throbber
(19) 1+1 Canadian
`
`Intellectual Property
`Office
`
`Office de Ia Propri,t,
`lntellectuelle
`du Canada
`
`An Agency of
`Industry Canada
`
`Un organisme
`d'lndustrie Canada
`
`(11) CA 2 383 971
`(40) 15.03.2001
`(43) 15.03.2001
`
`(13) A1
`
`(12)
`
`(21) 2 383 971
`
`(22) 05.09.2000
`
`11/251538 JP 06.09.1999
`
`ONO PHARMACEUTICAL CO., LTD.,
`1-5, Doshomachi 2-chome
`Chuo-ku
`Osaka-shi
`541-8526, OSAKA, XX (JP).
`SENJU PHARMACEUTICAL CO., LTD.,
`5-8 Hiranomachi 2-chome
`
`(30)
`
`(71)
`
`(54)
`(54)
`
`(57)
`
`(51)
`
`Int. Cl.':
`
`A61K 31/235, A61P 27/02,
`A61 K 47/04, A61 K 9/06,
`A61K 9/10, A61K 47/10,
`A61 K 47/12, A61 K 47/32
`
`(85) 05.03.2002
`
`(86) PCT/JP00/06014
`
`87 W001/017527
`Chuo-ku, Osaka-shi
`541-0046, OSAKA, XX (JP).
`
`(72)
`
`(74)
`
`KAWABATA, KAZUHITO (JP).
`NAKA, HIROAKI (JP).
`TOKUSHIGE, HIDEKI (JP).
`
`FETHERSTONHAUGH & CO.
`
`MEDICAMENTS THERAPEUTIQUE ET PROPHYLACTIQUE POUR TRAITER LES MALADIES OPHTALMIQUES
`PROPHYLACTIC AND THERAPEUTIC MEDICAMENTS FOR OPHTHALMIC DISEASES
`
`Preventive and therapeutic agents for eye diseases,
`eye diseases and corneal
`particularly
`inflammatory
`ulcer,
`containing
`as
`the
`active
`ingredient
`the
`compound of formula (1), pharmacologically acceptable
`salts thereof, or hydrates of both.
`
`Metrics EX1043, Page 1
`
`

`
`1+1 Office de Ia Propriete
`
`lntellectuelle
`du Canada
`Un organisme
`d'lndustne Canada
`
`Canadian
`Intellectual Property
`Office
`An agency of
`Industry Canada
`
`(86) Date de depllt PCT/PCT Filing Date: 2000/09/05
`(87) Date publication PCT/PCT Publication Date: 2001/03/15
`(85) Entree phase nationale/National Entry: 2002/03/05
`(86) W demande PCT/PCT Application No.: JP 2000/006014
`(87) N" publication PCT/PCT Publication No.: 2001/017527
`(30) Priorite/Priority: 1999/09/06 (11/251538) JP
`
`CA 2383971 A1 2001/03/15
`(21) 2 383 971
`c12l DEMANDE DE BREVET CANADIEN
`CANADIAN PATENT APPLICATION
`C13J A 1
`
`(51) Cllnt 7/lntCL 7 A61 K 31/235, A61 K 47/32, A61 K 47/12,
`A61 P 27/02, A61 K 47/10, A61 K 9/10, A61 K 9/06,
`A61K47/04
`(71) Demandeurs/Applicants:
`SENJU PHARMACEUTICAL CO, L TO., JP;
`ONO PHARMACEUTICAL CO., L TO., JP
`(72) lnventeurs/lnventors:
`NAKA, HIROAKI, JP;
`KAWABATA, KAZUHITO, JP;
`TOKUSHIGE, HIDEKI, JP
`(74) Agent: FETHERSTON HAUGH & CO.
`
`(54) Titre: MEDICAMENTS THERAPEUTIQUE ET PROPHYLACTIQUE POUR TRAITER LES MALADIES
`OPHTALMIQUES
`(54) Title: PROPHYLACTIC AND THERAPEUTIC MEDICAMENTS FOR OPHTHALMIC DISEASES
`
`(I)
`
`(57) Abrege/Abstract:
`Preventive and therapeutic agents for eye diseases, particularly Inflammatory eye diseases and corneal ulcer, containing as the
`active ingredient the compound of formula (I), pharmacologically acceptable salts thereof, or hydrates of both.
`
`d •••
`ana a JJttp:!lopk.gc.ca o Ottawa-Hull KlA OC9 o htrp:l!cipo.gc.ca
`C
`
`OPIC o CIPO 191
`
`0 PIC
`
`C I P 0
`
`Metrics EX1043, Page 2
`
`

`
`..
`
`•
`
`CA 02383971 2002-03-05
`
`Abstract of the disclosure:
`
`The present
`
`invention provides a prophylactic and
`
`therapeutic medicament for ophthalmic diseases, especially
`
`5
`
`ophthalmic
`
`inflammatory diseases
`
`and
`
`corneal ulcer,
`
`comprising as an active ingredient a compound represented
`
`by the formula (I):
`
`or a pharmacologically acceptable salt or hydrate
`
`10
`
`thereof.
`
`~---·- --- ·------------------------- -----------------
`
`Metrics EX1043, Page 3
`
`

`
`CA 02383971 2002-03-05
`
`1
`
`PROPHYLACTIC AND THERAPEUTIC MEDICAMENTS FOR OPHTHALMIC
`
`DISEASES
`
`5
`
`TECHNICAL FIELD
`
`The present invention relates to a prophylactic
`
`and therapeutic medicament for ophthalmic diseases
`
`having a leukocyte (neutrophil)-derived elastase
`
`inhibitory activity.
`
`BACKGROUND OF THE INVENTION
`
`JP-B 5-81586 and JP-A 5-194366 (corresponding to
`
`EP-A 539223) disclose a compound represented by the
`
`formula (I):
`
`(I)
`
`10
`
`15
`
`(hereinafter referred to as a compound of Formula (I))
`
`and a salt or hydrate thereof, which has a human
`
`neutrophil-derived elastase inhibitory activity and is
`
`20
`
`effective for preventing and treating diseases such as
`
`pulmonary emphysema, atherosclerosis and rheumatoid
`
`arthritis.
`
`On the other hand, the ophthalmologic field also
`
`Metrics EX1043, Page 4
`
`

`
`26456 233
`
`CA 02383971 2002-03-05
`
`2
`
`involves various diseases relating to leukocytes and
`
`their elastases. For example, ophthalmic infections,
`
`corneal traumas, corneal ulcers and uveitis may be
`
`mentioned.
`
`In an ophthalmic infection, the cellular
`
`5
`
`infiltration of leukocytes results in an intraocular
`
`abscess [Invest. Ophthalmol. Vis. Sci., 40, 385-391
`
`(1999)]. An alkaline trauma (erosion) which is one of
`
`corneal traumas allows leukocytes to be infiltrated
`
`into corneal stromal cells at an early stage of the
`
`10
`
`alkaline erosion, two to three weeks after which the
`
`elevation of leukocyte elastase activity is observed
`
`[Ophthalmic. Res., 29, 154-160 (1997)]. Also in a case
`
`of corneal ulcers, a corneal wound or detachment
`
`results in the infiltration of leukocytes into a
`
`15
`
`corneal stroma, which leads to the release or secretion
`
`of a protease such as an elastase or collagen [Klin.
`
`Monatsbl. Augenheilkd, 188, 593-595 (1986)). An
`
`uveitis, especially Behcet's disease, was reported to
`
`undergo an increase in a plasma leukocyte elastase
`
`20
`
`[Clin. Chim. Acta 236:129-134 (1995), Acta, Ophthalmol.
`
`Scand. 75:287-289 (1997), J.Reumatol. 25: 326-328
`
`(1998}]. While leukocytes or their elastases were
`
`reported to be involved in the ophthalmic diseases
`
`mentioned above, no actual effect of the administration
`
`25
`
`of an elastase inhibitor was reported.
`
`Metrics EX1043, Page 5
`
`

`
`•
`
`CA 02383971 2002-03-05
`
`3
`
`While in JP-A 5-221872 (corresponding to EP-A
`
`519354) and JP-A 6-509232 (corresponding to EP-A
`
`596118), a microbe-derived substance having human
`
`leukocyte elastase inhibitory activity is described
`
`5
`
`generally to be useful as a prophylactic and
`
`therapeutic medicament against a corneal scar tissue
`
`formation or a fibroblast proliferation [eye
`
`solidification (burn, mechanical or chemical damage,
`
`keratoconjunctivitis) and the like], it was not
`
`10
`
`administered actually to verify its effect, and is
`
`different totally from a compound of Formula (I).
`
`OBJECTS OF THE INVENTION
`
`An objective of the present invention is to
`
`15
`
`develop a prophylactic and therapeutic medicament for
`
`ophthalmic diseases containing as an active ingredient
`
`a compound of Formula (I).
`
`This objective as well as other objectives and
`
`advantages of the present invention will be explained
`
`20
`
`hereinafter with reference to the attached drawings.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Fig. 1 is a graph showing the effect of an eye
`
`drop formulation of N-[o-(p-pivaloyloxybenzenesulfonyl-
`
`25
`
`amino)benzoyl]glycine monosodium salt tetrahydrate
`
`Metrics EX1043, Page 6
`
`

`
`CA 02383971 2002-03-05
`
`4
`
`(hereinafter referred to as Compound A) on an
`
`endotoxin-induced keratitis (effect on a corneal
`
`opacity). Each symbol represents a mean ± standard
`
`deviation (n=4). A statistically significant
`
`5
`
`difference from a control is analyzed with p<0.05
`
`(Wilcoxon test, one-sided) .
`
`Fig. 2 is a graph showing the effect of a Compound
`
`A eye drop formulation on an endotoxin-induced
`
`keratitis (effect on a corneal ulcer). Each symbol
`
`10
`
`represents a mean ± standard deviation (n=4) . A
`
`statistically significant difference from a control is
`
`analyzed with p<O.OS (Wilcoxon test, one-sided).
`
`Fig. 3 is a graph showing the effect of a Compound
`
`A eye drop formulation on an endotoxin-induced
`
`15
`
`keratitis (effect on a vascularization). Each symbol
`
`represents a mean ± standard deviation (n=4).
`
`Fig. 4 shows the effect of a Compound A eye drop
`
`formulation 15 days after the challenge on an
`
`endotoxin-induced keratitis. Each column represents a
`
`20
`
`mean ± standard deviation (n=4). A statistically
`
`significant difference from a control is analyzed with
`
`p<0.05 (Wilcoxon test, one-sided).
`
`Fig. 5 is a graph showing the effect of a Compound
`
`A eye drop formulation on an alkaline erosion keratitis
`
`25
`
`(effect on a corneal opacity) . Each symbol represents
`
`-------------------·--·-----·--···-
`
`Metrics EX1043, Page 7
`
`

`
`CA 02383971 2002-03-05
`
`5
`
`a mean ± standard deviation (n=4).
`
`Fig. 6 is a graph showing the effect of a Compound
`
`A eye drop formulation on an alkaline erosion keratitis
`
`(effect on a corneal ulcer) . Each symbol represents a
`
`5
`
`mean ± standard deviation (n=4). A statistically
`
`significant difference from a control is analyzed with
`
`p<O.OS (Wilcoxon test, one-sided).
`
`Fig. 7 is a graph showing the effect of a Compound
`
`A eye drop formulation on an alkaline erosion keratitis
`
`10
`
`(effect on a vascularization) . Each symbol represents
`
`a mean ± standard deviation (n=4).
`
`Fig. 8 is a graph showing the effect of a Compound
`
`A eye drop formulation on a pyocyanic corneal ulcer
`
`immediately after the inoculation of the microbe. Each
`
`15
`
`symbol represents a mean ± standard deviation (n=6) . A
`
`statistically significant difference from a control is
`
`analyzed with p<O.OS (Wilcoxon test, one-sided).
`
`Fig. 9 is a graph showing the effects of the
`
`instillation of Compound A and lomefloxacin on a
`
`20
`
`pyocyanic corneal ulcer one day after the inoculation
`
`of the microbe and later. Each symbol represents a
`
`mean ± standard deviation (n=S-6) . A statistically
`
`significant difference from a control is analyzed with
`* p<O.OS and ** p<O.Ol (Steel test, one-sided).
`
`25
`
`Metrics EX1043, Page 8
`
`

`
`CA 02383971 2002-03-05
`
`6
`
`SUMMARY OF THE INVENTION
`
`The present inventors found out that a compound
`
`represented by Formula (I) or a pharmacologically
`
`acceptable salt or hydrate thereof exhibits a marked
`
`5
`
`prophylactic and therapeutic effect against various
`
`ophthalmic diseases.
`
`Thus, the present invention provides a
`
`prophylactic and therapeutic medicament for ophthalmic
`
`diseases, especially ophthalmic inflammatory diseases
`
`10
`
`and corneal ulcer, comprising as an active ingredient a
`
`compound represented by Formula (I) or a
`
`pharmacologically acceptable salt or hydrate thereof.
`
`The present invention also provides a method for
`
`preventing and treating an ophthalmic disease which
`
`15
`
`comprises administering an active ingredient mentioned
`
`above to a mammal in need of a treatment for such
`
`ophthalmic disease.
`
`Furthermore, the present invention provides use of
`
`an active ingredient mentioned above in the manufacture
`
`20
`
`of a prophylactic and therapeutic medicament for
`
`ophthalmic diseases.
`
`Moreover, the present invention provides an eye
`
`drop formulation in the form of an aqueous suspension
`
`of an active ingredient described above.
`
`25
`
`Metrics EX1043, Page 9
`
`

`
`CA 02383971 2002-03-05
`
`7
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The prophylactic and therapeutic medicament
`
`according to the present invention is preferably in a
`
`dosage form for a local administration such as an eye
`
`5
`
`drop formulation or an ophthalmic ointment, which is
`
`useful for preventing and treating various ophthalmic
`
`diseases such as ophthalmic infections (for example,
`
`corneal herpes, bacterial keratitis, bacterial
`
`conjunctivitis, mycotic keratitis, acanthamebic
`
`10
`
`keratitis, infectious endophthalmitis, infectious
`
`corneal ulcer and the like), corneal trauma,
`
`cicatricial keratoconjunctival diseases (for example,
`
`alkaline erosive keratoconjunctivitis, Stevens-Johnson
`
`syndrome, ophthalmic pemphigoid and the like), corneal
`
`15
`
`ulcer (for example, Mooren's ulcer, corneal ulcer
`
`subsequent to chronic rheumatoid arthritis or collagen
`
`disease, Terrien's margine degeneration, catarrhal
`
`corneal ulcer, infectious corneal ulcer and the like),
`
`vitamin A insufficiency-induced keratomalacia, necrotic
`
`20
`
`keratitis, neuroparalytic keratitis, diabetic
`
`keratophathy, keratoconjunctiva sicca, contact lens(cid:173)
`
`induced keratoconjunctivitis, vernal conjunctivitis,
`
`allergic conjunctivitis, uveitis, Behcet's syndrome,
`
`inflammation after cataract surgery and pseudopterygium,
`
`25
`
`especially a keratoconjunctival inflammatory disease
`
`~~ -~····-··---·-------
`
`Metrics EX1043, Page 10
`
`

`
`CA 02383971 2002-03-05
`
`8
`
`(for example, corneal herpes, bacterial keratitis,
`
`bacterial conjunctivitis, mycotic keratitis,
`
`acanthamebic keratitis, corneal trauma, alkaline
`
`erosive keratoconjunctivitis, corneal ulcer, vitamin A
`
`5
`
`insufficiency-induced keratomalacia, necrotic keratitis,
`
`neuroparalytic keratitis, diabetic keratophathy,
`
`keratoconjunctiva sicca, contact lens-induced
`
`keratoconjunctivitis, vernal conjunctivitis, allergic
`
`conjunctivitis and the like) .
`
`It is useful also for
`
`10
`
`preventing and treating corneal ulcer (including
`
`various corneal ulcers described above and those
`
`induced otherwise), especially an infectious corneal
`
`ulcer.
`
`A compound of Formula (I) used as an active
`
`15
`
`ingredient according to the present invention or a
`
`pharmacologically acceptable salt thereof is a known
`
`compound described in JP-B 5-81586, and can be produced,
`
`in accordance with the procedure described therein, by
`
`the amidation of p-pivaloyloxybenzenesulfonyl chloride
`
`20
`
`followed by the conversion into a salt by a known
`
`method. The resultant compound may also be converted
`
`into a hydrate by a known method.
`
`A pharmacologically acceptable salt of a compound
`
`of Formula (I) may for example be an inorganic salt
`
`25
`
`such as hydrochloride, hydrobromide, hydroiodide,
`
`---~-~ ------ ·----
`
`------------------··-····----
`
`Metrics EX1043, Page 11
`
`

`
`CA 02383971 2002-03-05
`
`9
`
`sulfate, phosphate and nitrate, an organic salt such as
`
`acetate, lactate, tartarate, benzoate, citrate,
`
`methanesulfonate, ethanesulfonate, benzenesulfonate,
`
`toluenesulfonate, isethionate, glucuronate and
`
`5
`
`gluconate, an alkaline metal salt (sodium salt,
`
`potassium salt and the like), an alkaline earth metal
`
`salt (calcium salt, magnesium salt and the like), an
`
`ammonium salt, a pharmacologically acceptable amine
`
`salt (tetramethylammonium salt, triethylamine salt,
`
`10
`
`methylamine salt, dimethylamine salt, cyclopentylamine
`
`salt, benzylamine salt, phenethylamine salt, piperidine
`
`salt, monoethanolamine salt, diethanolamine salt,
`
`tris(hydroxymethyl)aminomethane salt, lysine salt,
`
`arginine salt, N-methyl-D-glucamine salt and the like).
`
`15
`
`One preferred especially as an active ingredient
`
`used in the present invention is a sodium salt
`
`tetrahydrate of a compound of Formula (I), i.e., N-[o-
`
`(p-pivaloyloxybenzenesulfonylamino)benzoyl]glycine
`
`monosodium salt tetrahydrate (described in Example 3 in
`
`20
`
`JP-A 5-194366 corresponding to EP-A 539223) represented
`
`by Formula (I-A):
`
`Metrics EX1043, Page 12
`
`

`
`CA 02383971 2002-03-05
`
`10
`
`The prophylactic and therapeutic medicament for
`
`ophthalmic diseases according to the present invention,
`
`on the basis of its leukocyte-derived elastase
`
`inhibitory activity, is useful in preventing and
`
`5
`
`treating various ophthalmic diseases such as an
`
`ophthalmic infections (for example, corneal herpes,
`
`bacterial keratitis, bacterial conjunctivitis, mycotic
`
`keratitis, acanthamebic keratitis, infectious
`
`endophthalmitis, infectious corneal ulcer and the like),
`
`10
`
`corneal trauma, cicatricial keratoconjunctival diseases
`
`(for example, alkaline erosive keratoconjunctivitis,
`
`Stevens-Johnson syndrome, ophthalmic pemphigoid and the
`
`like), corneal ulcer (for example, Mooren's ulcer,
`
`corneal ulcer subsequent to chronic rheumatoid
`
`15
`
`arthritis or collagen disease, Terrien's margine
`
`degeneration, catarrhal corneal ulcer, infectious
`
`corneal ulcer and the like), vitamin A insufficiency(cid:173)
`
`induced keratomalacia, necrotic keratitis,
`
`neuroparalytic keratitis, diabetic keratophathy,
`
`20
`
`keratoconjunctiva sicca, contact lens-induced
`
`keratoconjunctivitis, vernal conjunctivitis, allergic
`
`conjunctivitis, uveitis, Behcet's syndrome,
`
`inflammation after cataract surgery and pseudopterygium,
`
`especially a keratoconjunctival inflammatory disease
`
`25
`
`(for example, corneal herpes, bacterial keratitis,
`
`------·----------
`
`Metrics EX1043, Page 13
`
`

`
`CA 02383971 2002-03-05
`
`11
`
`bacterial conjunctivitis, mycotic keratitis,
`
`acanthamebic keratitis, corneal trauma, alkaline
`
`erosive keratoconjunctivitis, corneal ulcer, vitamin A
`
`insufficiency-induced keratomalacia, necrotic keratitis,
`
`5
`
`neuroparalytic keratitis, diabetic keratophathy,
`
`keratoconjunctiva sicca, contact lens-induced
`
`keratoconjunctivitis, vernal conjunctivitis, allergic
`
`conjunctivitis and the like) .
`
`It is useful also for
`
`preventing and treating corneal ulcer (including
`
`10
`
`various corneal ulcers described above and those
`
`induced otherwise), especially infectious corneal ulcer.
`
`The prophylactic and therapeutic medicam.ent for
`
`ophthalmic diseases according to the present invention
`
`can be mixed with a pharmacologically acceptable
`
`15
`
`carrier, excipient or diluent which is known per se and
`
`formulated by a method known per se into a
`
`pharmaceutical or a veterinary medicine in various oral
`
`or parenteral dosage forms such as tablets, capsules,
`
`granules, injection solutions, eye drops and ophthalmic
`
`20
`
`ointments, and it is especially preferred to be used in
`
`a local dosage form, preferably an eye drop formulation
`
`or an ophthalmic ointment.
`
`The eye drop formulation may for example be
`
`aqueous formulations such as aqueous eye drops, aqueous
`
`25
`
`suspension eye drops, viscous eye drops and solubilized
`
`---------···--~~·---
`
`Metrics EX1043, Page 14
`
`

`
`CA 02383971 2002-03-05
`
`12
`
`eye drops as well as non-aqueous formulations such as
`
`non-aqueous eye drops and non-aqueous suspension eye
`
`drops, with an aqueous formulation being preferred.
`
`One preferred especially is an aqueous suspension eye
`
`5
`
`drop formulation.
`
`The aqueous eye drop formulation may contain
`
`various additives incorporated ordinarily, such as
`
`buffering agents (e.g., phosphate buffers, borate
`
`buffers, citrate buffers, tartarate buffers, acetate
`
`10
`
`buffers, amino acids, sodium acetate, sodium citrate
`
`and the like), isotonicities (e.g., saccharides such as
`
`sorbitol, glucose and mannitol, polyhydric alcohols
`
`such as glycerin, concentrated glycerin, polyethylene
`
`glycol and propylene glycol, salts such as sodium
`
`15
`
`chloride), preservatives or antiseptics (e.g.,
`
`benzalkonium chloride, benzethonium chloride, p(cid:173)
`
`oxybenzoates such as methyl p-oxybenzoate or ethyl p(cid:173)
`
`oxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic
`
`acid or its salt, thimerosal, chlorobutanol and the
`
`20
`
`like), solubilizing aids or stabilizing agents (e.g.,
`
`cyclodextrins and their derivative, water-soluble
`
`polymers such as polyvinyl pyrrolidone, surfactants
`
`such as polysorbate 80 (Tween 80)), pH modifiers (e.g.,
`
`hydrochloric acid, acetic acid, phosphoric acid, sodium
`
`25
`
`hydroxide, potassium hydroxide, ammonium hydroxide and
`
`Metrics EX1043, Page 15
`
`

`
`CA 02383971 2002-03-05
`
`13
`
`the like), thickening agents (e.g., hydroxyethyl
`
`cellulose, hydroxypropyl cellulose, methyl cellulose,
`
`hydroxypropylmethyl cellulose, carboxymethyl cellulose
`
`and their salts), chelating agents (e.g., sodium
`
`5
`
`edetate, sodium citrate, condensed sodium phosphate)
`
`and the like.
`
`The eye drop formulation in the form of an aqueous
`
`suspension may also contain suspending agents (e.g.,
`
`polyvinyl pyrrolidone, glycerin monostearate) and
`
`10
`
`dispersing agents (e.g., surfactants such as tyloxapol
`
`and polysorbate 80, ionic polymers such as sodium
`
`alginate) in addition to the additives listed above,
`
`whereby ensuring that the eye drop formulation is a
`
`further uniform microparticulate and satisfactorily
`
`15
`
`dispersed aqueous suspension.
`
`When the eye drop formulation in the form of an
`
`aqueous suspension is produced, it is preferable to use
`
`a pH modifier to make the formulation acidic pH (pH4 to
`
`5.5). A preferred pH modifier is hydrochloric acid.
`
`20
`
`The eye drop formulation in the form of an aqueous
`
`suspension preferably contains sodium citrate or sodium
`
`acetate as a buffering agent, concentrated glycerin
`
`and/or propylene glycol as an isotonicity and polyvinyl
`
`pyrrolidone as a suspending agent. A preferred
`
`25
`
`dispersing agent is a surfactant and/or sodium alginate.
`
`Metrics EX1043, Page 16
`
`

`
`CA 02383971 2002-03-05
`
`14
`
`Such surfactant is preferably tyloxapol or polysorbate
`
`80.
`
`The ophthalmic ointment may employ an ointment
`
`base known per se, such as purified lanolin, petrolatum,
`
`5
`
`plastibase, liquid paraffin, polyethylene glycol and
`
`the like.
`
`The prophylactic and therapeutic medicament of the
`
`present invention may be administered to a mammal which
`
`is or may be suffered from an ophthalmic disease (e.g.,
`
`10
`
`human, rabbit, dog, cat, cattle, horse, monkey) . While
`
`the administration route and the dose may vary
`
`depending on a symptom, age and body weight of a
`
`subject, the concentration is about 0.001 to 5 (w/v) %,
`
`preferably about 0.01 to 3 (w/v) % as a free form of a
`
`15
`
`compound of Formula (I) contained in an aqueous eye
`
`drop formulation when given to an adult, and is given
`
`preferably 1 to 8 times a day with a single dose being
`
`one to several drops.
`
`When given as the ophthalmic ointment, the dose is
`
`20
`
`about 0.001 to 5 (w/v) %, preferably about 0.01 to 3
`
`(w/v) %as a free form of a compound of Formula (I),
`
`and is given preferably 1 to 4 times a day as
`
`appropriate in view of the symptom.
`
`Unless the intended purpose of use is affected
`
`25
`
`adversely, the prophylactic and therapeutic medicament
`
`··------·----
`
`Metrics EX1043, Page 17
`
`

`
`CA 02383971 2002-03-05
`
`15
`
`of the present invention may contain or may be used
`
`together with other appropriate pharmacologically
`
`effective substances, for example, steroidal anti(cid:173)
`
`inflammatory agents (dexamethasone, prednisolone and
`
`5
`
`the like), non-steroidal anti-inflammatory agents
`
`(diclofenac sodium, pranoprofen and the like),
`
`antiallergic agents (tranilast, ketotifen fumarate,
`
`sodium cromoglicate and the like), antihistamic agents
`
`(diphenhydramine hydrochloride and the like), glaucoma-
`
`10
`
`treating agents (pilocarpine hydrochloride,
`
`physostigmine salicylate, timolol, isopropylunoprostone
`
`and the like), antibiotics (gentamycin sulfate,
`
`fradiomycin sulfate, tobramycin, sulbenicillin,
`
`cefmenoxime, erythromycin, colistin, oxytetracycline,
`
`15
`
`polymyxin B, chloramphenicol, micronomicin, dibekacin,
`
`sisomicin and the like), antibacterial agents
`
`(sulfamethizole, sulfamethoxazole, ofloxacin,
`
`norfloxacin, lomefloxacin hydrochloride, enoxacin,
`
`ciprofloxacin hydrochloride, cinoxacin, sparfloxacin,
`
`20
`
`tosufloxacin tosylate, nalidixic acid, pipemidic acid
`
`trihydrate, pipemidic acid, fleroxacin, levofloxacin
`
`and the like), and antiviral agents (idoxuridine,
`
`acyclovir and the like), and antimycotic agents
`
`(pimaricin, fluconazole, miconazole, amphotericin B,
`
`25
`
`flucytosine, itraconazole and the like).
`
`-------·-- --·-------------···--·----
`
`Metrics EX1043, Page 18
`
`

`
`CA 02383971 2002-03-05
`
`16
`
`The prophylactic and therapeutic medicament of the
`
`present invention is used preferably together with at
`
`least one selected from the antibiotic, antibacterial,
`
`antiviral and antimycotic agents listed above in
`
`5
`
`prophylaxis or therapy especially for an ophthalmic
`
`infection-induced inflammation or corneal ulcer.
`
`In
`
`such case, any of the antibiotic, antibacterial,
`
`antiviral and antimycotic agents can be combined with
`
`the prophylactic and therapeutic medicament of the
`
`10
`
`present invention in a single formulation, or may be
`
`instilled separately. When being instilled separately,
`
`the prophylactic and therapeutic medicament of the
`
`present invention may be instilled simultaneously with
`
`any of the antibiotic, antibacterial, antiviral and
`
`15
`
`antimycotic agents, or successively at a certain
`
`interval. When being instilled simultaneously, any of
`
`the prophylactic and therapeutic medicament of the
`
`present invention and the antibiotic, antibacterial,
`
`antiviral and antimycotic agents is first instilled and
`
`20
`
`then preferably after a certain time period another
`
`agent is instilled whereby avoiding any escape of the
`
`agent given previously. Any of the antibiotic,
`
`antibacterial, antiviral and antimycotic agents listed
`
`above may also be given systemically by means of an
`
`25
`
`oral or intravenous formulation.
`
`------·-----------~---·--
`
`Metrics EX1043, Page 19
`
`

`
`CA 02383971 2002-03-05
`
`17
`
`The present invention is further illustrated in
`
`detail by the following Experiments and Examples, which
`
`are not construed to limit the scope of the present
`
`invention.
`
`5
`
`EXPERIMENT 1
`
`The effect of Compound A on an ophthalmic
`
`inflammatory disease was investigated as described
`
`below.
`
`10
`
`The effect of Compound A when given as eye drops
`
`was investigated in a rabbit keratitis model using an
`
`endotoxin derived from Pseudomonas aeruginosa detected
`
`frequently in an ophthalmic infection as well as in a
`
`rabbit corneal alkaline erosion model.
`
`15
`
`MATERIALS AND METHODS
`
`(1) Animals
`
`Male Japanese albino rabbits each weighing about 2
`
`to 2.5 kg purchased from FUKUZAKI rabbit-raising
`
`association were used. Each animal was maintained at a
`
`20
`
`temperature of 24 ± 4°C and a humidity of 55± 15 %.
`
`(2) Test substances
`
`Compound A was given as a 1.0 % Compound A eye
`
`drop formulation prepared by suspending Compound A in a
`
`formulation base (0.1 % NaH2P04, 0.1 % polysorbate 80
`
`25
`
`and 0.9 % NaCl, pH 5.0). As a positive control, a
`
`Metrics EX1043, Page 20
`
`

`
`CA 02383971 2002-03-05
`
`18
`
`0.1 % betamethasone eye drop formulation (Rinderon~
`
`solution, Sionogi) was used.
`
`In a control group, the
`
`formulation base was given.
`
`(3) Methods
`
`5
`
`1) Effect on endotoxin-induced keratitis
`
`16 Male Japanese albino rabbits each weighing 2 to
`
`2.5 kg were used. The rabbits were divided into four
`
`groups each having 4 animals, which were anesthetized
`
`systemically by an intramuscular administration each of
`
`10
`
`1 ml/kg of an equal volume mixture of 5 % ketamine
`
`hydrochloride and 2 % xylazine hydrochloride. Each 10
`
`~1 of a 1 % solution of Pseudomonas aeruginosa-derived
`
`endotoxin in physiological saline was infused into each
`
`corneal stroma of a rabbit. An anterior part of an eye
`
`15
`
`was observed using a slit lamp every 5 days over a
`
`period from the day after the endotoxin infusion
`
`through the 30th day, and examined for the corneal
`
`opacity, the corneal ulcer and the vascularization,
`
`which were scored in accordance with the criteria shown
`
`20
`
`in Table 1. Each test substance was started to be
`
`instilled immediately after the endotoxin infusion, and
`
`then given 4 times a day in the volume of 20 ~1 every 2
`
`hours.
`
`2) Effects on alkaline erosive keratitis
`
`25
`
`16 Male Japanese albino rabbits each weighing 2 to
`
`---· ·--·--·--···--·-------·-------
`
`--------------
`
`Metrics EX1043, Page 21
`
`

`
`CA 02383971 2002-03-05
`
`19
`
`2.5 kg were used. The rabbits were divided into four
`
`groups each having 4 animals, which were anesthetized
`
`systemically by an intramuscular administration each of
`
`1 ml/kg of an equal volume mixture of 5 % ketamine
`
`5
`
`hydrochloride and 2 % xylazine hydrochloride and also
`
`locally by an instillation of oxybuprocaine
`
`hydrochloride. A filter paper whose diameter was 10 mm
`
`and which had been immersed in 2N NaOH was brought into
`
`contact with the center of the right cornea of a rabbit
`
`10
`
`for 1 minute to establish an alkaline erosion, and then
`
`the eye was rinsed immediately with 10 mL or more of
`
`physiological saline. The depth of the corneal ulcer
`
`and the vascularization were observed using a slit lamp
`
`every 5 days over a pe_riod from 5 days after the
`
`15
`
`alkaline erosion through the 30th day, and scored in
`
`accordance with the criteria shown in Table 1. Each
`
`test substance was started to be instilled immediately
`
`after the alkaline erosion, and then given 4 times a
`
`day in the volume of 20 ~1 every 2 hours.
`
`20
`
`Table 1
`
`Rabbit keratitis scoring criteria
`* Corneal opaci tyremarko 11
`
`A) Degree
`
`0: No opacity
`
`25
`
`1: Mild opacity but distinguishable anterior chamber
`
`-------------·---·--···------------------
`
`Metrics EX1043, Page 22
`
`

`
`CA 02383971 2002-03-05
`
`20
`
`2: Difficulty in distinguishing details of iris
`
`3: Almost no transparency in anterior chamber
`
`B) Corresponding size of corneal region
`
`1: 1/3 or less of entire
`
`5
`
`2: 1/3 to 2/3 of entire
`
`3: 2/3 or more of entire
`
`* Corneal ulcer
`O: No corneal ulcer
`
`1: Ulcer of less than 1/3 in depth from corneal surface
`
`10
`
`toward inside of anterior chamber
`
`2: Ulcer of 1/3 or more and less than 2/3 in depth from
`
`corneal surface toward inside of anterior chamber
`
`3: Ulcer of 2/3 or more in depth from corneal surface
`
`toward inside of anterior chamber
`
`15
`
`4: Perforation in cornea
`* Vascularizationremarko 11
`
`A) Length
`
`0: No vascularization into cornea
`
`1: Less than 1/3 from corneal limbus through center
`
`20
`
`2: Less than 2/3 from corneal limbus through center
`
`3: 2/3 or more from corneal limbus through center
`
`B) Region
`
`0.5: Less than 1/3 of corneal circumference
`
`1: 1/3 or more and less than 2/3 of corneal
`
`25
`
`circumference
`
`Metrics EX1043, Page 23
`
`

`
`CA 02383971 2002-03-05
`
`21
`
`2: 2/3 or more of corneal circumference
`
`Remarks 1) Each as score A x score B
`
`RESULTS AND DISCUSSION
`
`5
`
`1) Effects on endotoxin-induced keratitis
`
`Figs. 1 to 3 show the change in the keratitis
`
`symptoms over a period from 5 to 30 days after the
`
`endotoxin infusion.
`
`In the control group, the severity
`
`of each symptom peaked on the 15th day, and then a
`
`10
`
`gradual recovery was observed until the 30th day when
`
`almost all disappeared.
`
`In Compound A instillation
`
`group, inhibitory effects were observed on all of the
`
`evaluation items, i.e., the corneal opacity, the
`
`corneal ulcer and the vascularization, when compared
`
`15
`
`with the control group.
`
`In the 0.1 % betamethasone
`
`phosphate instillation group used as the positive
`
`control, the onset of the keratitis was inhibited
`
`almost completely over the observation period. Fig. 4
`
`shows the total score in each group on the 15th day
`
`20
`
`when the severity of each symptom peaked, and revealed
`
`that the % inhibition in the Compound A instillation
`
`group when compared with the control group was 59.4 %,
`
`with a statistically significant difference.
`
`Based on the results described above, the Compound
`
`25
`
`A eye drop formulation was proven to be effective
`
`- - - - - - - - - - c•••·~-·----· - - - - - - - - - - - - - - -
`
`Metrics EX1043, Page 24
`
`

`
`CA 02383971 2002-03-05
`
`22
`
`against various symptoms of the keratitis during an
`
`ophthalmic infection.
`
`While betamethasone phosphate used here as a
`
`positive control exhibited an extremely potent anti-
`
`S
`
`inflammatory activity, its use is limited frequently in
`
`view of a side effect experienced as the exacerbation
`
`of an infection over a prolonged therapy with a steroid
`
`in a clinical case of the ophthalmic infections.
`
`Accordingly, the Compound A eye drop formulation
`
`10
`
`expected to have a less risk of the exacerbation of an
`
`infection can serve as a hopeful agent against the
`
`ophthalmic infections.
`
`2) Effects on alkaline erosive keratitis
`
`Figs. 5 to 7 show the change in the keratitis
`
`15
`
`symptoms over a period from 5 to 30 days after the
`
`corneal alkaline exposure.
`
`In the control group, the
`
`severity peaked on the 20 to 25th day after the corneal
`
`alkaline exposure.
`
`In Compound A instillation group, a
`
`significant inhibitory effect on the corneal ulcer was
`
`20
`
`observed on the 20th day, but no effects were noted on
`
`the vascularization or the corneal opacity.
`
`In the
`
`0.1 % betamethasone phosphate instillation group used
`
`as the positive control, a significant inhibitory
`
`effect was observed on the vascularization on the 15th
`
`25
`
`day.
`
`Metrics EX1043, Page 25
`
`

`
`26456-233
`
`CA 02383971 2002-03-05
`
`23
`
`EXPERIMENT 2
`
`MATERIALS AND METHODS
`
`(1) Animals
`
`5
`
`Male Japanese albino rabbits each weighing about 2
`kg purchased from KITAYAMA LABES co., LTD. were used.
`
`Each animal was maintained at a temperature of 23 ± 3°C
`
`and a humidity of 55 ± 10 %.
`
`(2) Test substances
`
`10
`
`Compound A was given as a 1.0 % Compound A eye
`
`drop formulation prepared by suspending Compound A in a
`
`formulation base (0.1 % sodium acetate, 0.1 %
`
`polysorbate 80 and 0.9 % NaCl, pH 5.0). A 0.3 %
`
`lomefloxacin (LFLX) hydrochlorid

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