WO2024024920A1 - Composition ophtalmique - Google Patents

Composition ophtalmique Download PDF

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Publication number
WO2024024920A1
WO2024024920A1 PCT/JP2023/027677 JP2023027677W WO2024024920A1 WO 2024024920 A1 WO2024024920 A1 WO 2024024920A1 JP 2023027677 W JP2023027677 W JP 2023027677W WO 2024024920 A1 WO2024024920 A1 WO 2024024920A1
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WO
WIPO (PCT)
Prior art keywords
composition
acid
chondroitin sulfate
sodium
group
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PCT/JP2023/027677
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English (en)
Japanese (ja)
Inventor
一弘 鈴木
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マルホ株式会社
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Publication of WO2024024920A1 publication Critical patent/WO2024024920A1/fr

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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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • 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
    • A61P27/04—Artificial tears; Irrigation solutions

Definitions

  • the present invention relates to an ophthalmic composition that can be used for the treatment and/or prevention of dry eye and the like.
  • dry eye is a disease caused by decreased tear secretion, tear film imbalance, and/or excessive water loss from the ocular surface (e.g., meibomian gland dysfunction). , Sjögren's syndrome, eyelid closure failure, blinking failure due to Visual Display Terminal work, etc.), and as a result of insufficient protection of the cornea by lacrimal fluid, it can also lead to corneal damage.
  • one or more of the following symptoms typically occur: dry eyes, foreign body sensation, pain, fatigue, blurred vision, and bloodshot eyes.
  • Dry eye is generally treated with artificial tears, which contain sodium chloride, potassium chloride, etc. and have a composition similar to tears, or with eye drops containing active ingredients (e.g., rebamipide, sodium hyaluronate, etc.).
  • active ingredients e.g., rebamipide, sodium hyaluronate, etc.
  • diquafosol sodium, sodium chondroitin sulfate (also referred to as sodium chondroitin sulfate), hypromellose (also referred to as hydroxypropyl methylcellulose), etc.) are used.
  • Patent Document 1 describes a composition containing sodium hyaluronate, heparin sodium having a heparin activity of 2,000 I.U., and the like.
  • Patent Document 1 does not contain any description of pharmacological experiments. It is not clear how effective it is.
  • an object of the present invention is to provide a novel ophthalmic composition that has a curing effect on corneoconjunctival disorders and/or an effect on increasing lacrimal fluid volume, and is effective in treating dry eye.
  • an ophthalmic composition containing polysulfated chondroitin sulfate can solve the above problems.
  • the present invention relates to an ophthalmic composition having the following configuration.
  • An ophthalmological composition for preventing and/or treating corneal and conjunctival disorders and/or increasing tear volume which contains polysulfated chondroitin sulfate as an active ingredient.
  • An ophthalmological composition for preventing and/or treating dry eye containing polysulfated chondroitin sulfate as an active ingredient.
  • composition of the present invention has the effect of curing corneal and conjunctival disorders and/or increasing the amount of lachrymal fluid, so it is also effective in preventing and/or treating dry eye.
  • FIG. 1 is a graph showing corneal damage scores obtained from Example 1 (corneal damage healing experiment).
  • composition of the present invention contains polysulfated chondroitin sulfate and/or a salt thereof.
  • Polysulfated chondroitin sulfate has disaccharides consisting of N-acetyl-D-galactosamine and D-glucuronic acid as repeating units, and each unit (disaccharide) has about 2 to 4 sulfate ester residues, preferably It is a polymer containing about 2 to 3 molecules.
  • Polysulfated chondroitin sulfate can be easily produced by a known method of reacting a chondroitin component such as chondroitin or chondroitin sulfate (A, C, D, E) with a sulfating agent such as chlorosulfuric acid, concentrated sulfuric acid, or sulfur trioxide-pyridine complex. can be manufactured.
  • a chondroitin component such as chondroitin or chondroitin sulfate (A, C, D, E)
  • a sulfating agent such as chlorosulfuric acid, concentrated sulfuric acid, or sulfur trioxide-pyridine complex.
  • chondroitin sulfate A has a sulfate ester residue at the 4-position of acetylgalactosamine
  • chondroitin sulfate C has a sulfate ester residue at the 6-position of acetylgalactosamine
  • chondroitin sulfate D has a sulfate ester residue at the 6-position of acetylgalactosamine. It has a sulfate ester residue at the 6-position of galactosamine and the 2- or 3-position of glucuronic acid
  • chondroitin sulfate E has a sulfate ester residue at both the 4-position and the 6-position of acetylgalactosamine.
  • chondroitin sulfates examples include heparin-like substances listed in the Japanese Pharmaceutical Ingredient Standards outside the Japanese Pharmacopoeia. Specifically, it is polysulfated chondroitin sulfate that exhibits the following physicochemical properties. a) Sulfate group content: 25.8-37.3% by weight b) Intrinsic viscosity: 0.09 to 0.18
  • polysulfated chondroitin sulfate may be used in the form of a free acid derived from sulfuric acid residues, a base salt is usually used.
  • Examples of the base salt include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, and the like.
  • the weight average molecular weight of polysulfated chondroitin sulfate or its salt used in the present invention is not particularly limited, but is usually about 8,000 to 10,000,000, preferably 8,000 to 1,000,000. It is more preferably about 10,000 to 100,000, particularly preferably about 10,000 to 50,000.
  • the content of polysulfated chondroitin sulfate and/or its salt, which is an active ingredient, is preferably 0.001 to 10 w/v%, more preferably 0.5 to 5 w/v%, 1. Particularly preferred is 0 to 3.0 w/v%.
  • w/v% or content is a value expressed as a percentage of the weight (g) of each component contained in the ophthalmic composition with respect to the total volume (mL) of the ophthalmic composition.
  • w/v % corresponds to the weight (g) of each component in 100 mL of the ophthalmic composition.
  • the composition is used to prevent and/or treat corneal and conjunctival disorders (including corneal disorders and conjunctival disorders, particularly corneal disorders), and/or to increase tear volume, and/or to treat dry eyes. It can be used for prevention and/or treatment.
  • Corneal disorders include corneal damage (for example, damage to the corneal epithelium, corneal stroma, etc.), and include, for example, corneal ulcers, punctate superficial keratopathy, and corneal epithelial defects.
  • Conjunctival disorders include conjunctival damage (eg, damage to conjunctival epithelium, etc.), and include, for example, conjunctival epithelial defects.
  • the dosage form of the composition is not particularly limited as long as it can be used for the above purpose, but preferable examples include eye drops, eye washes, and eye ointments. Eye drops (also called eye drops or eye drops) are particularly preferred.
  • the composition is a sterile composition.
  • the dosage and frequency of administration of the composition are not particularly limited as long as they are within an ophthalmologically acceptable range, and may be adjusted as appropriate depending on the severity of the symptoms, age, weight, etc. of the patient. For example, when used in the form of eye drops, it is generally preferred to administer 1 to 2 drops at a time, 1 to 10 times, 2 to 8 times, or 3 to 6 times per day.
  • the composition contains, in addition to polysulfated chondroitin sulfate, other active ingredients (for example, one or more ingredients selected from rebamipide, sodium hyaluronate, diquafosol sodium, sodium chondroitin sulfate, hypromellose, etc.). It may be present or may not be included.
  • One embodiment of the composition includes a composition containing only polysulfated chondroitin sulfate as an active ingredient.
  • the composition may contain additives commonly used in ophthalmological compositions, if necessary.
  • additives such as buffering agents, tonicity agents, stabilizers, thickening agents, pH adjusters, preservatives, and surfactants may be included.
  • buffering agents include boric acid, borax, citric acid, sodium citrate, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, tartaric acid, gluconic acid, acetic acid, sodium acetate, carbonic acid, sodium hydrogen carbonate, Examples include epsilon-aminocaproic acid. These may be used alone or in combination of two or more.
  • the total content of buffering agents in the composition is preferably 0.001 to 5 w/v%, more preferably 0.01 to 3 w/v%, particularly preferably 0.02 to 1 w/v%.
  • tonicity agents examples include calcium chloride, sodium chloride, potassium chloride, magnesium chloride, magnesium sulfate, concentrated glycerin, propylene glycol, and the like. These may be used alone or in combination of two or more.
  • the total content of the tonicity agent in the composition is preferably 0.001 to 5 w/v%, more preferably 0.01 to 3 w/v%, particularly preferably 0.05 to 2 w/v%.
  • stabilizers examples include edetic acid, sodium edetate, cyclodextrin, sulfites, citric acid, citrates, butylated hydroxyanisole, dibutylated hydroxytoluene, and the like. These may be used alone or in combination of two or more.
  • the total content of stabilizers in the composition is preferably 0.001 to 5 w/v%, more preferably 0.01 to 3 w/v%, particularly preferably 0.05 to 2 w/v%.
  • thickening agents examples include polyvinylpyrrolidone, carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymer, xanthan gum, and the like. These may be used alone or in combination of two or more.
  • the total content of the thickening agent in the composition is preferably 0.001 to 5 w/v%, more preferably 0.01 to 3 w/v%, particularly preferably 0.05 to 2 w/v%.
  • pH adjusters examples include potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, sodium bicarbonate, hydrochloric acid, citric acid, boric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, Examples include tartaric acid, succinic acid, and salts thereof. These may be used alone or in combination of two or more.
  • the pH adjuster is used to adjust the pH of the composition to 4.0 to 9.0, preferably 4.5 to 8.5, particularly preferably 5.0 to 8.0.
  • the total content of pH adjusters is usually 0.001 to 1% w/v in the composition.
  • preservatives examples include sodium benzoate, benzalkonium chloride, benzethonium chloride, ethanol, chlorhexidine gluconate, sodium edetate, sorbic acid, potassium sorbate, paraoxybenzoic acid esters (methyl paraoxybenzoate, paraoxybenzoic acid) (ethyl, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), phenylethyl alcohol, chlorobutanol, and the like. These may be used alone or in combination of two or more.
  • the total content of preservatives in the composition is preferably 0.001 to 3 w/v%, more preferably 0.01 to 2.5 w/v%, particularly preferably 0.05 to 2 w/v%.
  • surfactants include nonionic surfactants, amphoteric surfactants, anionic surfactants, cationic surfactants, and the like. These may be used alone or in combination of two or more.
  • nonionic surfactants include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer, polyethylene glycol monostearate, etc.
  • amphoteric surfactants include N-[2-[[2-(alkylamino)ethyl]amino]ethyl]glycine and its salts.
  • anionic surfactants include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, and the like.
  • cationic surfactants include benzalkonium chloride, benzethonium chloride, and the like.
  • the total content of surfactants in the composition is preferably 0.001 to 3 w/v%, more preferably 0.01 to 2 w/v%, particularly preferably 0.05 to 1 w/v%.
  • the composition preferably uses water (e.g., distilled water, purified water, sterile purified water) as a solvent or base, is more preferably an aqueous eye drop, and is particularly preferably a sterile aqueous eye drop. .
  • the water content in the composition is preferably 80 w/v% or more, more preferably 85 w/v% or more, and particularly preferably 90 w/v% or more.
  • composition When the composition is an eye drop, its viscosity is preferably in the range of 1 to 100,000 mPa ⁇ s, particularly preferably in the range of 1 to 10,000 mPa ⁇ s.
  • the viscosity can be measured, for example, according to the 18th edition of the Japanese Pharmacopoeia "2.53 Viscosity Measurement Method” Method 2 Rotational Viscometer Method.
  • the osmotic pressure ratio (osmolarity of ophthalmic composition/osmolality of physiological saline [286 mOsm]) is preferably 0.4 to 3.0, and preferably 0.6 to 2. 0 is more preferable, and 0.7 to 1.3 is particularly preferable.
  • the osmotic pressure ratio can be determined according to the 18th edition Japanese Pharmacopoeia "2.47 Osmolality measurement method (osmolarity measurement method)".
  • composition of the present invention also includes compositions obtained by arbitrarily combining these components and each component. Also included are compositions obtained by arbitrarily combining the contents of.
  • numerical ranges regarding viscosity, pH, content, osmotic pressure ratio, etc. can be arbitrarily combined, and when multiple numerical ranges are listed, the upper and lower limits of each numerical range can also be arbitrarily combined.
  • polysulfated chondroitin sulfate or its salt is a heparin-like substance (abbreviation: MPS, organic sulfate group: 25.8 to 37.3% w/ (w/w, glucuronic acid content 19.0-24.0% w/w, Maruho Co., Ltd.) was used.
  • MPS organic sulfate group: 25.8 to 37.3% w/ (w/w, glucuronic acid content 19.0-24.0% w/w, Maruho Co., Ltd.)
  • sodium hyaluronate abbreviation: HA, Sigma-Aldrich
  • ChS sodium chondroitin sulfate
  • Physiological saline Otsuka Pharmaceutical Factory Co., Ltd. was used as the administration medium.
  • Example 1 Healing effect of corneal damage caused by MPS Using 8-week-old male SD rats, the extraorbital lacrimal gland was injected as follows according to the method of Murakami et al. (New Ophthalmology 21(1): 87-90 (2004)). An excision model (dry eye model) was created. After creating the model, the corneal damage score after eye drop administration was evaluated. Based on the body weight of the rats, the rats were divided into a normal group and a treatment group to avoid bias between the groups.
  • rats were generalized by inhalation of isoflurane (Mylan Pharmaceutical Co., Ltd.), then the analgesic Repetan Injection (Otsuka Pharmaceutical Co., Ltd.) was administered intramuscularly, and an incision was made below the sterilized ear to investigate the extraorbital lacrimal gland. was extracted.
  • the rats in the administration group were further divided into 5 groups (8 rats in each group) based on the amount of lachrymal secretion to avoid bias between the groups.
  • Schirmel test paper (Ayumi Pharmaceutical Co., Ltd.) was inserted between the rat's lower eyelid and eyeball, and the length wetted with tear fluid was measured using an electronic caliper.
  • the normal group received physiological saline
  • the 5 administration groups received physiological saline (control group), 0.3% HA, 1% ChS, 0.3% MPS, and 3% MPS 6 times a day ( (5 ⁇ L per time) was instilled into the eyes repeatedly for 14 days (8 animals in each group: only one eye was used).
  • the percentage of each component is w/v%.
  • a mydriatic agent (Midrin (registered trademark) P eye drops, Santen Pharmaceutical Co., Ltd.) was instilled into the rat's eyes, and then a Flores test strip (Flores (registered trademark) eye test strip 0.7 mg, Ayumi Pharmaceutical Co., Ltd.) was applied to the rat.
  • 0.1 mL of physiological saline solution (Otsuka Pharmaceutical Factory Co., Ltd.) was dropped onto the corneal limbus of the rat, and a Flawless test paper was brought into contact with the area from the limbus of the rat's cornea to the vicinity of the sclera for staining.
  • the degree of staining was scored according to the following criteria, and evaluated as a total score of 9 points, which is the sum of the scores of the three locations.
  • Table 1 and Figure 1 Each data in Table 1 is shown as the measured mean value ⁇ standard error of the scores of 8 animals. The lower the corneal damage score, the less damage to the cornea.
  • the ** mark in Table 1 and Figure 1 indicates that the p value calculated based on the normal group by Student's t test is less than 0.01, and the ⁇ mark indicates that the p value was calculated based on the control group by Dunnett's multiple comparison test. This indicates that the p value calculated as is less than 0.01.
  • Example 2 Increasing tear secretion by MPS
  • An extraorbital lacrimal gland removal model (dry eye model) was created in the same manner as in Example 1, and each of the three administration groups received physiological saline (control). Group), 3% ChS, and 3% MPS were repeatedly instilled into the eyes 6 times a day (5 ⁇ L per time) for 14 days (8 animals in each group: only one eye was used). On the day after the repeated eye drops for 14 days, each group received one more eye drop, and the amount of lacrimal secretion was measured 40 minutes later.
  • the amount of lacrimal secretion was determined by inserting Schirmel test paper (Ayumi Pharmaceutical Co., Ltd.) between the rat's lower eyelid and eyeball, and measuring the length wetted with tear fluid using an electronic caliper. The results are shown in Table 2. Each data is shown as the mean value ⁇ standard error of the measured tear secretion amount of 8 animals. In Table 2, the ⁇ mark indicates that the p value calculated based on the control group by Student's t test is less than 0.01, and the ⁇ mark indicates that it is less than 0.05.
  • the 3%ChS group and 3%MPS group each showed a significant increase in tear secretion compared to the control group, and the 3%MPS group showed a significantly higher tear secretion amount than the 3%ChS group. Increased secretion.
  • the ophthalmic composition according to the present invention has an excellent effect of curing corneoconjunctival disorders and an excellent effect of increasing lacrimal secretion, that is, has an effect of improving dry eye.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Ophthalmology & Optometry (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle composition ophtalmique. La composition ophtalmique comprend du sulfate de chondroïtine polysulfaté en tant que principe actif de celle-ci. Cette composition est efficace pour prévenir et/ou traiter un trouble kératoconjonctif, et/ou pour augmenter la quantité de liquide lacrymal, et/ou pour prévenir ou traiter l'oeil sec.
PCT/JP2023/027677 2022-07-29 2023-07-28 Composition ophtalmique WO2024024920A1 (fr)

Applications Claiming Priority (2)

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JP2022-121121 2022-07-29
JP2022121121 2022-07-29

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WO2024024920A1 true WO2024024920A1 (fr) 2024-02-01

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002226380A (ja) * 2001-02-02 2002-08-14 Maruho Co Ltd 多硫酸化多糖類によるｔｉｍｐ産生の亢進
JP2005513106A (ja) * 2001-12-12 2005-05-12 ウーアザファルマ アールツナイミッテル ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント カンパニー カーゲー ヘパリンを保有する眼薬剤
JP2005255678A (ja) * 2004-02-12 2005-09-22 Seikagaku Kogyo Co Ltd アレルギー性疾患処置剤
JP2006151828A (ja) * 2004-11-25 2006-06-15 Zeria Pharmaceut Co Ltd 眼科用組成物
JP2006193521A (ja) * 2004-12-17 2006-07-27 Rohto Pharmaceut Co Ltd 眼科用組成物
JP2017066065A (ja) * 2015-09-29 2017-04-06 小林製薬株式会社 眼科用組成物
WO2021220712A1 (fr) * 2020-04-30 2021-11-04 ロート製薬株式会社 Composition ophtalmique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002226380A (ja) * 2001-02-02 2002-08-14 Maruho Co Ltd 多硫酸化多糖類によるｔｉｍｐ産生の亢進
JP2005513106A (ja) * 2001-12-12 2005-05-12 ウーアザファルマ アールツナイミッテル ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント カンパニー カーゲー ヘパリンを保有する眼薬剤
JP2005255678A (ja) * 2004-02-12 2005-09-22 Seikagaku Kogyo Co Ltd アレルギー性疾患処置剤
JP2006151828A (ja) * 2004-11-25 2006-06-15 Zeria Pharmaceut Co Ltd 眼科用組成物
JP2006193521A (ja) * 2004-12-17 2006-07-27 Rohto Pharmaceut Co Ltd 眼科用組成物
JP2017066065A (ja) * 2015-09-29 2017-04-06 小林製薬株式会社 眼科用組成物
WO2021220712A1 (fr) * 2020-04-30 2021-11-04 ロート製薬株式会社 Composition ophtalmique

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