached to the container body, and the cap can be freely opened and resealed.
  • the multi-dose type eye drop container usually contains multiple doses of eye drop solution for use over a certain period of time.
  • a unit dose type eye drop container refers to an eye drop container in which a cap is fusion-sealed at the mouth of the bottle, and the fusion seal between the cap and the bottle-type body is broken open at the time of use.
  • the unit dose type eye drop container contains eye drop solution for one or multiple uses.
  • the ophthalmic compositions of the present invention may include a lubricant (e.g., a liquid polyol such as hydroxypropyl methyl cellulose (HPMC), carbomethylcellulose (CMC), polyvinyl alcohol, propylene glycol, polyethylene glycol), and a healing agent. It may contain additives that promote (e.g., hyaluronic acid) or electrolyte compositions that mimic the natural tear film or additives that promote retention of the composition on the ocular surface (e.g., gelling agents such as carbomers).
  • a lubricant e.g., a liquid polyol such as hydroxypropyl methyl cellulose (HPMC), carbomethylcellulose (CMC), polyvinyl alcohol, propylene glycol, polyethylene glycol
  • a healing agent e.g., a lubricant
  • a lubricant e.g., a liquid polyol such as hydroxypropyl methyl cellulose (HPMC), carb
  • One aspect of the present invention provides a method for treating or improving dry eye syndrome or a dry eye-related disease in an individual, and in particular, provides a method for treating or improving dry eye disease or a disease related to dry eye in an individual, using a method for treating or improving dry eye disease in an individual, which is represented by the following formula (1) at a concentration of 0.01 to 0.3% (w/v): It includes the step of administering a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, or stereoisomer thereof as an active ingredient, wherein the administration is administered 1-3 drops per eye once, 1-7 times per day. Provides a method for treating or improving dry eye syndrome or dry eye-related diseases through instillation.
  • the above treatment or improvement method can be used as a treatment therapy for dry eye disease or dry eye disease-related diseases.
  • An individual in whom the composition of the present invention is instilled into the eye of an individual through this treatment regimen may exhibit an increase in tear volume, an effect of improving corneal erosion, and a decrease in the expression of various inflammatory cytokines present in the cornea and conjunctiva.
  • the compound of Formula 1 can be used in treatment for the treatment, prevention, or improvement of dry eye syndrome or dry eye disease-related diseases.
  • Diseases related to dry eye syndrome may include diseases caused or worsened by decreased tear volume, or eye diseases prevented or improved by increased tear volume. Examples may include conjunctivitis, meibomian gland dysfunction, ocular surface damage (preferably corneal damage) due to dry eye, burning, itching, foreign body sensation, or rough sensation.
  • the cause of the dry eye syndrome is not particularly limited.
  • the active ingredient may be administered to the subject at a concentration of 0.01 to 0.3% (w/v) upon single administration.
  • an administration method suitable for administering the active ingredient at the above concentration can be provided by administering 1-3 drops per eye once, 1-7 times a day.
  • one aspect of the present invention is to effectively use a compound represented by the following formula (1) at a concentration of 0.01 to 0.3% (w/v), or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, or stereoisomer thereof.
  • a method, treatment or improvement therapy for the treatment or improvement of dry eye or dry eye-related diseases that is administered as an ingredient to an individual in need, and is instilled 1-7 times a day, with 1-3 drops per eye once. provides.
  • the method according to one embodiment may include 0.5% (w/v) or less of the CFTR activator as an active ingredient based on the total composition when instilled in the subject once per eye.
  • the compound of Formula 1 is used in an amount of 0.01 to 0.3% (w/v), 0.04 to 0.25% (w/v), 0.05 to 0.2% (w/v), or 0.01 to 0.25% (w) based on the total composition.
  • the method according to one embodiment may include the active ingredient in the subject at a concentration of 0.4-3 mg/ml when instilled once per eye.
  • the method of the present invention may include the active ingredient at a concentration of 0.45-2.5 mg/ml, 0.43-2.3 mg/ml when instilled once per eye.
  • the amount of active ingredient instilled per eye may be about 3 mg or less, about 2.5 mg or less, about 2.2 mg or less, and about 0.01 to about 3 mg, about 0.015 mg. to about 2.8 mg, from about 0.018 to about 2.5 mg, from about 0.02 to about 2.4 mg, from about 0.05 to about 2.3 mg, from about 0.08 to about 2.28 mg, from about 0.09 to about 2.25 mg, from about 0.095 to about 2.2 mg, from about 0.01 to about 0.01 mg.
  • mg, about 0.095 to about 1.1 mg, about 0.01 to about 1 mg, about 0.015 to about 0.8 mg, about 0.018 to about 0.5 mg, about 0.02 to about 0.4 mg, about 0.05 to about 0.3 mg, about 0.08 to about 0.28 mg, About 0.09 to about 0.25 mg, about 0.095 to about 0.2 mg, about 0.095 to about 0.15 mg can be instilled, for example, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2mg, 0.225mg, 0.25mg, 0.3mg, 0.35 mg, 0.375mg, 0.4mg, 0.45mg, 0.5mg, 0.525 mg, 0.6mg, 0.7 mg, 0.75mg, 0.8mg, 0.9mg, 1.0mg, 1.05 mg , 1.2 mg, 1.4 mg, 1.5 mg, 1.8 mg, 2.0 mg, or 2.1 mg of the active ingredient can be instilled.
  • the eye drop of the present invention can be administered 1 to 7 times per day, 1 to 3 drops per eye.
  • the interval between drops of the eye drops of the present invention may be at least 1 hour.
  • One drop is usually about 10 to 100 ⁇ l, 20 to 80 ⁇ l, 30 to 70 ⁇ l, 40 to 60 ⁇ l, and may be, for example, 50 ⁇ l.
  • the active ingredient in the above content is administered by eye drop in the amount of 1 to 5 drops, 1 to 4 drops, or 1 to 3 drops at a time to achieve the purpose or effect of the present invention, such as the stability of the formulation, the degree of distribution on the ocular surface, and the effect of reducing corneal erosion. can do.
  • the usage of the composition may be applied once to several times a day, for example, 1 to 7 times a day, 1 to 6 times a day, 1 to 5 times a day, 1 to 4 times a day, 1 It may be applied 1-3 times a day, 1-2 times a day, once a day, or occasionally or irregularly as needed.
  • treatment or amelioration comprises daily administration of a therapeutic agent for at least two consecutive weeks.
  • the eye drop composition may be administered more than once per day, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day.
  • the treatment regimen may comprise daily administration of a therapeutic agent for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more consecutive weeks. You can.
  • Treatment and “improvement,” as defined herein, mean reducing the severity of symptoms to some extent. In the case of treatment or improvement of dry eye disease or dry eye-related disease, which is an eye disease described herein, it may mean increasing tears, tear retention, reducing tear evaporation, increasing tear production, reducing inflammation of the ocular surface, etc. As used herein, the terms “treat” and “improve” are not intended to be absolute terms. Treatment may refer to delaying onset, improving symptoms, improving the patient's quality of life, etc. Treatment effects can be compared to untreated individuals or populations of individuals, or to the same patients at different time points prior to or during treatment.
  • treating refers to treating or treating a disease or medical condition in a patient, such as a mammal (particularly a human or animal), i.e., improving the disease or medical condition in the patient, i.e., improving the disease or medical condition in the patient. removal or suspension of; Inhibition of a disease or medical condition in a patient, i.e., slowing or stopping the progression of a disease or medical condition; or alleviating one or more symptoms of a disease or medical condition in a patient.
  • the term encompasses prophylactic treatment of a disease or condition to prevent or reduce the risk of developing or progressing a particular disease or condition, or to prevent or reduce the risk of recurrence.
  • “individual” or “patient” may include humans as well as other animals such as other primates, rodents, dogs, cats, horses, sheep, pigs, etc., and preferably includes humans. .
  • the eye drop composition of the present invention significantly suppresses the decrease in tear secretion caused by dry eye syndrome, keratoconjunctivitis, and changes in corneal shape, restores damaged corneas, and increases tear secretion, making it safe and effective for dry eye disease or It can be used to develop treatments for diseases related to dry eye syndrome.
  • the scope of the present invention is not limited by this effect.
  • the eye drop, eye drop composition, and eye drop method according to the present invention provide the effect of increasing tear secretion, recovering corneal damage, and alleviating eye inflammation.
  • the ophthalmic composition of the present invention can be well distributed to target tissues of the eye, including the cornea and conjunctiva.
  • the eye drop of the present invention has sufficient solubility so that it can be used as an eye drop preparation.
  • Figure 1 shows the activity of the CFTR chloride ion channel by a compound of formula 1 (i.e., 16d).
  • A Shows a representative trace of apical membrane currents from FRT cells expressing human CFTR. CFTR was activated by the indicated concentrations of compounds of formula 1 in the presence of 50 nM forskolin (FSK) and inhibited by 10 ⁇ M CFTR inh -172.
  • C Whole-cell currents in CHO-K1 cells expressing human CFTR were recorded at a holding potential of 0 mV and pulsed at voltages between ⁇ 80 mV (20 mV increments).
  • CFTR was activated by 20 ⁇ M forskolin or 30 ⁇ M compound of formula 1 and inhibited by 20 ⁇ M CFTR inh -172.
  • D This is a current/voltage plot of the average current in the middle of each voltage pulse.
  • Figure 2 shows the properties of the compound of Formula 1 and its effect on CFTR activity in primary cultured human conjunctival epithelial cells.
  • A Apical membrane currents were measured in ANO1-expressing FRT cells. ANO1 was activated by 100 ⁇ M ATP and inhibited by 10 ⁇ M Ani9, and ANO1 inhibitor. Cells were pretreated with compound 1 (30 ⁇ M) and Ani9 for 10 min.
  • B The effect of the compound of Formula 1 on VRAC chloride ion channel activation was measured in HeLa cells expressing YFP-F46L/H148Q/I152L. Cells were treated with the compound of Formula 1 (30 ⁇ M) in hypotonic solution for 5 minutes.
  • VRAC was inhibited by 10 ⁇ M VI-116, a VRAC inhibitor.
  • E Shows a representative trace of the short-circuit current of primary cultured human conjunctival epithelial cells. CFTR was activated by the indicated concentrations of compounds of formula 1 and blocked by 10 ⁇ M CFTR inh -172.
  • Figure 3 shows the average concentration-time profile of Compound 1 in rabbits following a single topical instillation of 0.1 mg/eye of Compound 1 eye drops.
  • Figures 4A and 4B show the effect of compound 1 and Cact-3 on tear volume in wild-type mice.
  • Mice were treated with 2.5 ⁇ l vehicle (5% polyoxyl 35 castor oil in sodium phosphate buffer), compound of formula 1, and Cact-3 as eye drops.
  • Figures 5A to 5D show the effect of the compound of Formula 1 on tear volume and ocular surface damage in a scopolamine-induced dry eye mouse model.
  • C Representative image of a mouse eye stained with corneal fluorescein.
  • mice were administered 5 ⁇ l of eye drops vehicle (5% polyoxyl 35 castor oil in sodium phosphate buffer), compound of formula 1 (2,060 ⁇ M, 5% polyoxyl 35 castor oil in sodium phosphate buffer), and diquafosol into the eye. Treatment was performed 3 times a day for 10 days while maintaining dryness. NT: untreated; Diquas: diquafosol; ns: not significant. * p ⁇ 0.05, ** p ⁇ 0.01. (D) Tear volume in each group.
  • Figures 6A-6F show the effect of compounds of formula 1 on the mRNA expression levels of inflammatory cytokines and MMPs in the cornea and conjunctiva.
  • A-F The mRNA expression levels of IL-1 ⁇ , IL-6, IL-17, TNF-a, MMP2, and MMP9 in the cornea and conjunctiva are shown.
  • Mice were administered 5 ⁇ l of eye drops vehicle (5% polyoxyl 35 castor oil in sodium phosphate buffer), IL-1 ⁇ , IL-6, IL-17, TNF- ⁇ , MMP2, and MMP9 (2,060 ⁇ M, in sodium phosphate buffer).
  • 5% polyoxyl 35 castor oil) and diquafosol were treated 3 times a day for 10 days while maintaining dry eye condition.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • DIPEA N,N-diisopropylethylamine
  • HBTU 3-[bis(dimethylamino)methylliumyl]-3H-benzotriazole-1-oxide hexafluorophosphate
  • PBS phosphate buffered saline
  • TBAF tetra- n -butylammonium fluoride
  • TBDMS tert -butyldimethylsilyl chloride
  • YFP yellow fluorescent protein
  • YFP fluorescence quenching assay Wild-type human CFTR expression using halide sensor YFP-H148Q/I152L CHO-K1 cells (CHO-CFTR-YFP cells) were dispensed into 96-well microplates at a concentration of 2 ⁇ 10 4 cells per well. CHO-CFTR-YFP cells were cultured at 37 °C for 48 h. Analysis was performed using the FLUOstar Omega microplate reader (BMG labtech, Allmendgrun, Ortenberg, Germany) and MARS Data Analysis Software (BMG labtech). Each well of the 96-well microplate was washed three times with PBS (200 ⁇ L/wash). Then, 100 ⁇ L PBS was added to each well.
  • PBS 200 ⁇ L/wash
  • Test compounds (1 ⁇ L) were added to each well at a final concentration of 25 ⁇ M. After 10 minutes, the 96-well microplate was transferred to a microplate reader preheated to 37 °C for fluorescence analysis. To confirm the change in fluorescence caused by I - flowing through CFTR, fluorescence was measured continuously (400 ms per point) for 2 seconds (baseline) in each well. Then, 100 ⁇ L of 140 mM I - solution was added for 2 seconds, and YFP fluorescence was recorded for 14 seconds. The initial I -inflow rate was calculated through nonlinear regression analysis from the initial slope of the fluorescence decrease immediately after I -inflow.
  • Phosphate-buffered saline PBS, pH 7.5
  • PBS Phosphate-buffered saline
  • NaCl NaCl
  • the test compounds were dissolved at 0.5 mg/mL in PBS (pH 7.5) and vortexed for 90 minutes, and then the compounds dissolved in PBS were sequentially filtered through 0.45, 1.2, and 5.0 ⁇ m syringe filters (Minisart NML, CA). did.
  • Concentrations of filtered test compounds were determined by LC-MS/MS using an Agilent 1290 Infinity UPLC coupled to a Sciex Triple Quadrupole 5500 system with appropriate dilutions of the samples.
  • all calibration curves consisted of at least six calibration concentrations, blank samples (with internal standard) and duplicate blank samples (without internal standard).
  • the calibration curve was designed using a weighted linear or quadratic regression method (1/x) of the peak area ratio of the analyte to the internal standard relative to the actual concentration.
  • the solubility of the test compound was back calculated by substituting the peak area ratio of the analyte to the internal standard of the filtered test compound into the calibration curve.
  • apical and basolateral baths were filled with HCO 3 - - buffer solution.
  • the cells were aerated with a 95% O 2 /5% CO 2 mixed gas and stabilized at 37°C for 20 minutes. Afterwards, it was treated with apical and basolateral bath solutions in the following order: Forskolin, the compound of Formula 1, and CFTR inh -172.
  • Apical membrane currents and short-circuit currents were measured using an EVC4000 multi-channel V/I clamp (World Precision Instruments, Sarasota, FL) and recorded using a PowerLab 4/35 (AD Instruments, Colorado Springs, CO, USA). . Data were collected and analyzed using Labchart Pro 7 software (AD Instruments). The sampling rate was 4Hz.
  • Plasma, tear, cornea, conjunctiva, and retina samples were collected at 0.5, 1, 4, 8, 12, 24, 48, and 72 hours post-dose.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • Corneal and conjunctival epithelial cytotoxicity test Immortalized human corneal epithelial cells and conjunctival epithelial cells (Innoprot, Bizkaia, Spain) were plated in 96-well microplates. After 24 hours of culture, cells were treated with 30 ⁇ M candidate compound or 0.01% Triton X-100 (Sigma-Aldrich, St Louis, MO, USA) and cultured for 2 days. The control group was treated with the same amount of DMSO. Afterwards, the cells were cultured for 2 days, and the culture medium containing the test substance was sampled every 12 hours. Then, to evaluate cell proliferation, MTS was added to each well and reacted for 1 hour.
  • Water-soluble formazan produced by cellular reduction of MTS was quantified by measuring absorbance at 490 nm with an Infinite M200 microplate reader (Infinite M200 Pro, Tecan Group Ltd., Grodig, Austria). MTS analysis was performed using the CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit (Promega, Madison, WI, USA).
  • Snapwell inserts containing FRT cells expressing human ANO1 were mounted in Ussing chambers.
  • the apical bath was filled with half-Cl - solution
  • the basolateral bath was filled with HCO 3 - -buffer solution to create a transepithelial Cl - gradient (apical, 64mM; basolateral, 129mM), and the basolateral was permeable with 250 ⁇ g/mL amphotericin B. raised it
  • the cells were stabilized at 37°C for 20 minutes while aerated with a 95% O 2 /5% CO 2 - mixed gas.
  • ATP was added to the apical bath solution to induce an increase in intracellular calcium.
  • the compound of Formula 1 or Ani9 was added to the apical and basolateral bath solutions.
  • Apical membrane current was measured with an EVC4000 multi-channel V/I clamp and PowerLab 4/35 20 minutes before ANO1 activation and analyzed using Labchart Pro 7. The sampling rate was 4Hz.
  • YFP fluorescence was measured for 0.4 seconds as a baseline, and then 100 ⁇ L of 140mM I - solution was added at 0.4 seconds to determine the extent of the initial I - fluorescence change.
  • the influx rate was calculated through nonlinear regression from the initial slope of fluorescence decline after I - injection.
  • each eye was treated with 0.3% diquafosol sodium (Diquas, ophthalmic solution Santen Pharmaceutical Co. Ltd., Osaka, Japan), Vehicle (5% polyoxyl 35 castor oil in sodium phosphate buffer), or Compound of Formula 1 (2060 ⁇ M, 5% polyoxyl 35 castor oil in sodium phosphate buffer) was instilled 3 times a day (11 AM, 2 PM, 5 PM) for 10 days, the first 8 days of the administration period. At the same time, 0.5 mg/0.1 ml of scopolamine hydrobromide was injected subcutaneously. 5ul of the test substance was dropped into each eye and held for 30 seconds.
  • diquafosol sodium Diquas, ophthalmic solution Santen Pharmaceutical Co. Ltd., Osaka, Japan
  • Vehicle 5% polyoxyl 35 castor oil in sodium phosphate buffer
  • Compound of Formula 1 2060 ⁇ M, 5% polyoxyl 35 castor oil in sodium phosphate buffer
  • Corneal erosion grade To assess corneal epithelial erosion, 5 ⁇ L of 1% fluorescein dye with 0.5% proparacaine was applied to the ocular surface of mice 10 days after each treatment. Photographs of the front part of the eye were taken with a digital camera built into the microscope under cobalt blue filtered light. Corneal erosion was scored from 0 to 5 according to the Oxford scheme.
  • GPDH housekeeping gene
  • Primer sequences used were as follows: GAPDH, sense (5-AACGACCCCTTCATTGACCT-3, Seq.ID 1) and antisense (5-ATGTTAGTGGGGTCTCGCTC-3, Seq.ID 2), size of PCR product 155 base pairs; IL-1 ⁇ , sense (5-ACTCATTGTGGCTGTGGAGA-3, Seq.ID 3) and antisense (5-TTGTTCATCTCGGAGCCTGT-3, Seq.ID 4), PCR product size 199 base pairs; IL-6, sense (5-CTGCAAGAGACTTCCATCCAG-3, Seq.ID 5) and antisense (5-AGTGGTATAGACAGGTCTGTTGG-3, Seq.ID 6), PCR product size 131 base pairs; IL-17, sense (5- GCTGACCCCTAAGAAACCCC-3, Seq.ID 7) and antisense (5- GAAGCAGTTTGGGACCCCTT-3, Seq.ID 8), PCR product size 162 base pairs; TNF- ⁇ , sense (5-AGCACAGAA
  • solubility refers to solubility in PBS (pH 7.5).
  • a CFTR channel activity was measured by YFP quenching assay in CHO-K1 cells expressing human wild-type CFTR. Results are expressed as the average of three trials.
  • c cLogD 7.4 values were calculated with ACD/Percepta software (ACD/Labs, Toronto, Canada).
  • the compound of Formula 1 had particularly excellent solubility and high potency among CFTR activators. It was confirmed that the compound of Formula 1 of the present invention is suitable for use as an eye drop.
  • ANO1 calcium-activated chloride ion channel TMEM16A/Anoctamin 1
  • VRAC volume-regulated anion channel
  • ANO1 apical membrane current was measured in FRT cells expressing human ANO1 and VRAC activity was measured using a YFP fluorescence quenching assay in LN215 cells expressing the halide sensor YFP-F46L/H148Q/I152L.
  • High concentration (30 ⁇ M) of the compound of Formula 1 did not affect the channel activity of ANO1 and VRAC, but ANO1 and VRAC were completely blocked by Ani9 and VI-116.
  • Figures 2A,B CFTR is activated by the cAMP signaling pathway.
  • the compound of Formula 1 slightly increased cAMP levels compared to the control group, but did not increase cAMP levels as strongly as forskolin ( Fig. 2 ).
  • Compound 1 had no effect on cell viability of CorE and ConjE at 30 ⁇ M ( Figure 2D ).
  • T 1/ 2 may not be estimated accurately.
  • the average concentration was used when calculating PK parameters.
  • tear volume was evaluated using the phenol red thread test in a scopolamine-induced dry eye mouse model.
  • Figure 5A subcutaneous injection of scopolamine significantly reduced yarn wetting length in both untreated and vehicle-treated groups compared to the control group .
  • the compound of Formula 1 Treatment significantly and almost completely restored the decrease in tear volume caused by scopolamine, and diquafosol also showed significant recovery of tear volume in dry eye mice.
  • Compound 1 improved ocular surface damage in dry eye mice we examined changes in corneal erosion in a scopolamine-induced dry eye mouse model treated with vehicle, Compound 1, or diquafosol. observed. Each eye drop was applied to each eye three times a day for 10 days.
  • Compound of Formula 1 significantly reduced corneal erosion compared to the control group ( Figure 5B, Figure 5C ). These results show that the compound of Formula 1 improves tear secretion and reduces corneal erosion in dry eye mice with an efficacy equal to or higher than diquafosol.
  • the ocular surface of dry eye mice induces high levels of inflammatory cytokines such as IL-1 ⁇ , IL-6, IL-17, and TNF- ⁇ , as well as matrix-metalloproteinase (MMP)-2 and MMP-9. It is known that The mRNA expression levels of MMP-2, MMP-9, and inflammatory cytokines, including IL-1 ⁇ , IL-6, IL-17, and TNF- ⁇ , were measured in the cornea and conjunctiva of normal or dry eye mice using the vehicle, the compound of Formula 1 , and This was investigated by real-time PCR in the presence or absence of quaposol.
  • MMP-2, MMP-9, and inflammatory cytokines including IL-1 ⁇ , IL-6, IL-17, and TNF- ⁇
  • mRNA expression levels of IL-1 ⁇ , IL-17, TNF- ⁇ , and MMP-2 in the cornea and conjunctiva were significantly decreased upon treatment with the compound of Formula 1 ( Figure 6 ).
  • the mRNA expression levels of IL-17, TNF- ⁇ , and MMP-2 were also significantly decreased by diquafosol.
  • the purpose of this study was to provide eye drops with excellent solubility to achieve high ocular bioavailability and reduce ocular surface damage.
  • the compound of Formula 1 potently and selectively activated CFTR chloride ion channels in corneal and conjunctival epithelial cells without cytotoxicity.
  • the compound of Formula 1 was well distributed in the cornea and conjunctiva of rabbits and maintained for a long period of time (>8 hours), and systemic exposure was negligible.
  • the compound of Formula 1 significantly increased tear volume recovery and improved corneal erosion compared to diquafosol in scopolamine-induced dry eye mice.
  • the compound of Formula 1 significantly reduced the mRNA expression levels of inflammatory cytokines, including MMP2 and IL-1 ⁇ , IL-17, and TNF- ⁇ , in the cornea and conjunctiva of scopolamine-induced dry eye mice.
  • the ophthalmic composition was instilled into mammalian subjects (mouse, rabbit, and dog) according to the following instillation schedule.
  • a composition formulated with a compound of Formula 1 together with a surfactant polysorbate 80, PEG 40-stearate, polyoxyl-35 castor oil or a combination thereof
  • this composition can be obtained by the method disclosed in Korean Patent Application No. 10-2022-0049160.
  • the compound of Formula 1 contained in the composition was administered at different concentrations and administration times, and when instilled at the concentration and administration frequency of the present invention, the effects aimed at by the present invention, such as increasing tear volume and suppressing inflammation, were achieved. was achievable.
  • the ophthalmic composition of the present invention having the above administration (eye drop) schedule is excellent in the treatment and improvement of dry eye syndrome or dry eye-related diseases.
  • the present invention provides eye drops.
  • the present invention can be used to treat and/or improve dry eye syndrome.

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004170323A (ja) * 2002-11-22 2004-06-17 Sumitomo Pharmaceut Co Ltd 皮膚疾患治療剤のスクリーニング方法
KR20170096034A (ko) * 2014-12-23 2017-08-23 프로테오스타시스 테라퓨틱스, 인크. Cftr 활성을 증가시키는 화합물, 조성물 및 방법
KR20190110088A (ko) * 2016-11-18 2019-09-27 시스틱 파이브로시스 파운데이션 쎄러퓨틱스, 인크. Cftr 강화제로서의 피롤로피리미딘
WO2022084741A1 (en) * 2020-10-23 2022-04-28 Ildong Pharmaceutical Co., Ltd. Cftr modulator compounds, compositions, and uses thereof
KR20220100625A (ko) * 2019-11-12 2022-07-15 젠자임 코포레이션 결핍된 cftr 활성에 의해 매개되는 질환 및 병태를 치료하기 위한 6원 헤테로아릴아미노설폰아미드

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004170323A (ja) * 2002-11-22 2004-06-17 Sumitomo Pharmaceut Co Ltd 皮膚疾患治療剤のスクリーニング方法
KR20170096034A (ko) * 2014-12-23 2017-08-23 프로테오스타시스 테라퓨틱스, 인크. Cftr 활성을 증가시키는 화합물, 조성물 및 방법
KR20190110088A (ko) * 2016-11-18 2019-09-27 시스틱 파이브로시스 파운데이션 쎄러퓨틱스, 인크. Cftr 강화제로서의 피롤로피리미딘
KR20220100625A (ko) * 2019-11-12 2022-07-15 젠자임 코포레이션 결핍된 cftr 활성에 의해 매개되는 질환 및 병태를 치료하기 위한 6원 헤테로아릴아미노설폰아미드
WO2022084741A1 (en) * 2020-10-23 2022-04-28 Ildong Pharmaceutical Co., Ltd. Cftr modulator compounds, compositions, and uses thereof

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