WO2005003111A1 - Agent de prevention ou de traitement de la conjonctivite virale - Google Patents

Agent de prevention ou de traitement de la conjonctivite virale Download PDF

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Publication number
WO2005003111A1
WO2005003111A1 PCT/JP2004/009701 JP2004009701W WO2005003111A1 WO 2005003111 A1 WO2005003111 A1 WO 2005003111A1 JP 2004009701 W JP2004009701 W JP 2004009701W WO 2005003111 A1 WO2005003111 A1 WO 2005003111A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
conjunctivitis
active ingredient
agent
preventing
Prior art date
Application number
PCT/JP2004/009701
Other languages
English (en)
Japanese (ja)
Inventor
Jun Hiroi
Eisaku Tsujii
Tatsuo Suzutani
Hisatoshi Kaneko
Akihiko Miyatake
Original Assignee
Astellas Pharma Inc.
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 Astellas Pharma Inc. filed Critical Astellas Pharma Inc.
Publication of WO2005003111A1 publication Critical patent/WO2005003111A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to an antiviral agent for adenovirus. More specifically, the present invention relates to a prophylactic or therapeutic agent for viral conjunctivitis, comprising cromoglycic acid or a non-toxic salt thereof as an active ingredient, and a virus comprising administering these to humans or animals. And a method for preventing or treating conjunctivitis conjunctivitis.
  • a prophylactic or therapeutic agent for viral conjunctivitis comprising cromoglycic acid or a non-toxic salt thereof as an active ingredient, and a virus comprising administering these to humans or animals.
  • a method for preventing or treating conjunctivitis conjunctivitis comprising cromoglycic acid or a non-toxic salt thereof as an active ingredient
  • Adenovirus is responsible for 80 to 90% of viral conjunctivitis, and it is said to affect about 100,000 people a year in Japan. ⁇ Since conjunctivitis is a highly contagious infectious disease, daily life is restricted and forced to leave school and workplaces if it becomes ill. Furthermore, hospital-acquired infections caused by the 7 denovirus have recently become an important social issue in public health, and have become an economic and ethical issue in hospitals.
  • adenoviridae Human adenovirus was discovered by Rowe and Hillman.
  • adenoviridae viral particles without a positive 2 0 tetrahedron (diameter 7 0 to 9 0 nm)
  • the genome is a double-stranded DNA (molecular weight 2 0 ⁇ 2 5 X 1 0 6 ) It has an inverted repeat sequence of 100 to 160 bases at both ends.
  • serotypes range to 51, with the addition of a new strain isolated from AIDS patients. It is divided into six groups (subgenus) based on indicators such as genome homology and recombination ability within the group. Minute of adenovirus The types are shown in Table 1.
  • Types 3, 4, 7, 8, 11, 19 and 37 have been reported.
  • the subgenus B (3, 7, 11), E (4) and D (8, 19, 37) fall into this category (Hideo Uchio, New Ophthalmology, 20 (3), p289-295 (2003 )).
  • adenovirus types 8, 19 and 37 are responsible for the outbreak of conjunctivitis in Asian countries including Japan, especially in East and Southeast Asia (K. Aoki et al., Br. J. Ophthalmol. ., 66 p776-780 (1982)).
  • adenovirus types 8, 19 and 37 are well known epidemiological causes of nosocomial infections (J.A. Jernigan et al., J. Infect. Dis., 167 pl307-1313 (1993)).
  • sodium cromoglycate is used clinically as an antiallergic agent for bronchial asthma and allergic rhinitis and allergic conjunctivitis, and its side effects are minimal, such as cough sometimes seen when inhaling powdered formulations It is clinically recognized as a very safe drug.
  • Sodium cromoglycate has not been reported to have any serious side effects, despite its long history of clinical administration, and most notably, it has established its effects and safety in children. To date, there is no finding that sodium lipodium molycdate is effective for viral conjunctivitis. For antiviral effects against adenovirus, see Penttinen et al.
  • This report describes the antiviral activity of sodium cromoglycate. This report describes experiments using viruses different from adenoviruses that cause conjunctivitis (Adenovirus 5, Echovirus 7, Herpes simplex, and Semi iki Forest virus). Sodium cromoglycate does not affect the growth of the virus but inhibits the cell damage caused by the virus (K. Penttinen et al., Brit. Med. J., I, 6053, p82 (1977)
  • the present invention has been made in view of the current situation in the prior art, and has as its object to provide an antiviral agent for adenovirus which is highly safe for the human body, and particularly for safety for children.
  • the purpose is to provide existing drugs with established sexual properties as preventive or therapeutic agents for viral conjunctivitis. Disclosure of the invention
  • the present inventors have found that sodium cromoglycate is effective for adenoviruses that cause conjunctivitis in the process of examining the antiviral effect of sodium cromoglycate, particularly for adenoviruses 8, 19 and 37.
  • the present invention has been completed. Therefore, according to the present invention, there is provided an agent for preventing or treating viral conjunctivitis, comprising as an active ingredient cromoglycic acid or a salt thereof as shown in the following [1] to [S], Also provided is a method for preventing or treating diarrheal conjunctivitis comprising administering these to humans or animals.
  • An antiviral agent against adenovirus comprising cromoglycic acid or a salt thereof as an active ingredient.
  • An antiviral agent against adenovirus type 8, type 19 or type 37 comprising cromoglycic acid or a salt thereof as an active ingredient.
  • An agent for preventing or treating viral conjunctivitis comprising cromoglycic acid or a salt thereof as an active ingredient.
  • a method for preventing or treating viral conjunctivitis comprising administering an effective amount of cromoglycic acid or a salt thereof to a human or animal.
  • a method for preventing the onset or alleviating the clinical symptoms of viral conjunctivitis comprising administering an effective amount of cromoglycic acid or a salt thereof to a human or animal.
  • Viral conjunctivitis which is the subject of the present invention, is initiated by the attachment of adenovirus, particularly adenovirus type 8, 19 or 37, to a receptor present in epithelial cells of the conjunctiva. It is a disease. After infection, the virus transfers into the cells and multiplies in the nucleus. When the virus particles fill the nucleus, the virus releases virus particles and the infection spreads.
  • adenovirus particularly adenovirus type 8, 19 or 37
  • the cromoglycic acid used in the present invention is a known compound 5,5 '-(2-hydroxytrimethylenedioxy) bis (4-oxo-1H-1-benzopyran-12-carboxylic acid).
  • Non-toxic salts of cromoglycic acid include, for example, salts with alkali metals such as sodium or potassium, salts with alkaline earth metals such as calcium or magnesium, ammonium salts, and quaternary ammonium salts. Salts may be mentioned, and among these, sodium cromoglycate is particularly preferred.
  • the agent for preventing or treating viral conjunctivitis of the present invention is preferably used as a topical preparation containing the active ingredient cromoglycic acid or a nontoxic salt thereof, for example, as an eye drop.
  • the content (concentration) of sodium cromoglycate in the topical preparation of the present invention is 0.5 to 5%, preferably 1 to 2%.
  • sodium cromoglycate is dissolved in purified water or sterilized purified water by stirring.
  • These preparations may optionally contain a tonicity agent such as sodium chloride.
  • Buffers eg, boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.
  • preservatives eg, benzalkonium chloride, etc.
  • thickeners eg, carboxyl vinyl polymer, etc.
  • stabilizers eg, Commonly used additives such as sodium detorate, a refreshing agent (eg, 1-menthol), dl-camphor, d-borneol, fennel oil, heart oil, heart water can be added. .
  • the thus obtained topical preparation of the present invention is administered once to several times a day depending on the condition of the patient.
  • Cromoglycic acid or a salt thereof may be used in combination with other drugs, antihistamines (eg, diphenhydramine hydrochloride, chlorpheniramine maleate, promethazine, diphenirarine hydrochloride, clemastine fumarate, etc.), vasoconstrictors (eg, norfuenefrin hydrochloride, It can also be used in combination with feneryphrine hydrochloride, naphazoline hydrochloride, gyrometazoline, mitodrine hydrochloride, methoxamine hydrochloride, tetrahydrooctrozoline nitrate), steroid anti-inflammatory agents, antibiotics and the like.
  • antihistamines eg, diphenhydramine hydrochloride, chlorpheniramine maleate, promethazine, diphenirarine hydrochloride, clemastine fumarate, etc.
  • vasoconstrictors eg, norfuenef
  • Eye drops containing cromoglycic acid or its salts that are effective for the prevention or treatment of viral conjunctivitis are administered once or several times daily, depending on the type of human or animal being treated and the condition of the patient .
  • the present invention When the present invention is administered as a prophylactic agent for viral conjunctivitis, it can be started during the viral conjunctivitis epidemic season, and can be carried out with increasing or decreasing as needed. In other words, when viral conjunctivitis epidemic is imminent, or before or after possible infection (such as swimming in a pool) or before the onset of viral conjunctivitis.
  • the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
  • Example 1 Sodium cromoglycate, d1-chlorpheniramine maleate, tifazoline hydrochloride and sodium edetate were dissolved in purified water, benzonalconium chloride was added thereto, and the mixture was stirred. A prescribed nasal drop was obtained.
  • Sodium cromoglycate, d1-chlorpheniramine maleate, sodium edetate, benzalkonium chloride, and sodium chloride were added to sterile purified water, stirred, dissolved and sterile-filtered to obtain eye drops of the following formulation.
  • Adenoviruses the three strains as shown in Table 2, the amount of virus, respectively 100MTT ID 5. It was used after dilution.
  • Type 37 clinical isolate The ID (Infectious dose) indicating the amount of virus infection is a unit of the amount of virus required for infection of host cells, and was measured and determined as follows.
  • the sodium cromoglycate solution was dissolved in a MEM medium to a concentration of 20 mg / ml and sterilized with a 0.2 m filter. This solution was transferred in a 96-well plate into which 200 1 of MEM medium was dispensed, and a test dilution of 5-fold dilution of sodium cromoglycate was prepared.
  • each virus indicated that the culture supernatant up to a concentration 2 QmgZml or al the suction advance another plate to the 5-fold serial dilutions of sodium cromoglycate solution to 0 more Table 1 was added in each IOOI the 100MTT ID 5. Diluted, and the culture medium and uninfected control media 100 l containing no virus added to the different cells as 37 ° C, 5% concentration C0 2 6 days in the presence of containing virus.
  • an anti-adenovirus agent highly safe for the human body more specifically, a prophylactic or therapeutic agent for viral conjunctivitis, which comprises cromoglycic acid or a salt thereof as an active ingredient, and A method for preventing or treating viral conjunctivitis comprising administering these to humans or animals is provided.

Abstract

La présente invention concerne agent antiviral dirigé contre les adénovirus, en particulier l'adénovirus de type 8, de type 9 ou de type 37 et un agent de prévention de traitement de la conjonctivite virale induite par des adénovirus, qui se caractérise en ce qu'il contient un acide cromoglicique ou les sels de celui-ci comme principe actif. Cette invention concerne aussi une technique de prévention ou de traitement de la grippe A qui consiste à administrer cet agent à des sommes ou à des animaux
PCT/JP2004/009701 2003-07-04 2004-07-01 Agent de prevention ou de traitement de la conjonctivite virale WO2005003111A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003191575 2003-07-04
JP2003-191575 2003-07-04

Publications (1)

Publication Number Publication Date
WO2005003111A1 true WO2005003111A1 (fr) 2005-01-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4132507A1 (fr) * 2020-04-06 2023-02-15 The General Hospital Corporation Méthodes de traitement d'états inflammatoires induits par des coronavirus

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5040720A (fr) * 1973-05-25 1975-04-14
JPS5927814A (ja) * 1982-07-02 1984-02-14 フアイソンズ・ピ−エルシ− 処方物
JPS61143318A (ja) * 1984-11-23 1986-07-01 フアイソンズ・ピ−エルシ− 新規な製剤およびその調整方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5040720A (fr) * 1973-05-25 1975-04-14
JPS5927814A (ja) * 1982-07-02 1984-02-14 フアイソンズ・ピ−エルシ− 処方物
JPS61143318A (ja) * 1984-11-23 1986-07-01 フアイソンズ・ピ−エルシ− 新規な製剤およびその調整方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WEBER C.M. ET AL: "Acute red eye: Differentiating viral conjunctivitis from other, less common causes", POSTGRADUATE MEDICINE, vol. 101, no. 5, 1997, XP002981997 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4132507A1 (fr) * 2020-04-06 2023-02-15 The General Hospital Corporation Méthodes de traitement d'états inflammatoires induits par des coronavirus

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