WO2021261576A1 - Agent favorisant la sécrétion de lipide - Google Patents

Agent favorisant la sécrétion de lipide Download PDF

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Publication number
WO2021261576A1
WO2021261576A1 PCT/JP2021/024074 JP2021024074W WO2021261576A1 WO 2021261576 A1 WO2021261576 A1 WO 2021261576A1 JP 2021024074 W JP2021024074 W JP 2021024074W WO 2021261576 A1 WO2021261576 A1 WO 2021261576A1
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lipid
secretion
diquafosol
salt
sodium
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PCT/JP2021/024074
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English (en)
Japanese (ja)
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健一 遠藤
幸史 藤澤
明日香 神村
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参天製薬株式会社
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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
    • A61K31/70—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to a lipid secretion-promoting agent containing diquafosol or a salt thereof (hereinafter, also simply referred to as "diquafosol") as an active ingredient, wherein the lipid secretion is a holocrine type.
  • the present invention also relates to a tear film stabilizer containing the lipid secretion promoter.
  • the present invention also relates to an ophthalmic composition containing diquafosol as an active ingredient for promoting lipid secretion, wherein the lipid secretion is a holocrine type.
  • Dry eye is a disease that causes dry eye symptoms such as eye discomfort or visual dysfunction due to quantitative or qualitative abnormalities in tears, and may cause damage to the surface of the eye (cornea, etc.). .. Quantitative abnormalities mainly refer to a state in which the amount of tears secreted is low. On the other hand, qualitative abnormalities mainly refer to abnormalities in the tear film component, for example, the stability of the tear film layer is reduced due to a small amount of lipid component or protein component contained in the tear fluid, and tear fluid is secreted. Even if it is done, it can cause thirst on the surface of the eye.
  • diquafosol is P 1, P 4 - di (uridine-5 ') and purine receptor agonist, also called tetraphosphate or Up4U, 3% (w / v ) concentration of Diquafosol tetrasodium salt (hereinafter, "Axis An ophthalmic solution containing (also referred to as “ahosol sodium”) is used as a therapeutic agent for dry eye (product name: Diquafosol (registered trademark) ophthalmic solution 3%).
  • Axis Aho Sol sodium acts to P2Y 2 receptors on conjunctival epithelial and goblet cell membranes, by increasing the intracellular calcium concentration, it promotes the secretion of water and mucin (Jikuasu ® ophthalmic solution 3% Attachment (Non-Patent Document 1)).
  • diquafosol sodium has a mucin-containing tear secretion promoting action and a mucin production promoting action of corneal epithelial cells (Non-Patent Document 1).
  • the tear film is composed of three layers, a lipid layer (oil layer), an aqueous layer, and a mucin layer, and the outermost lipid layer prevents water from evaporating from the tear fluid, so that the tear film is stable. It is considered to be important for the conversion. Most of the lipids in tears are supplied as meibomian glands from the meibomian glands. However, even at present, there is no drug that improves the lipid layer (oil layer).
  • the subject of the present invention is to elucidate a new mechanism of diquafosol and to provide a new agent.
  • the present inventors have found that diquafosol acts on meibomian gland cells to promote holocrine lipid secretion, and completed the present invention.
  • the present invention is based on surprising results, as no agent has been found to date that acts on meibomian gland cells to promote holocrine lipid secretion. Therefore, the present invention is useful for the prevention or treatment of eye diseases prevented or treated by promoting lipid secretion, eye diseases requiring lipid supplementation, eye diseases caused by lipid reduction, and the like.
  • it is useful for the prevention or treatment of meibomian gland dysfunction (also referred to as MGD (meibomian gland dysfunction)), blepharitis, and dry eye (including dry eye caused by lipid loss).
  • the present invention relates to the following.
  • the lipid is at least one selected from the group consisting of wax esters, triglycerides, omega hydroxide lipids, cholesterol, cholesterol esters, total cholesterol, phospholipids, fatty acids and fatty alcohols, (1) or (2). ).
  • the lipid secretion promoter is at least one selected from the group consisting of wax esters, triglycerides, omega hydroxide lipids, cholesterol, cholesterol esters, total cholesterol, phospholipids, fatty acids and fatty alcohols, (1) or (2). ).
  • a tear layer stabilizer containing the lipid secretion promoter according to any one of (1) to (3).
  • An ophthalmic composition which is at least one selected from the group consisting of cholesterol, cholesterol esters, total cholesterol, phospholipids, fatty acids and fatty alcohols.
  • a preventive or therapeutic agent for dry eye containing the lipid secretion-promoting agent according to any one of (1) to (3).
  • a method for preventing or treating dry eye which comprises administering to a patient the lipid secretion-promoting agent according to any one of (1) to (3).
  • a preventive or therapeutic agent for dry eye which comprises the tear film stabilizer according to (4).
  • a method for preventing or treating dry eye which comprises administering to a patient the tear film stabilizer according to (4).
  • a method for preventing or treating dry eye which comprises administering to a patient the ophthalmic composition according to any one of (5) to (7).
  • Diquafosol via the P2Y 2 receptor signaling has excellent lipid secretion promoting action because it enhances lipid secretion in meibomian gland cells, ocular disease to be prevented or treated by lipid secretagogue, require replenishment of lipids It is useful for the prevention or treatment of eye diseases caused by diquafosol and eye diseases caused by decreased lipids. For example, it is useful for the prevention or treatment of meibomian gland dysfunction (MGD), blepharitis, dry eye (including dry eye caused by lipid loss) and the like.
  • MMD meibomian gland dysfunction
  • blepharitis dry eye (including dry eye caused by lipid loss) and the like.
  • FIG. 3A is a diagram showing the expression state of the apoptosis marker after the addition of diquafosol
  • FIG. 3B is a diagram showing the amount of apoptosis generated after the addition of diquafosol.
  • the lipid secretion-promoting agent of the present invention is a lipid secretion-promoting agent containing diquafosol or a salt thereof as an active ingredient, and is characterized by a holocrine type of lipid secretion.
  • Diquafosol is a compound represented by the following chemical structural formula.
  • the “salt of diquafosol” is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a metal salt with lithium, sodium, potassium, calcium, magnesium, zinc, etc .; hydrochloric acid, hydrobromic acid, hydrogen iodide.
  • Salts with inorganic acids such as nitrate, sulfuric acid, phosphoric acid; acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, Lactic acid, horse uric acid, 1,2-ethandisulfonic acid, isetionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Salts with organic acids such as lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid; quaternary ammonium salts with methyl bromid
  • diquafosol or a salt thereof also includes a hydrate and an organic solvate of diquafosol (free form) or a salt thereof.
  • crystal polymorphs are present in “diquafosol or salts thereof"
  • those polymorphs and polymorphs are also within the scope of the present invention.
  • the crystal polymorph group is an individual crystal shape and its process at each stage when the crystal shape changes due to conditions and conditions such as production, crystallization, and storage of those crystals. Means the whole.
  • the "diquafosol or a salt thereof" in the present invention is preferably a sodium salt of diquafosol, and a diquafosol tetrasodium salt represented by the following chemical structural formula is particularly preferable.
  • Diquafosol or a salt thereof can be produced by the method disclosed in Japanese Patent Publication No. 2001-510484.
  • diquafosol is also effective as a stabilizer for the tear film because it promotes the secretion of lipids.
  • the present invention also provides a tear film stabilizer containing the above-mentioned lipid secretion promoter.
  • the present invention also provides an ophthalmic composition containing diquafosol or a salt thereof as an active ingredient for promoting lipid secretion, wherein the lipid secretion is a holocrine type.
  • the "ophthalmic composition” refers to a composition for use in the prevention and / or treatment of eye diseases and the like.
  • the lipid secretion promoter, tear film stabilizer, and ophthalmic composition of the present invention may contain an active ingredient other than diquafosol or a salt thereof, or may contain diquafosol or a salt thereof as the only active ingredient. You can also.
  • the concentration of diquafosol or a salt thereof is not particularly limited, but is preferably 0.0001 to 10% (w / v), and is preferably 0.001 to 10% (w / v), for example. ), More preferably 0.01 to 10% (w / v), even more preferably 0.1 to 10% (w / v), and even more preferably 1 to 10% (w / v). It is more preferably w / v), more preferably 1 to 5% (w / v), and particularly preferably 3% (w / v).
  • lipid secretion promoter tear film stabilizer, and ophthalmic composition of the present invention may be appropriately changed according to the dosage form, the severity of the patient's symptoms to be administered, age, weight, judgment of the doctor, and the like.
  • the number of eye drops is preferably 6 times a day, 5 times a day, 4 times a day, 3 times a day, 2 times a day or once a day, 6 times a day.
  • 4 times a day, 3 times a day or 2 times a day is more preferable, 4 times a day, 3 times a day or 2 times a day is more preferable, and 3 times a day is particularly preferable.
  • holocrine is one of the modes of release of secretions from cells, and means a mode in which glandular cells themselves are disrupted and various substances in the cells are released as secretory substances, and the release of cell contents.
  • the accompanying cell death is characterized by a mode of programmed cell death such as apoptosis.
  • Holocrine is also called holocrine or holocrine.
  • promoting the secretion of lipids like holocrine can also be referred to as holocrine-type promotion of lipid secretion.
  • the secreted lipid is not particularly limited, but for example, wax ester, triglyceride (also referred to as triacylglycerol), omega hydroxide lipid, cholesterol (also referred to as free cholesterol), cholesterol ester, total fatty acid. , Phosphoric lipids, fatty acids (eg, oleic acid, etc.), fatty alcohols and the like.
  • the total of cholesterol ester and free cholesterol is total cholesterol (also referred to as TC (total cholesterol)).
  • the present invention is, diquafosol via the P2Y 2 receptor signaling, based on the result of promoting lipid secretion in all secreted from meibomian gland cells. Therefore, the lipid secretion promoter, tear film stabilizer, and ophthalmic composition of the present invention are caused by eye diseases prevented or treated by promoting lipid secretion, eye diseases requiring lipid supplementation, and lipid reduction. It is useful for the prevention or treatment of eye diseases. Examples include, but are not limited to, meibomian gland dysfunction (MGD), blepharitis, dry eye (including dry eye due to lipid loss), and the like.
  • MMD meibomian gland dysfunction
  • blepharitis dry eye (including dry eye due to lipid loss)
  • Dry eye is defined as "a chronic disease of tears and keratoconjunctival epithelium caused by various factors and is accompanied by eye discomfort and visual abnormalities", and keratoconjunctivitis sicca (KCS) is included in dry eye. .. In the present invention, the occurrence of dry eye symptoms caused by wearing soft contact lenses is also included in dry eye.
  • Dry eye symptoms include subjective symptoms such as dry eyes, discomfort, eye fatigue, dullness, dullness, eye pain, and blurred vision (blurred vision), as well as other symptoms such as congestion and keratoconjunctival epithelial disorders. Findings are also included.
  • meibomian gland dysfunction is, for example, "a state in which the function of the meibomian glands is diffusely abnormal due to various causes, accompanied by chronic eye discomfort.”
  • the "state in which the function of the meibomian gland is diffusely abnormal” is not a local meibomian gland abnormality observed in, for example, chalazion or hordeolum, but is a dilation of the meibomian gland or obstruction of the opening of the meibomian gland. It means that meibomian gland abnormalities such as are found diffusely.
  • the MGD is divided into a secretion-reducing MGD (low-delivery state) and a secretion-increasing MGD (high-delivery state), and further as a secretion-reducing MGD (low-delivery state MD), "hyposectory MGD (meibomian gland) meibomian gland". "And" meibomian gland obstruction ".
  • the secretion of meibomian gland fat is reduced due to obstruction of the meibomian gland opening.
  • the secretion of meibomian gland fat increases due to various causes.
  • MGD meibomian gland concretion
  • meibomian gland concretion a state in which obstruction of the meibomian gland opening is observed but not accompanied by subjective symptoms
  • MGD in the present invention refers to meibomian gland infarction. Is also included.
  • MGD that diquafosol can treat is a hyposecretory MGD.
  • MGD may cause dry eye and may also cause posterior blepharitis.
  • MGD includes “MGD with (combined) dry eye and / or posterior blepharitis”, “MGD causing dry eye and / or posterior blepharitis”, “MGD without (uncomplicated) dry eye”. , “MGD that does not cause dry eye”, “MGD that does not accompany (do not combine) with posterior blepharitis” and “MGD that does not cause posterior blepharitis” are included.
  • Blepharitis is a symptom of inflamed eyelids and includes anterior blepharitis, blepharitis, posterior blepharitis, blepharitis, and blepharitis.
  • the lipid secretion promoter, tear layer stabilizer, and ophthalmic composition of the present invention can be used for in vivo administration.
  • the lipid secretion promoter, tear layer stabilizer, and ophthalmic composition of the present invention can be used in an in vivo treatment method.
  • the lipid secretion promoter, tear film stabilizer, and ophthalmic composition of the present invention are preferably used for the prevention and / or treatment of eye diseases and the like.
  • Examples of the dosage form of the lipid secretion promoter, the tear film stabilizer, and the ophthalmic composition of the present invention include eye drops, eye ointments, injections, ointments (for example, which can be administered to the eyelid skin) and the like. It is preferably an eye drop.
  • eye drops are synonymous with eye drops or eye drops, and eye drops for contact lenses are also included in the definition of eye drops.
  • the lipid secretion promoter, tear layer stabilizer, and ophthalmic composition of the present invention preferably use water as a solvent (base), and more preferably an aqueous eye drop.
  • the lipid secretion promoter, tear film stabilizer, and ophthalmic composition of the present invention may be a soluble eye drop or a suspension type eye drop depending on the properties and contents of the active ingredient and the additive. May be.
  • the lipid secretion promoter, tear film stabilizer, and ophthalmic composition of the present invention can be further added with pharmaceutically acceptable additives as needed by using a general-purpose technique.
  • pharmaceutically acceptable additives such as sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, epsilon-aminocaproic acid; isotonic agents such as calcium chloride, sodium chloride, potassium chloride, concentrated glycerin; edetonic acid.
  • Stabilizers such as sodium; Surface active agents such as polysorbate; Antioxidants such as ascorbic acid; Preservatives such as benzalkonium chloride and chlorhexizing luconate; pH adjusters such as hydrochloric acid and sodium hydroxide are required. It can be selected and added accordingly. These additives may be used alone or in any combination of two or more.
  • the pH of the lipid secretion promoter, the tear film stabilizer, and the ophthalmic composition of the present invention is not limited to a specific value as long as it is within the range acceptable for pharmaceuticals.
  • the pH of the lipid secretion promoter, the tear film stabilizer, and the ophthalmic composition of the present invention is preferably 8 or less, more preferably in the range of 4 to 8, still more preferably in the range of 5 to 8, and even more. It is preferably in the range of 6 to 8, particularly preferably in the vicinity of 7.
  • the present invention also provides an ophthalmic composition containing diquafosol or a salt thereof for use in an in vivo treatment method for promoting holocrine lipid secretion from meibomian gland cells.
  • the present invention further comprises an ophthalmic composition comprising diquafosol or a salt thereof for use in an in vivo treatment method for promoting lipid secretion from mybome gland cells, wherein the lipid is a wax ester, triglyceride, omega water. Also provided is an ophthalmic composition which is at least one selected from the group consisting of lipid oxides, cholesterol, cholesterol esters, total cholesterol, phospholipids, fatty acids and fatty alcohols.
  • Diquafosol sodium is dissolved in purified water to prepare an 8.5% (w / v) aqueous solution, which is then diluted with Ham F-12 to the desired concentration of diquafosol sodium (hereinafter abbreviated as "DQS"). ) Liquid was prepared.
  • Diquafosol sodium is dissolved in purified water to prepare an 8.5% (w / v) aqueous solution, which is then diluted with Ham F-12 to the desired concentration of diquafosol sodium (hereinafter abbreviated as "DQS"). ) Liquid was prepared.
  • Meibomian gland cells were isolated from white rabbits by enzyme treatment and cultured without serum in Ham F-12 medium containing various culture additives. After inducing cell differentiation, the cells were washed and various concentrations of diquafosol sodium (final concentrations: 0.03%, 0.3%, 0.85%) were added. Note in the group applying the P2Y 2 receptor antagonist AR-C118925XX (hereinafter generally as "AR-C", final concentration: 3 [mu] M) was also added at the same time. After incubation for 4 hours, the culture supernatant and cells were collected separately.
  • AR-C P2Y 2 receptor antagonist
  • the culture supernatant sample was left as it was, while the cell sample was subjected to extraction treatment of lipid components, and then the total cholesterol (TC) content was measured using a total cholesterol quantifying reagent (Amplex Red Cholesterol Assay, Invitrogen).
  • sample preparation Dissolve diquafosol sodium in purified water to prepare an 8.5% (w / v) aqueous solution, and 1 volume of this diquafosol sodium (hereinafter abbreviated as "DQS") solution for 9 volumes of the culture solution. was added and used in the ratio of.
  • DQS diquafosol sodium
  • Meibomian gland cells were isolated from white rabbits by enzyme treatment and cultured without serum in Ham F-12 medium containing various culture additives. After inducing cell differentiation, the cells were washed, DQS solution was added, and the cells were incubated for 2 to 6 hours. The cells were collected together with the culture supernatant, and each fragmented DNA sample was obtained using ApopRadder Ex (Takara Bio Inc.). Fragmented DNA samples were electrophoresed on a 1.5% agarose gel and then stained with SYBR Green I dye to visualize DNA bands. At the same time, SYBR Green I dye was added to the fragmented DNA sample, the fluorescence intensity was measured, and the amount of fragmented DNA was quantified.
  • FIG. 3A a ladder-shaped DNA band characteristic of apoptotic cells was detected in the fragmented DNA prepared from cultured meibomian gland cells. Moreover, this characteristic DNA ladder pattern was not disturbed even after the addition of DQS.
  • FIG. 3 (b) the amount of fragmented DNA increased significantly 4 hours after the addition of DQS. That is, it was shown that the apoptotic cell death constitutively occurring in meibomian gland cells is promoted after the addition of DQS.
  • each formulation such as eye drops can be prepared.
  • Diquafosol or a salt thereof via the P2Y 2 receptor signaling has excellent lipid secretion promoting action because it enhances lipid secretion in meibomian gland cells, ocular disease to be prevented or treated by lipid secretagogue, recruitment of lipids It is useful for the prevention or treatment of eye diseases that require meibomian glands, eye diseases caused by lipid reduction, and the like.

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Abstract

Agent promoteur permettant la sécrétion d'un lipide, qui contient du diquafosol ou un sel de ce dernier en tant que principe actif, le type de sécrétion du lipide étant un type holocrine. L'invention concerne une composition ophtalmique contenant du diquafosol ou un sel de ce dernier en tant que principe actif, qui est destinée à être utilisée pour favoriser la sécrétion d'un lipide, le type de sécrétion du lipide étant un type holocrine. Composition ophtalmique contenant du diquafosol ou un sel de ce dernier, qui est destinée à être utilisée dans une méthode de traitement in vivo pour favoriser la sécrétion de type holocrine d'un lipide à partir d'une cellule de glande de Meibomius. Composition ophtalmique contenant du diquafosol ou un sel de ce dernier, qui est destinée à être utilisée dans une méthode de traitement in vivo pour favoriser la sécrétion d'un lipide à partir d'une cellule de glande de Meibomius, le lipide étant au moins un constituant choisi dans le groupe constitué par un ester de cire, un triglycéride, un oméga-hydroxy lipide, le cholestérol, un ester de cholestérol, le cholestérol total, un phospholipide, un acide gras et un alcool gras.
PCT/JP2021/024074 2020-06-26 2021-06-25 Agent favorisant la sécrétion de lipide WO2021261576A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011527709A (ja) * 2008-07-10 2011-11-04 インスパイアー ファーマシューティカルズ，インコーポレイティド 眼瞼炎の治療方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011527709A (ja) * 2008-07-10 2011-11-04 インスパイアー ファーマシューティカルズ，インコーポレイティド 眼瞼炎の治療方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ENDO KEN-ICHI, SAKAMOTO ASUKA, FUJISAWA KOUSHI: "Diquafosol tetrasodium elicits total cholesterol release from rabbit meibomian gland cells via P2Y2 purinergic receptor signalling", SCIENTIFIC REPORTS, vol. 11, no. 1, 26 March 2021 (2021-03-26), pages 6989, XP055893672, DOI: 10.1038/s41598-021-86433-6 *
FUKUOKA SHIMA, ARITA REIKO: "Increase in tear film lipid layer thickness after instillation of 3% diquafosol ophthalmic solution in healthy human eyes", OCULAR SURFACE, vol. 15, no. 4, 1 October 2017 (2017-10-01), pages 730 - 735, XP055893665, ISSN: 1542-0124, DOI: 10.1016/j.jtos.2017.03.005 *
FUKUOKA SHIMA, ARITA REIKO: "Tear film lipid layer increase after diquafosol instillation in dry eye patients with meibomian gland dysfunction: a randomized clinical study", SCIENTIFIC REPORTS, vol. 9, no. 9091, 24 June 2019 (2019-06-24), XP055893668, DOI: 10.1038/s41598-019-45475-7 *
SIN MAN LAM, LOUIS TONG, SIEW SIAN YONG, BOWEN LI, SHYAM S. CHAURASIA, GUANGHOU SHUI, MARKUS R. WENK: "Meibum Lipid Composition in Asians with Dry Eye Disease", PLOS ONE, PUBLIC LIBRARY OF SCIENCE, vol. 6, no. 10, 1 January 2011 (2011-01-01), pages e24339, XP055013727, ISSN: 19326203, DOI: 10.1371/journal.pone.0024339 *

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