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WO1996004911A1 - Procede de prevention et de traitement d'une inflammation et/ou d'une blessure ophtalmiques - Google Patents

Procede de prevention et de traitement d'une inflammation et/ou d'une blessure ophtalmiques Download PDF

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Publication number
WO1996004911A1
WO1996004911A1 PCT/JP1995/001570 JP9501570W WO9604911A1 WO 1996004911 A1 WO1996004911 A1 WO 1996004911A1 JP 9501570 W JP9501570 W JP 9501570W WO 9604911 A1 WO9604911 A1 WO 9604911A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
carbostyril
salts
ophthalmic
drug containing
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1995/001570
Other languages
English (en)
Inventor
Toshiki Kitazawa
Shigeki Fujisawa
Hiroki Urashima
Hisashi Shinohara
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka 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 Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Priority to KR1019970700856A priority Critical patent/KR970704439A/ko
Priority to AU31917/95A priority patent/AU3191795A/en
Priority to EP95927986A priority patent/EP0774968A1/fr
Priority to MX9701010A priority patent/MX9701010A/es
Publication of WO1996004911A1 publication Critical patent/WO1996004911A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines

Definitions

  • This invention relates to a method of preventing and treating ophthalmic inflammation and/or wound.
  • R 1 and R 2 respectively indicate a lower alkyl group, and a bond between carbons of a carbostyril skeleton at the 3- and 4-positions indicates a single bond or a double bond
  • salts thereof are effective as bronchodilators, peripheral vasodilators and antihypertensive drugs.
  • U.S. Patent No. 4,322,425 there is disclosed that the above compounds are effective as remedies for glaucoma.
  • Japanese Laid-Open Patent Publication No. 64-52727 there is disclosed that the above compounds are useful as antiallergic eye drops.
  • the inventors have intensively studied about the carbostyril derivatives represented by the formula (1) or salts thereof.
  • the carbostyril derivatives or salts thereof particularly 8- hydroxy-5-(l-hydroxy-2-isopropylaminobutyl)carbostyril hydrochloride accelerate the growth of various ophthalmic tissue cells such as ectocorneal cells, conjunctival cells, keratocytes, corneaendothelial cells, scleral fibroblasts, etc., and inhibit the destruction of the blood-aqueous humor shelf or the increase of the thickness of the cornea, whereby they are effective for various ophthalmic inflammations and/or wounds which are not related to allergy.
  • various ophthalmic tissue cells such as ectocorneal cells, conjunctival cells, keratocytes, corneaendothelial cells, scleral fibroblasts, etc.
  • this invention provides a preventive and a remedy for ophthalmic inflammation and/or wound, which comprises carbostyril derivatives represented by the formula (1) or salts thereof, particularly 8-hydroxy-5-(l-hydroxy-2- isopropylaminobutyl)carbostyril hydrochloride as an active ingredient.
  • the preventive and remedy for ophthalmic inflammation and/or wound of this invention can be suitably used for ophthalmic inflammations and/or wounds other than allergic ophthalmic diseases, for example, blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, uveitis of anterior eye part, postoperative inflammation, chronic conjunctivitis, vernal conjunctivitis, lamellar keratitis, blepharitis marginalis, acute conjunctivitis, secretory epiphora, herpes corneae, prevention of corneal xerosis and protection of corneal disorder during an ophthalmic operation, intraocular irrigation (perfusion) and ablution upon ophthalmic operation (e.g.
  • Fig. 1 is a graph illustrating the results of the pharmacological test 1.
  • Fig. 2 is a graph illustrating the results of the pharmacological test 2.
  • Fig. 3 is a graph illustrating the results of the pharmacological test 3.
  • Fig. 4 is a graph illustrating the results of the pharmacological test 4. ⁇ Best Mode for Carrying Out the Invention>
  • the lower alkyl group represented by R A and R ⁇ include a straight- or branched-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
  • a compound containing an acid group can form a salt with a pharmacologically acceptable basic compound.
  • the basic compound include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, etc. ; alkali metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, etc.; alkali metal alcoholates such as sodium methylate, potassium ethylate, etc.
  • a compound having a basic group can form a salt easily with a pharmacologically acceptable acid.
  • the acid examples include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc.; organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, benzole acid, etc.
  • inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc.
  • organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, benzole acid, etc.
  • acid addition salts are particularly preferred.
  • Examples of the carbostyril derivative represented by the formula (1) include the followings.
  • the preventive and remedy for ophthalmic inflammation and/or wound of this invention are prepared into a suitable dosage unit form by mixing the carbostyril derivative represented by the formula (1) or a salt thereof with a conventional carrier for ophthalmic preparation.
  • a dosage unit form various normal forms can be optionally used. Examples of the form for local administration include ophthalmic ointment, eye drop, intraocular irrigating solution, etc., and examples of the form for general administration include tablet, granule, injection, etc. It is particularly preferred that the drug of this invention is prepared into the form of eye drop or intraocular irrigating solution.
  • the dose of the drug of this invention is not specifically limited, and it is advantageous that an amount of the active ingredient in the drug may be normally administered to an adult patient 2 to 3 times per day with a dairy dose of 0.01 to 0.5 mg, preferably 0.05 to 0.1 mg. Further, it is preferred that an amount of the active ingredient in the drug is normally within a range of 0.04 to 2 % by weight.
  • the drug of this invention can be produced using a normal method. For example, it is produced by mixing the carbostyril derivative represented by the formula (1) or a salt thereof as the active ingredient with a suitable base, and adding excipients, if necessary. In case of ophthalmic ointment, eye drop, injection, etc., the drug of this invention is produced by subjecting to an additional sterilization treatment.
  • the base to be used may be suitably selected according to the form of the drug.
  • conventional emulsifiable bases, water-soluble bases, suspending bases, etc. can be used.
  • Typical examples of the base include white vaseline, purified lanolin, liquid paraffin and the like.
  • sterilized distilled water can be typically used as the base.
  • solubilizers can also be blended in the drug of this invention.
  • solubilizer include polyoxyethylene glycol ethers such as sodium carboxymethyl cellulose, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, etc.; polyoxyethylene fatty acid esters such as polyethylene glycol monolaurate, polyethylene glycol higher fatty acid esters, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, etc.
  • the stabilizer include hydroxypropylmethyl cellulose, polyvinyl alcohol, carboxymethyl cellulose, hydroxyethyl cellulose, glycerin, EDTA and the like.
  • buffering agent examples include sodium hydrogenphosphate, potassium hydrogenphosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate and the like.
  • antioxidant examples include sodium bisulfite, sodium thiosulfite, ascorbic acid and the like.
  • antiseptic examples include chlorobutanol, benzalkonium chloride, cetylpyridinium chloride, phenylmercury salt, thimerosal, phenethyl alcohol, methylparaben, propylparaben and the like.
  • the eye drop is isotonized with the lacrimal fluid. Therefore, it is preferred to add isotonicities such as sodium chloride, etc., if necessary. It is desirable to adjust the pH of the eye drop within a range of 5.5 to 8.5, preferably 6.5 to 7.5.
  • the drug of this invention thus obtained is administered using various administration methods according to the dosage unit form.
  • eye drop it is dropped into eyes through a suitable eye dropper or sprayed to eyes through a spraying device.
  • ophthalmic ointment it is applied into eyes.
  • tablet, granule, etc. it is orally administered.
  • injection it is subcutaneously, intramuscularly or intravenously administered.
  • the concentration of the carbostyril derivative represented by the formula (1) or a salt thereof in the intraocular irrigating solution is about
  • the intraocular irrigating solution can be suitably used for ophthalmic operation, washing, etc.
  • the irrigation may be normally conducted once a day.
  • Methyl cellulose 0.8 g The above ingredients were mixed using a normal method, and then the resulting mixture was subjected to press molding to produce 1000 tablets.
  • lacrimal fluid increasing action test Nictitating membranes of New Zealand White domestic rabbits were excised and animals having no eye abnormality were selected. Tests were initiated after one week. An amount of lacrimal fluid was measured by using a modified primary process of Schirmer's test. That is, the domestic rabbit was fixed to a cylindrical fixing device and, after the animal calmed down, 50 ⁇ l of 0.4 % oxybuprocaine hydrochloride (0.4 % Benoxil, manufactured by Santen Seiyaku Co., Ltd.) was instilled into the right eye.
  • 0.4 % oxybuprocaine hydrochloride 0.4 % Benoxil, manufactured by Santen Seiyaku Co., Ltd.
  • a drug [8-hydroxy-5-(l-hydroxy-2- isopropylaminobutyl)carbostyril hydrochloride (Procaterol hydrochloride) dissolved into a distilled water at a concentration of 0.001 % by weight] was also instilled into the right eye.
  • a piece of Schirmer test paper was inserted into the inferior ophthalmic conjunctiva part.
  • the Schirmer test paper was removed to measure the length of the part of the paper wet with tear (for five minutes between 5 and 10 minutes after instillation of the drug).
  • a Schirmer test paper was again inserted into the inferior ophthalmic conjunctiva part to measure the amount of lacrimal fluid from 10 to 15 minutes after instillation of the drug.
  • New Zealand White domestic rabbits were slaughtered by intravenously administering 250 mg of pentobarbital and their eyeballs were excised. After the tunica conjunctiva bulbi was removed, the cornea and sclera were separated using ophthalmic scissors. The cornea was placed in phosphate buffered saline (PBS) and the Descemet's membrane was removed using tweezers under stereoscopic microscopy.
  • PBS phosphate buffered saline
  • the cornea sampled from the eyeball was sufficiently washed with PBS and the cells were cultured by the following method to measure the growth acceleration activity of the drug [8-hydroxy-5-(1- hydroxy-2-isopropylaminobutyl )carbostyril hydrochloride (Procaterol hydrochloride)] on the respective cells.
  • a piece 2 to 3 mm square of the cornea was made from the cornea using a razor.
  • the piece of the cornea was closely placed on a dish for tissue culture and, after a Dulbecco modified Eagle's medium F12 (DME/F-12, 1:1) containing 10 % fetal calf serum (FCS), 10 ng/ml of an epidermal growth factor (EGF) and 10 g/ml of insulin was added, it was cultured at 37 in 5 % CC*2 for two days. After the piece of the cornea was removed, the culturing was conducted for three additional days. The removed piece of the cornea was used for culturing keratocytes.
  • DME/F-12 Dulbecco modified Eagle's medium F12
  • FCS 10 % fetal calf serum
  • EGF epidermal growth factor
  • insulin 10 g/ml of insulin
  • Keratocytes A piece of the cornea was closely placed on a dish for tissue culture and, after a Dulbecco modified Eagle's medium (DMEM) containing 10 % FCS was added, it was cultured at 37 "C in 5 % CO2 to obtain growth-out keratocytes from the piece of the cornea. (4) Measurement of growth acceleration activity
  • the respective cultured cells were subjected to a 0.25 % trypsin-0.01 % EDTA treatment to disengage the cells from the surface of the dish.
  • the disengaged cells were suspended in the medium used for culturing the respective cells and, after centrifuging at 1000 rpm for five minutes, the medium was removed under vacuum.
  • the cell pellets were again suspended in the medium, and the cell density was adjusted to 4 x 10 4 cells/ml.
  • the cells (0.51 ml/well) were then inoculated in a cell culture plate with 24 holes and cultured overnight at 37 "C in 5 % CO2.
  • Rabbits (New Zealand White derivation, weight of 2 to 3 kg) were preliminary bred for about one week and slaughtered by intravenously administering pentobarbital. Then, eyeballs were extracted to prepare a corneosclera fragment.
  • a carbostyril derivative i.e., 8-hydroxy-5-(1- hydroxy-2-isopropylaminobutyl)carbostyril hydrochloride (Procaterol hydrochloride)] was dissolved in physiological saline at a concentration of 10 " ° M and the irrigating solution thus obtained was subjected to irrigation of the corneal endothelium side to measure the thickness of the cornea using an Ultrasonic Pachymeter.
  • ⁇ Thickness means the increased thickness of the cornea.
  • the corneal transition of the aqueous humor attended with disorder endothelialis cornea was prevented by adding the carbostyril derivative to an intraocular irrigating solution, which results in inhibition of the increase of the thickness of the cornea attended with corneal edema.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Procédé de prévention ou de traitement d'une inflammation et/ou d'une blessure ophtalmiques, qui comprend au moins un dérivé sélectionné parmi des dérivés de carbostyrile représentés par la formule (1), dans laquelle R1 et R2 représentent respectivement un groupe alkyle inférieur et dans laquelle une liaison entre les atomes de carbone d'un squelette de carbostyrile au niveau des positions 3 et 4 représente une liaison simple ou une liaison double, ainsi qu'un de ses sels en tant qu'ingrédient actif.
PCT/JP1995/001570 1994-08-10 1995-08-07 Procede de prevention et de traitement d'une inflammation et/ou d'une blessure ophtalmiques Ceased WO1996004911A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1019970700856A KR970704439A (ko) 1994-08-10 1995-08-07 눈의 염증 및/또는 상처의 예방 및 치료 방법(Method of preventing and treating ophthalmic inflammation and/or wound)
AU31917/95A AU3191795A (en) 1994-08-10 1995-08-07 Method of preventing and treating ophthalmic inflammation and/or wound
EP95927986A EP0774968A1 (fr) 1994-08-10 1995-08-07 Procede de prevention et de traitement d'une inflammation et/ou d'une blessure ophtalmiques
MX9701010A MX9701010A (es) 1994-08-10 1995-08-07 Un preventivo y un remedio para herida y/o inflamacion oftalmica.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6/188303 1994-08-10
JP18830394 1994-08-10

Publications (1)

Publication Number Publication Date
WO1996004911A1 true WO1996004911A1 (fr) 1996-02-22

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/001570 Ceased WO1996004911A1 (fr) 1994-08-10 1995-08-07 Procede de prevention et de traitement d'une inflammation et/ou d'une blessure ophtalmiques

Country Status (6)

Country Link
EP (1) EP0774968A1 (fr)
KR (1) KR970704439A (fr)
AU (1) AU3191795A (fr)
CA (1) CA2197123A1 (fr)
MX (1) MX9701010A (fr)
WO (1) WO1996004911A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997013515A1 (fr) * 1995-10-12 1997-04-17 Otsuka Pharmaceutical Co., Ltd. Derive carbostyrylique pour le traitement de maladies oculaires
US6569903B2 (en) 1999-12-07 2003-05-27 Rohto Pharmaceutical Co., Ltd. Ophthalmic compositions
US7879877B2 (en) 2003-07-30 2011-02-01 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives for accelerating salivation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0020765A1 (fr) * 1978-07-14 1981-01-07 Otsuka Pharmaceutical Co., Ltd. Remede contre le glaucome
JPS6452727A (en) * 1988-05-02 1989-02-28 Santen Pharmaceutical Co Ltd Antiallergic eye drop

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0020765A1 (fr) * 1978-07-14 1981-01-07 Otsuka Pharmaceutical Co., Ltd. Remede contre le glaucome
JPS6452727A (en) * 1988-05-02 1989-02-28 Santen Pharmaceutical Co Ltd Antiallergic eye drop

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE FILE 399: CA SEARCH host: dialog; *
DATABASE WPI Derwent World Patents Index; AN 89-104873 *
Y.SAKUMA ET AL.: "Suppression of ocular reactions in cedar pollinosis by procaterol hydrochloride eyedrops", JPN.J.CLIN.OPHTHALMOL., vol. 46, no. 10, October 1992 (1992-10-01), pages 1437 - 1440 *
Y.SAKUMA, ATARASHII GANKA, vol. 12, no. 3, 1995, pages 466 - 468 *
Y.YAMAMOTO ET AL.: "Usefulness of Procaterol Eyedrops on Experimental Models of Allergic Conjunctivitis", YAKURI TO CHIRYO, vol. 21, no. 9, September 1993 (1993-09-01), pages 3075 - 3084 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997013515A1 (fr) * 1995-10-12 1997-04-17 Otsuka Pharmaceutical Co., Ltd. Derive carbostyrylique pour le traitement de maladies oculaires
US6060486A (en) * 1995-10-12 2000-05-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivative for curing ophthalmological diseases
US6569903B2 (en) 1999-12-07 2003-05-27 Rohto Pharmaceutical Co., Ltd. Ophthalmic compositions
US7879877B2 (en) 2003-07-30 2011-02-01 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives for accelerating salivation

Also Published As

Publication number Publication date
AU3191795A (en) 1996-03-07
MX9701010A (es) 1997-05-31
KR970704439A (ko) 1997-09-06
EP0774968A1 (fr) 1997-05-28
CA2197123A1 (fr) 1996-02-22

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