WO2005058932A1 - Stabilisateur du film lacrymal - Google Patents

Stabilisateur du film lacrymal Download PDF

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Publication number
WO2005058932A1
WO2005058932A1 PCT/JP2004/018883 JP2004018883W WO2005058932A1 WO 2005058932 A1 WO2005058932 A1 WO 2005058932A1 JP 2004018883 W JP2004018883 W JP 2004018883W WO 2005058932 A1 WO2005058932 A1 WO 2005058932A1
Authority
WO
WIPO (PCT)
Prior art keywords
mannose
corneal
dry eye
tear film
eye
Prior art date
Application number
PCT/JP2004/018883
Other languages
English (en)
Japanese (ja)
Inventor
Masatsugu Nakamura
Shin-Ichiro Hirai
Akio Kimura
Kayoko Sakamoto
Yukiko Sugihara
Original Assignee
Santen Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO2005058932A1 publication Critical patent/WO2005058932A1/fr

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Classifications

    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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 tear film stabilizing agent comprising mannose as an active ingredient.
  • the present invention relates to a therapeutic agent for dry eye or a corneal conjunctival epithelial disorder caused by dry eye, which contains mannose as an active ingredient.
  • the cornea is a transparent avascular tissue with a diameter of about lcm and a thickness of about lmm, and the conjunctiva is a mucous membrane covering the surface of the eyeball behind the limbus and the back of the eyelid. Is known to have a significant effect on visual function.
  • the tear film covering the surface of the eyeball is kept extremely thin and smooth, but when the tear film becomes unstable, the surface becomes less smooth, resulting in a short time before blinking. During this time, a dry area called a dry spot is formed, and a part of the cornea may be exposed. If the tear film on the surface of the eyeball becomes unstable in this way, dryness and discomfort may occur in the eye, and frequent exposure of the cornea may cause symptoms such as dry eye.
  • Dry eye is a condition in which the tears decrease or the function of the tears deteriorates, and thus the surface of the eyes can be damaged, resulting in eye fatigue, pain, redness, etc. It also causes keratoconjunctival epithelial damage (Non-Patent Document 1). In recent years, corneal epithelial damage due to dry eye has been increasing with the wearing of contact lenses.
  • Patent Document 1 describes an invention relating to a wound treatment agent for severe burns, burns, pressure sores, etc., comprising sugar, potassium and a disinfectant (antibiotic 'antibacterial agent), and glucose, mannose, maltose as sugar.
  • Patent Document 2 describes an invention relating to a pharmaceutical composition for treating skin or mucosal diseases such as allergic rhinitis and allergic conjunctivitis, and one of the pharmaceutical compositions is Darco.
  • Sugars such as sugar, galactose and mannose.
  • Patent Document 1 JP-A-63-215631
  • Patent Document 2 Japanese Patent Application Laid-Open No. 2002-308783
  • Non-Patent Document 1 Rinsei, 46, 738-743 (1992)
  • An object of the present invention is to provide a safe eye drop having an excellent therapeutic effect on dry eye and keratoconjunctival epithelial disorder caused by dry eye.
  • the present inventor first performed a corneal surface irregularity index change test, instilled a mannose-containing eye drop, and then applied a spherical irregularity on the eyeball surface (the spherical irregularity was caused by the tear film on the corneal surface).
  • the spherical irregularity was caused by the tear film on the corneal surface.
  • mannose which is easily available and has excellent safety for the human body, has a stabilizing effect on the tear film. I found something.
  • the present inventors have found out that mannose exerts an excellent ameliorating effect on corneal epithelial disorder by conducting a test on the effect of curing corneal epithelial disorder on a dry eye model.
  • the present invention provides a tear film stabilizer containing mannose as an active ingredient.
  • the concentration of mannose is preferably 0.01 20% (wZv).
  • the present invention also provides a therapeutic agent for dry eye or a corneal conjunctival epithelial disorder caused by dry eye, comprising mannose as an active ingredient.
  • Corneal conjunctival epithelial disorders caused by dry eye include, for example, corneal ulcer, keratitis, conjunctivitis, punctate keratopathy, corneal epithelial defect, conjunctival epithelial defect, keratoconjunctivitis sicca, upper limbal keratoconjunctivitis, or filamentous Keratitis.
  • a preferred dosage form is an eye drop.
  • the present invention provides a tear film on the surface of an eyeball by instilling an eye drop containing mannose. Also provides a system to stabilize.
  • the ophthalmic solution containing mannose of the present invention is intended to stabilize the tear film and treat keratoconjunctival epithelial disorder caused by dry eye or dry eye.
  • the treatment of corneal epithelial disorders associated with the use of is also included in the object of the present invention. It is presumed that the ophthalmic solution containing mannose of the present invention exerts a therapeutic effect on corneal epithelial damage by the dry eye model based on the stabilization of the tear film by mannose.
  • Mannose used in the present invention is not particularly limited, and commercially available mannose may be used as it is.
  • Mannose is a component of glycoproteins of animals and plants and is used as an additive for pharmaceuticals, so that it is highly safe for the human body.
  • a preferred administration form of the tear film stabilizer or the therapeutic agent for keratoconjunctival epithelial disorder of the present invention includes, for example, eye drops, which can be formulated using a commonly used technique. .
  • the concentration of mannose in the ophthalmic solution of the present invention is not particularly limited, but from the viewpoint of the properties and effects of the ophthalmic solution, the mannose concentration is 0.01-1% (w / v), Preferably 0.1-15
  • the ophthalmic solution containing mannose of the present invention may contain other drugs as long as the object of the present invention is not impaired.
  • examples of such drugs include antibacterial agents, anti-inflammatory agents, antihistamines, antiglaucoma agents, antiallergic agents, immunosuppressants, antimetabolites and the like.
  • the eye drops of the present invention may appropriately contain isotonic agents, buffers, pH adjusters, solubilizers, stabilizers, preservatives and the like.
  • tonicity agent examples include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.
  • buffer examples include phosphoric acid, phosphate, citric acid, acetic acid, ⁇ -aminocaproic acid, trometamol, and the like.
  • Examples of the pH regulator include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.
  • Examples of the solubilizing agent to be added when the drug or other additives are hardly water-soluble are polysonolate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000 and the like. it can.
  • Examples of the stabilizer include edetic acid and sodium edetate.
  • Examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like. These preservatives may be used in combination. You can also.
  • the pH of the eye drop of the present invention is set to 4.0 8.0, and the osmotic pressure ratio is 1
  • the present invention also relates to a method for treating a disease caused by tear film instability, which comprises administering a therapeutically effective amount of mannose to a patient.
  • Mannose preferably at a concentration of 0.011 20
  • the present invention further relates to a method for treating dry eye or a corneal conjunctival epithelial disorder caused by dry eye, comprising administering a therapeutically effective amount of mannose to a patient.
  • Corneal conjunctival epithelial disorders caused by dry eye include, for example, corneal ulcers, keratitis, conjunctivitis, punctate keratopathy, corneal epithelial defect, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbal keratoconjunctivitis or filamentous keratitis. is there.
  • the number of times of eye drops of the eye drops of the present invention can be appropriately selected depending on symptoms, age, dosage form and the like, but is preferably about six times once a day.
  • the dosage of mannose is preferably 2 ⁇ g / day to about 10 Omg.
  • This test measures the tear stabilizing effect of each test ophthalmic solution by measuring the irregularity of the corneal surface (tear layer irregularity) after instillation of the test ophthalmic solution using a corneal shape measuring device. To evaluate.
  • the spherical irregularity index is a value that increases as the shape of the tear film on the corneal surface becomes irregular.
  • the value subtracted from the spherical irregularity index was calculated. Table 1 shows the results.
  • the change in spherical irregularity index of each test solution indicates the average value of three or five cases.
  • the aqueous solution containing mannose shows a remarkable tear stabilizing effect as compared with the physiological saline containing no mannose.
  • Nembutal was administered to male SD rats to perform general anesthesia.
  • the extraorbital lacrimal gland was excised and induced corneal epithelial damage over 2 months.
  • the damaged part of the corneal epithelium was stained with fluorescein.
  • the degree of fluorescein staining was determined for each of the upper, middle and lower parts of the corneal epithelium according to the following criteria, and the amelioration rate of corneal epithelial disorder was calculated from the average of the sum of the scores of each part.
  • Staining is moderate, and a part of the dot-like stained portion is adjacent.
  • the improvement rate of the 5% mannose (w / v) eye drop group was calculated based on the average value of the scores of the respective parts in the physiological saline eye drop group (control) (the improvement rate: 0%). This is shown in Table 2.
  • the average of the scores is the average of eight cases.
  • the improvement rate was calculated by the following formula.
  • Improvement rate (%) ⁇ (control) — (mannose) ⁇ / disability X 100
  • eye drops containing 100 mg, lg, 3 g, and 10 g of mannose in 100 ml can be prepared.
  • An ophthalmic solution containing mannose stably retains the tear film on the eyeball surface.
  • the ophthalmic solution containing mannose exhibits an excellent healing effect similar to a dry eye model, and is useful as a therapeutic agent for corneal conjunctival epithelial disorder caused by 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)
  • Public Health (AREA)
  • 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)
  • Chemical Kinetics & Catalysis (AREA)
  • Ophthalmology & Optometry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un traitement de l'insuffisance lacrymale ainsi que de l'épithéliopathie cornéenne ou conjonctivale en découlant. En l'occurrence, stabilisant le film lacrymal, les collyres au mannose apportent une amélioration à un tel état.
PCT/JP2004/018883 2003-12-18 2004-12-17 Stabilisateur du film lacrymal WO2005058932A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003420418 2003-12-18
JP2003-420418 2003-12-18

Publications (1)

Publication Number Publication Date
WO2005058932A1 true WO2005058932A1 (fr) 2005-06-30

Family

ID=34697249

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/018883 WO2005058932A1 (fr) 2003-12-18 2004-12-17 Stabilisateur du film lacrymal

Country Status (1)

Country Link
WO (1) WO2005058932A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002308783A (ja) * 2001-04-13 2002-10-23 Geo Co Ltd 皮膚または粘膜疾患予防、治療用医薬組成物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002308783A (ja) * 2001-04-13 2002-10-23 Geo Co Ltd 皮膚または粘膜疾患予防、治療用医薬組成物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEHER H. ET AL: "Mannose Induces the Release of Cytopathic Factors from Acanthamoeba castellannii", vol. 66, no. 1, 1998, pages 5 - 10, XP002989820 *

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