Note: Descriptions are shown in the official language in which they were submitted.
87383532
DESCRIPTION
Title of the Invention: COMBINATIONS COMPRISING A SULFONAMIDE
COMPOUND FOR THE TREATMENT OF GLAUCOMA
OR OCULAR HYPERTENSION
This application is a division of Canadian Application
Serial No. 2,878,370, filed on July 11, 2013, and claims
priority from Japanese Patent Application Serial
No. 2012-157204, filed on July 13, 2012.
Technical Field
The present invention relates to a preventive or
therapeutic agent for glaucoma or ocular hypertension, or an
intraocular pressure lowering agent comprising a combination
of isopropyl
(6-([4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)
aminomethyl)pyridin-2-ylamino)acetate with other preventive
or therapeutic drug for glaucoma or ocular hypertension.
Background Art
Glaucoma is an intractable ocular disease with a risk
of blindness, involving an increase in intraocular pressure
due to various predisposing factors and the disorder of
internal tissues of eyeballs (retina, an optic nerve, and the
like). A general method of treating glaucoma is intraocular
pressure lowering therapy, which is exemplified by
pharmacotherapy, laser therapy, surgical therapy, and the
like.
In the pharmacotherapy, a drug such as a sympa.thomimetic
drug (a nonselective stimulant such as dipivefrin or an
a2-receptoragonist such as brimonicline) , a sympatholytic drug
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(a13-receptor antagonist such as timolol, befunolol, carteolol,
nipradilol, betaxolol, levobunolol or metipranolol, or an
al-receptor antagonist such as bunazosin hydrochloride) , a
parasympathomimetic drug (such as pilocarpine) , a carbonic
= anhydrase inhibitor (such as a.cetazolamide) , a prostaglandin
(such as isopropyl unoprostone, latanoprost, travoprost or
bimatoprost) is used. Further, Rho-kinase inhibitors (such
as SNJ-1656) , adenosine agonists (such as INO-8875) , serotonin.
antagonists (VT-28949) , and the like have been under
development as novel drugs. Other than these, a prostaglandin
E2 receptor subtype 2 agonist (EP2 agonist) is known to have
an intraocular pressure lowering effect, and it is reported
in WO 2010/113957 (Patent Literature 1) that a sulfonamide
compound having high EP2 receptor selectivity and a potent EP2
agonistic activity is promising as a therapeutic drug for
glaucoma.
There are several reports of the combined use of drugs
having an intraocular pressure lowering effect to treat
glaucoma. For example, Japanese Patent No. 2726672 (Patent
Literature 2) reports the combined administration of a
sympatholytic drug with a prostaglandin. WO 2002/38158
(Patent Literature 3) discloses a method of treating glaucoma
by the combined administration of several drugs having an
intraocular pressure lowering effect to eyes. WO 2004/019951
(Patent Literature 4) reports the combined administration of
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a Rho-kinase inhibitor with a prostaglandin, and WO 2004/045644
(Patent Literature 5)reports the combined administration of
a Rho-kinase inhibitor with a 13-receptor antagonist.
However, there have been no reports specifically
disclosing a combination of isopropyl
(6-{ [4- (pyrazol-1-y1) benzyl] (pyridin-3-ylsulfonyl)
aminomethyl)pyridin-2-ylamino)acetate, which has a high EP2
receptor selectivity and a potent EP2 agonistic activity, with
other preventive or therapeutic drug for glaucoma or ocular
hypertension, and naturally, it has not been known at all as
to what effect of such a combination is exerted on the
intraocular pressure.
Patent Literature 1: WO 2010/113957
Patent Literature 2: Japanese Patent No. 2726672
Patent Literature 3: WO 2002/38158
Patent Literature 4: WO 2004/019951
Patent Literature 5: WO 2004/045644
Disclosure of Invention
Technical Problem
It is a very interesting subject to discover a
combination of preventive or therapeutic drugs for glaucoma
or ocular hypertension, which is useful as a preventive or
therapeutic agent for glaucoma or ocular hypertension.
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Solution to Problem
The present inventors made intensive studies on the
effect of a combination of preventive or therapeutic agents
for glaucoma or ocular hypertension, and as a result, they found
that by combining isopropyl
( 6 - { 4 - (pyrazol-1-y1 ) benzyl] (pyridin-3 -ylsulf onyl )
aminomethyllpyridin.-2-ylarnino) acetate with other preventive
or therapeutic agent for glaucoma or ocular hypertension, the
in.traocular pressure lowering effect is enhanced as compared
with the case where each agent is used singly, and thus
completed the invention. That is, the invention relates to
the following aspects.
(1) A preventive or therapeutic agent for glaucoma or
ocular hypertension, comprising a combination of isopropyl
( 6 - { [ 4- (pyraz o 1-1-yl ) benzyl] (pyridin- 3 -ylsulfonyl )
aminomethyl}pyridin-2-ylamino)acetate with one or more other
preventive or therapeutic drugs for glaucoma or ocular
hypertension (with the proviso that tafluprost is excluded) .
(2) An intraocular pressure lowering agent, comprising
a combination of isopropyl
( 6- { [ 4- (pyraz ol- 1-y1 ) ben.zyl I (pyridin- 3 -yl sul f onyl )
amin.omethyl}pyridin.-2-ylamino) acetate with one or more other
preventive or therapeutic drugs for glaucoma or ocular
hypertension(with the proviso that tafluprost is excluded) .
(3) The preventive or therapeutic agent or the
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intraocular pressure lowering agent according to the above (1)
or (2)., wherein the other preventive or therapeutic drug for
glaucoma or ocular hypertension(with the proviso that
tafluprost is excluded) is one or more preventive or
therapeutic agents selected from the group consisting of a
= nonselective sympathomimetic drug, an 0:2-receptor agonist, an
al-receptor antagonist, a 0-receptor antagonist, a
parasympathomimetic drug, a carbonic anhydrase inhibitor, a
prostaglandin and a Rho-kinase inhibitor.
(4) The preventive or therapeutic agent or the
intraocular pressure lowering agent according to the above (3) ,
wherein the nonselective sympathomirnetic drug is dipivefrin.
(5) The preventive or therapeutic agent or the
intraocular pressure lowering agent according to the above (3)
or (4), wherein the a2-receptor agonist is brimonidine or
apraclonidine.
(6) The preventive or therapeutic agent or the
intraocular pressure lowering agent according to any one of
the above (3) to (5), wherein the al-receptor antagonist is
bunazosin..
(7) The preventive or therapeutic agent or the
intraocular pressure lowering agent according to any one of
the above (3) to (6), wherein the I3-receptor antagonist is
timolol, befunolol, carteolol, nipradilol, betaxolol,
levobunolol or metipranolol.
Date Recue/Date Received 2020-11-16
87383532
(8) The preventive or therapeutic agent or the
intraocular pressure lowering agent according to any one of
the above (3) to (7), wherein the parasympathomimetic drug is
pilocarpine.
(9) The preventive or therapeutic agent or the
intraocular pressure lowering agent according to any one of
the above (3) to (8) , wherein the carbonic anhydrase inhibitor
is dorzolamide, brinzolamide or acetazolamide.
(10) The preventive or therapeutic agent or the
intraocular pressure lowering agent according to any one of
the above (3) to (9), wherein the prostaglandin is isopropyl
unoprostone, latanoprost, travoprost or bimatoprost.
(11) The preventive or therapeutic agent or the
intraocular pressure lowering agent according to any one of
the above (3) to (10), wherein the Rho-kinase inhibitor is
(R)-trans-N-(pyridin-4-y1)-4-(1-aminoethyl)
cyclohexanecarboxamide,
(R) ( ) -N-
(1H-pyrrolo [ 2,3 -b] pyridin-4-y1 ) -4- (1-aminoethyl )
-benz amide , 1- ( 5 - is oquinol inesul f onyl ) homopipera.zine or
1- ( 5 s oquinolinesul f onyl ) -2 -methylp ipera z ine
Incidentally, from the above-described respective
configurations (1) to (11), one or more configurations can be
arbitrarily selected and combined.
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87383532
The present invention as claimed relates to:
- use of a pharmaceutical composition for the prevention
or treatment of glaucoma or ocular hypertension, wherein the
composition comprises a combination of isopropyl (6-{[4-
(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyllpyridin-
2-ylamino)acetate with brimonidine; and
- use of a pharmaceutical composition to lower intraocular
pressure, wherein the composition comprises a combination of
isopropyl (6-{[4-(pyrazol-1-y1)benzyl](pyridin-3-
ylsulfonyl)aminomethyllpyridin-2-ylamino)acetate with
brimonidine.
Herein after in the specification, "the other preventative
or therapeutic drugs for glaucoma or ocular hypertension" means
"the
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other preventive or therapeutic drugs for glaucoma or ocular
hypertension except for tafluprost"
Advantageous Effects of Invention
By the combined administration of isopropyl
(6-{[4-(pyrazol-1-ya)benzyl](pyridin-3-ylsulfonyl)
aminomethyl)pyridin-2-ylamino)acetate with one or more other
preventive or therapeutic drug for glaucoma or ocular
hypertension to eyes, the intraocular pressure lowering effect
is enhanced. Therefore, the invention is useful as a
preventive or therapeutic agent for glaucoma or ocular
hypertension or an intraocular pressure lowering agent.
Description of Embodiments
The invention is directed to a preventive or therapeutic
agent for glaucoma or ocular hypertension or an intraocular
pressure lowering agent, comprising a combination of isopropyl
( 6- { [4- (pyrazol-1-yl)benzyl] (pyridin-3 -ylsulfonyl)
aminomethyl Ipyridin-2-ylamino) acetate (hereinafter also
referred to as "present compound") represented by the following
formula (1) with one or more other preventive or therapeutic
drugs for glaucoma or ocular hypertension, where these drugs
complement and/or enhance their intraocular pressure lowering
effects each other.
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PN
011 0 (1)
NNLO
The present compound in the invention can be synthesized
by the method described in WO 2009/113600 or WO 2010/113957.
The invention is characterized in that glaucoma or ocular
hypertension is prevented or treated by administering a
combination of the present compound with other preventive or
therapeutic drug for glaucoma or ocular hypertension.
Glaucoma in the invention includes primary open angle glaucoma,
normal tension glaucoma, hypersecretion glaucoma, ocular
hypertension, acute angle-closure glaucoma, chronic
angle-closure glaucoma, combined-mechanism glaucoma,
steroid-induced glaucoma, amyloid glaucoma, neovascular
glaucoma/ malignant glaucoma, capsular glaucoma, plateau iris
syndrome and the like.
In the invention, the combination of the present compound
with one or more other preventive or therapeutic drugs for
glaucoma or ocular hypertension is preferably a combination
of the present compound with one to three other preventive or
therapeutic drugs for glaucoma or ocular hypertension, and more
preferably a combination of the present compound with one or
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two other preventive or therapeutic drugs for glaucoma or
ocular hypertension.
The other preventive or therapeutic drug for glaucoma
or ocular hypertension in the invention may be any as long as
the drug has an intraocular pressure lowering effect and is
useful for treating glaucoma, and examples thereof include a
nonselective sympathomimetic drug, an a2-receptor agonist, an
al-receptor antagonist, a 0-receptor antagonist, a
parasympathomimetic drug, a carbonic anhydrase inhibitor, a
prostaglandin, a Rho-kinase inhibitor and the like. In the
case where the present compound is combined with two other
preventive or therapeutic drugs for glaucoma or ocular
hypertension, the two other preventive or therapeutic drugs
for glaucoma or ocular hypertension are preferably two
preventive or therapeutic agents selected from the group
consisting of a 13-receptor antagonist, a carbonic anhydrase
inhibitor and a prostaglandin, and more preferably a 0-receptor
antagonist and a carbonic anhydrase inhibitor, or a 0-receptor
antagonist and a prostaglandin.
Specific examples of the nonselective sympathomimetic
drug include dipivefrin. Specific examples of the Cc2-receptor
agonist include brimonidine and apraclonidine. Specific
examples of the al-receptor antagonist include, bunazosin.
Specific examples of the 0-receptor antagonist include timolol,
befunolol, carteolol, nipradilol, betaxolol, levobunolol and
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metipranolol. Specific examples of the parasympathomimetic
drug include pilocarpine. Specific examples of the carbonic
anhydrase inhibitor include dorzolamide, brin.zolamide and
acetazolamide.
Specific examples of the prostaglandin include
prostaglandins disclosed in JP-A-59-1418 (particularly, a
natural prostaglandin such as prostaglandin F2a) ,
prostaglandins such as latanoprost disclosed in JP-T-3-501025,
prostaglandins such as isopropyl unoprostone disclosed in
JP-A-2-108, prostaglandins such as bimatoprost disclosed in
JP-T-8-501310, prostaglandins such as travoprost disclosed in
JP-A-10-182465, prostaglandins such as AL-6598 disclosed in
Sury Opthalmol 47 (Suppl 1) : S13-S33, 2002, and prostaglandins
such as PF-04475270 disclosed in Exp Eye Res . 89: 608-17, 2009.
Among these, the prostaglandin is preferably PGF2a or a PGF2a
derivative, more preferably isopropyl unoprostone,
latanoprost, travoprost or bimatoprost.
The Rho-kinase inhibitor in the invention refers to a
compound which inhibits serine/threonine kinase activated
with the activation of Rho. Examples of such a compound include
compounds which inhibit ROKa (ROCK-II), pl60ROCK (ROK13,
ROCK-I) or other proteins having a serine/threonine kinase
activity. Specific examples of the Rho-kinase inhibitor
include Rho-kinase inhibitors such as
(R) -trans-N- (pyridin-4-y1) -4- (1-aminoethyl)
Date Recue/Date Received 2020-11-16
cyclohexanecarboxamide and
(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-y1)-4-(1-aminoethyl)
benzamide disclosed in WO 98/06433 and WO 00/09162, Rho-kinase
inhibitors such as 1-(5-isoquinolinesulfonyl)homopiperazine
and 1- (5-isoquinolinesulfonyl) -2-methylpiperazine disclosed
in WO 97/23222 and Nature, 389, 990-994 (1997), Rho-kinase
inhibitors such as
(1-benzylpyrrolidin-3-y1)-(1H-indazol-5-yl)amine disclosed
in WO 01/56988, Rho-kinase inhibitors such as
(1-benzylpiperidin-4-y1)-(115-indazol-5-yl)amine disclosed
in WO 02/100833, Rho-kinase inhibitors such as
N-12-(4-fluoropheny1)-6,7-dimethoxy-4-quinazoliny1]-N-(1H-
indazol-5-yl)amine disclosed in WO 02/076976, Rho-kinase
inhibitors such as
N-4-(1H-indazol-5-y1)-6,7-dimethoxy-N-2-pyridin-4-y1
-quinazolin-2,4-diamine disclosed in WO 02/076977,- and
Rho-kinase inhibitors such as
4-methy1-5-(2-methyl-[1,4]diazepan-1-sulfonyl)isoquinoline
disclosed in WO 99/64011. Among these, particularly,
(R)-trans-N-(pyridin-4-ya)-4-(1-aminoethyl)
cyclohexanecarboxamide,
(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-y1)-4-(1-aminoethyl)
benzamide, 1-(5-isoquinolinesulfonyl)homopiperazine or
1-(5-isoquinolinesulfony1)-2-methylpiperazine is preferred.
In the case where the present compound is combined with
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two other preventive or therapeutic drugs for glaucoma or
ocular hypertension, specific examples of the two other
preventive or therapeutic drugs for glaucoma or ocular
hypertension _include timolol and dorzolamide, timolol and
latanoprost, and timolol and travoprost.
= The present compound and the other preventive or
therapeutic drug for glaucoma or ocular hypertension in the
invention include salts thereof. Such a salt is not
particularly limited as long as it is a pharmaceutically
acceptable salt, and examples of the salt include a salt with
an inorganic acid, a salt with an organic acid, a quaternary
ammonium salt, a salt with a halogen ion, a salt with an alkali
metal, a salt with an alkaline earth metal, a metal salt, a
salt with ammonia, and a salt with an organic amine. Examples
of the salt with an inorganic acid include salts with
hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric
acid, sulfuric acid, phosphoric acid or the like. Examples
of the salt with an organic acid include salts with acetic acid,
oxalic acid, fumaric acid, maleic acid, succinic acid, citric
acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic
acid, glucuronic acid, terephthalic acid, methanesulfonic
acid, lactic acid, hippuric acid, 1, 2-ethanedisulfonic acid,
isethionic acid, lactobionic acid, oleic acid, pamoic acid,
polygalacturon.ic acid, stearic acid, tannic acid,
trifluorometha_nesulfonic acid, benzenesulfonic acid,
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p-toluenesulfonic acid, lauryl sulfate, methyl sulfate,
napthalenesulfon.ic acid, sulfosalicylic acid or the like.
Examples of the quaternary ammonium salt include salts with
methyl bromide, methyl iodide or the like. Examples of the
salt with a halogen ion include salts with a chloride ion, a
bromide ion, an iodide ion or the like. Examples of the salt
with an alkali metal include salts with lithium, sodium,
potassium or the like. Examples of the salt with an alkaline
earth metal include salts with calcium, magnesium or the like.
Examples of the metal salt include salts with iron, zinc or
the like. Examples of the salt with an organic amine include
salts with triethylenediamine, 2-aminoethanol,
2, 2- iminobis ( ethanol) , 1-deoxy- 1- (methyl amino ) -2 -D-s o rbi t ol ,
2 -amino-2 - (hydroxymethyl ) -1, 3 -propanediol, procaine,
N, N-bis (phenylmethyl) -1, 2 -ethanediamine or the like.
In addition, the present compound and the other
preventive or therapeutic drug for glaucoma or ocular
hypertension in the invention also include derivatives thereof
such as an ester and an amide. Specific examples of the ester
include esters obtained by condensation of a hydroxyl group
in the other preventive or therapeutic drug for glaucoma or
ocular hypertension with a carboxylic acid such as acetic acid,
propionic acid, isopropionic acid, butyric acid, isobutyric
acid or pivalic acid, and esters obtained by condensation of
a carboxyl group in the other preventive or therapeutic drug
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for glaucoma or ocular hypertension with an alcohol such as
methanol, ethanol, propanol or isopropyl alcohol. Specific
examples of the amide include amides obtained by condensation
of an amino group in the present compound and/or the other
preventive or therapeutic drug for glaucoma or ocular
hypertension with a carboxylic acid such as acetic acid,
propionic acid, isopropionic acid, butyric acid, isobutyric
acid or pivalic acid, and amides obtained by condensation of
a carboxyl group in the other preventive or therapeutic drug
for glaucoma or ocular hypertension with an amine such as
methylamine, ethylamine, propylamine or isopropylamine.
Further, the present compound and the other preventive
or therapeutic drug for glaucoma or ocular hypertension in the
invention may be in the form of a hydrate or a solvate.
As the administration form, the present compound and the
other preventive or therapeutic drug for glaucoma or ocular
hypertension may be administered in the form of a plurality
=
of preparations obtained by separately formulating the
respective components (concomitant administration) , and also,
the respective components may be administered in the form of
one preparation obtained by mixing the respective components
(combination drug) . The case of the combination drug is
preferred. Further, in the case where the present compound
is combined, with a plurality of the other preventive or
therapeutic drugs for glaucoma or ocular hypertension, the
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Date Recue/Date Received 2020-11-16
respective components may be concomitantly administered, or
a combination drug obtained by mixing arbitrary components
among the present compound and the other preventive or
therapeutic drugs for glaucoma or ocular hypertension and the
remaining component (s) maybe concomitantly administered, or
a combination drug obtained by mixing all of the components
may be formed.
The preparation of the invention can be administered
orally or parenterally. The formulation of the preparation
does not require a special technique, and can be achieved using
a widely used technique. Examples of the dosage form include
an eye drop, an ophthalmic ointment, an injection, a tablet,
a capsule, a granule and a powder, and an eye drop or an
ophthalmic ointment is preferred.
In the case where the present compound and the other
preventive or therapeutic drug for glaucoma or ocular
hypertension are separately formulated, the respective
preparations can be prepared according to a known method. For
example, the preparation of the present compound can be
prepared with reference to the Preparation Example described
in WO 2009/113600 or WO 2010/113957. As the preparation of
the other preventive or therapeutic drug for glaucoma or ocular
hypertension, a preparation which has already been
commercially available such as dipivefrin, brimonidine,
apraclonidine, bunazosin, timolol, befunolol, carteolol,
Date Recue/Date Received 2020-11-16
nipradilol, betaxolol, levobunolol, metipranolol,
pilocarpine, dorzolamide, brinzolamide, acetazolamide,
isopropyl unoprostone, latanoprost, travoprost, bimatoprost,
COSOPT (registered trademark) combination ophthalmic solution,
Xalacom (registered trademark) combination ophthalmic
solution, or DuoTray (registered trademark) combination
ophthalmic solution, or a preparation similar thereto can also
be used. The preparation of a Rho-kinase inhibitor can be
prepared with reference to the Preparation Example described
in the above-described WO 00/09162, WO 97/23222 or the like.
In the case where a single preparation comprising an
arbitrary combination among the present compound and a
preventive or therapeutic drug for glaucoma or ocular
= hypertension is prepared, the preparation can be carried out
in accordance with a known method.
In the case where an eye drop is prepared, by adding the
present compound or the other preventive or therapeutic drug
for glaucoma or ocular hypertension to purified water, a buffer
or the like, followed by stirring, and then, adjusting the pH
of the resulting mixture with a pH adjusting agent, whereby
a desired eye drop can be prepared. Further, if necessary,
a widely used additive can be used in the eye drop, and examples
of the additive include a tonicity agent, a buffer, a surfactant,
a stabilizer and a preservative. Examples of the tonicity
agent include sodium chloride and concentrated glycerin.
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Examples of the buffer include sodium phosphate, sodium acetate,
boric acid, borax and citric acid. Examples of the surfactant
include polyoxyethylene sorbitan monooleate, polyoxyl
stearate and. polyoxyethylene hydrogenated castor oil.
Examples of the stabilizer include sodium citrate and disodium
edeta.te. Examples of the preservative include benzalkoniurn
chloride and paraben.
Any pH of the eye drop is permitted as long as it falls
within the range that is acceptable for an ophthalmic
preparation, but is preferably in the range of from 4 to, 8,
more preferably in the range of from 5 to 7.
=
In the case where an ophthalmic ointment is prepared,
the preparation can be carried out using a widely used base.
Examples of the base include white petrolatum and liquid
paraffin.
In the case where an oral preparation such as a tablet,
a capsule, a granule or a powder is prepared, the preparation
can be carried out by adding an extender, a. lubricant, a binder,
a disintegrant, a coating agent or a film forming agent as
needed. Examples of the extender include lactose, crystalline
cellulose, starch and a vegetable oil. Examples of the
lubricant include magnesium stearate and talc. Examples of
the binder include hydroxypropyl cellulose and
polyvinylpyrrolidone. Examples of the disintegra.nt include
carboxyrnethyl cellulose calcium and low-substituted
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hydroxypropylmethyl cellulose. Examples of the coating agent
include hydroxypropylmethyl cellulose, macrogol and a
silicone resin. Examples of the film forming agent include
a gelatin film.
The dose of the present compound and the other preventive
or therapeutic drug for glaucoma or ocular hypertension can
be appropriately changed depending on the dosage form, severity
of symptoms, age or body weight of the patient to which the
present compound or the drug is to be administered,
administration route, medical opinion or the like.
Hereinafter, the case of instillation administration will be
mainly described as an example.
As for the dose of the present compound, in the case of
an eye drop, the present compound can be generally administered
once or several times per day at a daily dose of from 0.05 to
500 pg, which can be appropriately increased or decreased
depending on the age or symptoms of the patient or the like.
The concentration of the present compound in the eye drop is
not particularly limited, but an eye drop containing the
present compound at a concentration of from 0.00001 to 3 w/v%,
preferably from 0.0001 to 1 w/v%, more preferably from 0.001
to 0.1 w/v%, further more preferably from 0.003 to 0.03 w/v%
can be instilled once or several times per day. Incidentally,
the concentration of the present compound in an eye drop may
be calculated on the basis of the weight of the present compound
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either in a free form or in the form of a salt (hereinafter,
the same shall apply) Further, in the case of an ophthalmic
ointment, the present compound can be generally administered
once or several times at a daily dose of generally from 0.0001
to 30 mg, preferably from 0.0003 to 10 mg, more preferably from
0.001 to 3 mg, further more preferably from 0.003 to 1 mg.
The dose of the nonselective sympathomimetic drug varies
depending on the type of the drug, but it can be administered
once or several times per day at a daily dose of generally from
1 to 5000 p.g. More specifically, in the case of dipivefrin.,
a daily dose of from 2 to 3000 1.tg is generally used, and such
a dose can be appropriately increased or decreased depending
on the age or symptoms of the patient or the like. Also for
other nonselective sympathomimetic drugs, the dose thereof can
be determined on the basis of the same criteria. The
concentration of the nonselective sympathomimetic drug in an
eye drop is not particularly limited, but in the case of
dipivefrin, an eye drop containing dipivefrin at a
concentration of from 0.001 to 3 w/v%, preferably from 0.04
to 0.1 w/v%, more preferably 0.04 w/v% or 0.1 w/v% can be
instilled once or several times per day.
The dose of the a2-receptor agonist varies depending on
the type of the drug, but it can be administered once or several
times per day at a daily dose of generally from 2 to 3000 gg.
More specifically, in the case of brimonidin.e, a daily dose
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of from 2 to 1000 jig is generally used and in the case of
apraclonidine, a daily dose of from 20 to 3000 pg is generally
used. Such a dose can be appropriately increased or decreased
depending on the age or symptoms of the patient or the like.
Also for other a2-receptor agonists, the dose thereof can be
determined on the basis of the same criteria. The
concentration of the a2-receptor agonist in an eye drop is not
particularly limited, but, in the case of brimonidine, an eye
= drop containing brimonidine at a concentration of from 0.01
to 5 w/v%, preferably from 0.1 to 0.5 w/v%, more preferably
0.1 w/v%, 0.15 w/v%, 0.2 w/v% or 0.5 w/v% can be instilled once
or several times per day. Further, in the case of apraclonidine,
an eye drop containing apraclonidine at a concentration of from
0.01 to 5 w/v%, preferably from 0.5 to 1 w/v%, more preferably
0.5 w/v% or 3. w/v% can be instilled once or several times per
day.
The dose of the al-receptor antagonist varies depending
on the type of the drug, but it can be administered once or
several times per day at a daily dose of generally from 1 to
5000 jig. More specifically, in the case of buna.zosin, a daily
dose of from 2 to 3000 jig is generally used, and such a dose
can be appropriately increased or decreased depending on the
age or symptoms of the patient or the like. Also for other
al-receptor antagonists, the dose thereof can be determined
on the basis of the same criteria. The concentration of the
Date Recue/Date Received .2020-11-16
al-receptor antagonist in an eye drop is not particularly
limited, but, in the case of bunazosin, an eye drop containing
bunazosin at a concentration of from 0.001 to 0.3 w/v%,
preferably from 0.003 to 0.03 w/v%, more preferably 0.01 w/v%
can be instilled once or several times per day.
The dose of the 3-receptor antagonist varies depending
on the type of the drug, but it can be administered once or
several times per day at a daily dose of generally from 5 to
5000 g. More specifically, in the case of timolol, a daily
dose of from 5 to 1500 jig is generally used, in the case of
befunolol, a daily dose of from 10 to 2000 g is generally used,
in the case of carteolol, a daily dose of from 10 to 5000 jig
is generally used, in the case of nipra.dilol, a daily dose of
from 10 to 1250 jig is generally used, in the case of betaxolol,
a daily dose of from 50 to 1000 jig is generally used, in the
case of levobunolol, a daily dose of from 5 to 5000 jig is
generally used, and in the case of metipranolol, a daily dose
of from 5 to 5000 jig is generally used. Such a dose can be
appropriately increased or decreased depending on the age or
symptoms of the patient or the like. Also for other P.-receptor
antagonists, the dose thereof can be determined on the basis
of the same criteria. The concentration of the 13-receptor
antagonist in an eye drop is not particularly limited, but,
in the case of timolol, an eye drop containing timolol at a
concentration of from 0.01 to 5 w/v%, preferably from 0.1 to
21
Date Recue/Date Received 2020-11-16
0.5 w/v%, more preferably 0.1 w/v%, 0.25 w/v% or 0.5 w/v% can
be instilled once or several times per day. Further, in the
case of befun.olol, an eye drop containing befunolol at a
concentration of from 0.01 to 5 w/v%, preferably from 0.25 to
1 w/v%, more preferably 0.25 w/v%, 0.5 w/v% or 1 w/v% can be
=
instilled once or several times per day. In the case of
carteolol, an eye drop containing carteolol at a concentration
of from 0.01 to 5 w/v%, preferably from 1 to 2 w/v%, more
preferably 1 w/v% or 2 w/v% can be instilled once or several
times per day. In the case of nipradilol, an eye drop
containing nipradilol at a concentration of from 0.01 to 5 w/v%,
preferably 0.25 w/v% can be instilled once or several times
per day. In the case of betaxolol, an eye drop containing
betaxolol at a concentration of from 0.01 to 5 w/v%, preferably
from 0.25 to 0.5 w/v%, more preferably 0.25 w/v% or 0.5 w/v%
can be instilled once or several times per day: In the case
of levabunolol, an eye drop containing levobunolol at a
concentration of from 0.01 to 5 w/v%, preferably from 0.25 to
0.5 w/v%, more preferably 0.25 w/v% or 0.5 w/v% can be instilled
once or several times per day. In the case of metipranolol,
an eye drop containing metipranolol at a concentration of from
0.01 to 5 w/v%, preferably 0.3 w/v% can be instilled once or
several times per day.
The dose of the para.sympa.thomimetic drug varies
depending on the type of the drug, but it can be administered
22
Date Recue/Date Received 2020-11-16
once or several times per day at a daily dose of generally from
to 300000 jig. More specifically, in the case of pilocarpine,
a daily dose of from 5 to 200000 jig is generally used, and such
a dose can be appropriately increased or decreased depending
on the age or symptoms of the patient or the like. Also for
other parasympathomimetic drugs, the dose thereof can be
determined on the basis of the same criteria. The
concentration of the parasympathomimetic drug in an eye drop
is not particularly limited, but, in the case of pilocarpine,
an eye drop containing pilocarpine at a concentration of from
0.01 to 20 w/v%, preferably from 0.1 to 5 w/v%, more preferably
0.5 w/v%, 1 w/v%, 2 w/v%, 3 w/v% or 4 w/v% can be instilled
once or several times per day.
The dose of the carbonic anhydrase inhibitor varies
depending on the type of the drug, but it can be administered
once or several times per day at a daily dose of generally from
to 10000 jig. More specifically, in the case of dorzolamide,
a daily dose of from 10 to 10000 jig is generally used and in
the case of brinzolamide, a daily dose of from 20 to 5000 jig
is generally used. Such a dose can be appropriately increased
or decreased depending on the age or symptoms of the patient
or the like. Also for other carbonic anhydrase inhibitors,
the dose thereof can be determined on the basis of the same
criteria. The concentration of the carbonic anhydrase
inhibitor in an eye drop is not particularly limited, but, in
23
Date Recue/Date Received 2020-11-16
the case of dorzolamide, an eye drop containing dorzolamide
at a concentration of from 0.01 to 5 w/v%, preferably from 0.5
to 2 w/v%, more preferably 0.5 w/v%, 1 w/v% or 2 w/v% can be
instilled once or several times per day. Further, in the case
of brinzolamide, an eye drop containing brinzolamide at a
concentration of from 0.01 to 5 w/v%, preferably from 0.1 to
2 w/v%, more preferably 1 w/v% can be instilled once or several
times per day. Further, in the case of acetazolamide, an eye
drop containing acetazolamide at a concentration of from 0.01
to 5 w/v%, preferably from 1 to 5 w/v% can be used. Incidentally,
in the case where acetazolamide is orally administered, a daily
dose of from 250 to 1000 mg can be used.
The dose of the prostaglandin varies depending on the
type of the drug, but it can be administered once or several
times per day at a daily dose of generally from 0.1 to 1000
pg. More specifically, in the case of latanoprost, a daily
dose of from to 5 j.tg is generally used, in the case of isopropyl
unoprostone, a daily dose of from 30 to 300 lag is generally
used, in the case of bimatoprost, a daily dose of from 2 to
301.1g is generally used, and in the case of travoprost, a daily
dose of from 0.5 to 5 pg is generally used. Such a dose can
be appropriately increased or decreased depending on the age
or symptoms of the patient or the like. Also for other
prostaglandins, the dose thereof can be determined on the basis
of the same criteria. The concentration of the prostaglandin
24
Date Recue/Date Received 2020-11-16
in an eye drop is not particularly limited, but, in the case
of latanoprost, an eye drop containing latanoprost at a
concentration of from 0.0001 to 5 w/v%, preferably from 0.0005
to 1 w/v%, more preferably 0.001 to 0.1 w/v%, further more
preferably 0.005 w/v% can be instilled once or several times
per day. In the case of isopropyl unoprostone, an eye drop
=
containing isopropyl unoprostone at a concentration of from
0.001 to 5 w/v%, preferably from 0.01 to 1 w/v%, more preferably
0.12 to 0.15 w/v%, further more preferably 0.12 w/v% or 0.15
w/v% can be instilled once or several times per day. In the
case of bimatoprost, an eye drop containing bimatoprost at a
concentration of from 0.0001 to 5 w/v%, preferably from 0.001
to 1 w/v%, more preferably 0.01 to 0.03 w/v%, further more
preferably 0.01 w/v% or 0.03 w/v% can be instilled once or
several times per day. In the case of travoprost, an eye drop
containing travoprost at a concentration of from 0.0001 to 5
w/v%, preferably 0.001 to 1 w/v% more preferably 0.004 w/v%
can be instilled once or several times per day.
The dose of the Rho-kinase inhibitor varies depending
on the type of the drug, but it can be administered once or
several times per day at a daily dose of generally from 0.025
to 10000 gig, and such a dose can be appropriately increased
or decreased depending on the age or symptoms of the patient
or the like. The concentration of the Rho-kinase inhibitor
in an eye drop is not particularly limited, but an eye drop
25
=
Date Recue/Date Received 2020-11-16
containing the Rho-kinase inhibitor at a concentration of from
0.0001 to 5 w/v%, preferably from 0.001 to 1 w/v% can be
instilled once or several times per day.
Such a dose is applied when the present compound and the
other preventive or therapeutic drug for glaucoma or ocular
hypertension are concomitantly administered. In the case
where a combination drug comprising an arbitrary combination
of the present compound and the other preventive or therapeutic
drugs for glaucoma or ocular hypertension is administered, a
preparation in which the mixing ratios are appropriately
selected so that the daily dose of each component falls within
the above-described dose range is prepared, and the thus
prepared combination preparation can be administered once or
several times per day.
Hereinafter, preparation examples and pharmacological
tests will be shown, but these are for understanding the
invention better, and are not meant to limit the scope of the
invention.
Preparation Examples
Hereinafter, specific preparation examples of an eye
drop and an ophthalmic 'ointment containing the present compound
and the other preventive or therapeutic drug for glaucoma or
ocular hypertension according to the invention will be shown.
26
Date Recue/Date Received 2020-11-16
Preparation Example 1
Eye Drop (in 100 mL)
Present compound 0.01 g
Dipivefrin hydrochloride 0.04 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 2
Eye Drop (in 100 mL)
Present compound 0.01 g
Timolol maleate 0.25 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
27
Date Recue/Date Received 2020-11-16
Preparation Example 3
Eye Drop (in 100 mL)
Present compound 0.01 g
Timolol maleate 0.5 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 4
Eye Drop (in 100 mL)
Present compound 0.01 g
Dorzolamide hydrochloride 0.5 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
28
Date Recue/Date Received 2020-11-16
Purified water q.s.
Preparation Example 5
Eye Drop (in 100 mL)
Present compound 0.01 g
Brinzolamide 1 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 6
Eye Drop (in 100 mL)
Present compound 0.01 g
Dorzolamide hydrochloride 1 g
Timolol maleate 0.5 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
29
Date Recue/Date Received 2020-11-16
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 7
Eye Drop (in 100 mL)
Present compound 0.01 g
Isopropyl unoprostone 0.12 g
Sodium dihydrogen phosphate 0.15 g
Glycerin' q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 8
Eye Drop (in 100 mL)
Present compound 0.01 g
Latanoprost 0.005 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Date Recue/Date Received 2020-11-16
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 9
Eye Drop (in 100 mL)
Present compound 0.01 g
Bimatoprost 0.01 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s. =
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 10
Eye Drop (in 100 mL)
Present compound 0.01 g
Travoprost 0.004 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
31
Date Recue/Date Received 2020-11-16
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 11
Eye Drop (in 100 mL)
Present compound 0.01 g
Latanoprost 0.005 g
Timolol maleate 0;5 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 12
Eye Drop (in 100 mL)
Present compound 0.01 g
Brimonidine tartrate 0.1 g
Sodium dihydrogen phosphate 0.15 g
32
Date Recue/Date Received 2020-11-16
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 13
Eye Drop (in 100 mL)
Present compound 0.01 g
Brimonidine tartrate 0.2 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 14
Eye Drop (in 100 mL)
Present compound 0.01 g
Bunazosin hydrochloride 0.01 g
33
Date Recue/Date Received 2020-11-16
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
PolydXyl 35 castor oil 1.7 g
Disodium edetate 0,05 g
Benzalkonium chloride 0.005 g
Diluted hydrochlOric acid q.s. .
Sodium hydroxide
Purified water q.s.
Preparation Example 15
Eye Drop (in 100 mL)
Present compound 0.01 g
Pilocarpine hydrochloride 0_5 g
Sodium dihydrogen phosphate 0.15 g
Glycerin q.s.
Polyoxyl 35 castor oil 1.7 g
Disodium edetate 0.05 g
Benzalkonium chloride 0.005 g
Diluted hydrochloric acid q,s.
Sodium hydroxide q.s.
Purified water q.s.
Preparation Example 16
Ophthalmic Ointment (in 100 g)
Present compound 0.01 g
34
Date Recue/Date Received 2020-11-16
Timolol maleate 0.5 g
Liquid paraffin 10.0 g
White petrolatum q.s.
Preparation Example 17
Ophthalmic Ointment (in 100 g)
Present compound 0.01 g
Isopropyl unoprostone 0.12 g
Liquid paraffin 10.0 g
White petrolatum q.s.
Preparation Example 18
Ophthalmic Ointment (in 100 g)
= Present compound 0.01 g
Latanoprost 0.005 g
Liquid paraffin 10.0 g
White petrolatum q.s.
In the above formulations, by changing the amount of the
present compound to 0.001 g, 0.003 g, 0.03 g, 0.1 g, etc., and
by changing the type and amount of the other preventive or
therapeutic drug for glaucoma or ocular hypertension and/or
the additive, an eye drop or an ophthalmic ointment having a
desired combination and a desired concentration can be
prepared.
Date Recue/Date Received 2020-11-16
Pharmacological Tests
Example 1
In order to study the usefulness of the combination of
the present compound with a 13-receptor antagonist, an
intraocular pressure lowering effect when the present compound
and timolol were concomitantly administered to experimental
animals (rabbits with normal intraocular pressure) was
examined.
(Preparation of Test Compound Solution)
(1) Preparation of Base
To 1.7 g of polyoxyl 35 castor oil, 10 nth of a 0.5% disodium
edetate/10% glycerin solution, 1 mL of a 1% benzalkonium
chloride solution, 30 mL of purified water, and 50 ruL of a 2%
boric acid/0.2% sorbic acid solution were added and dissolved.
After confirming that a solution was obtained, an appropriate
amount of a sodium hydroxide solution or diluted hydrochloric
acid was added thereto to adjust the pH of the preparation to
around 6.5. Then, an appropriate amount of purified water was
added thereto to make the total volume 100 mL.
(2) Preparation of Present Compound Solution
To 0.8 g of polyoxyl 35 castor oil, 0.001 g of the present
compound was added, and then, 10 mL of a 0.5% disodium edetate/
10% glycerin solution, 1 mL of a 1% benzalkonium chloride
solution, 30 mL of purified water, and 50 mL of a 2% boric
36
Date Recue/Date Received 2020-11-16
acid/0.2% sorbic acid solutionwere added thereto and dissolved.
After confirming that a solution was obtained, an appropriate
amount of a sodium hydroxide solution or diluted hydrochloric
acid was added thereto to adjust the pH of the preparation to
around 6.5. Then, an appropriate amount of purified water was
added thereto to make the total volume 100 mL.
(3) Preparation of Physiological Saline
Commercially available physiological saline (trade
name: Otsuka Normal Saline, obtained from Otsuka
Pharmaceutical Factory, Inc.) was used as such.
(4) Preparation of Timolol Solution
A commercially available timolol eye drop was used as
such.
(Test Method)
An intraocular pressure lowering effect when the present
compound and timolol were concomitantly administered was
examined. As comparison subjects, intraocular pressure
lowering effects when the present compound or timolol was
administered singly were also examined. As a control, the base
and physiological saline were administered.
(Drugs and Animals Used in Test)
Present compound solution: a 0.001 w/v% present compound
solution (instillation amount: 50 L)
Timolol solution: a timolol eye drop (trade name:
Timoptol (registered trademark) eye drop (0.5%), instillation
37
Date Recue/Date Received 2020-11-16
amount: 50 pu,
Experimental animal: Japanese white rabbit (strain: jW,
sex: male, six rabbits per group)
(Administration Method and Measurement Method)
[1] Concomitant Administration of Present Compound and Timolol
(1) One drop of a 0.4% oxybuprocaine hydrochloride eye
drop (trade name: Benoxil (registered trademark) eye drop
(0.4%)) was instilled into both eyes of each experimental
animal to effect local anesthesia.
(2) In.traocular pressure was measured immediately before
administering the test compound solution, and the measured
intraocular pressure was defined as initial intraocular
pressure.
(3) The present compound solution was instilled into one
eye of each experimental animal (the other eye was not treated) .
A few minutes later, the timolol solution was instilled into
the same eye.
(4) At 2, 4 and 6 hours after instilling the present
compound solution, one drop of the 0.4% oxybuprocaine
hydrochloride eye drop was instilled into the eyes for which
intraocular pressure was to be measured to effect local
anesthesia, and then, intraocular pressure was measured. The
intraocular pressure was measured in triplicate for each eye
to obtain an average of three measurements, which is shown as
the result.
38
Date Recue/Date Received 2020-11-16
[2] Single Administration of Present Compound
A test was carried out in the same manner as in the
above-described concomitant administration test except that
physiological saline was used in place of the timolol solution.
[3] Single Administration of Timolol
A test was carried out in. the same manner as in the
above-described concomitant administration test except that
the base was used in place of the present compound solution.
[4] Control
A test was carried out in the same manner as in the
above-described concomitant administration test except that
the base was used in place of the present compound solution
and physiological saline was used in place of the timolol
solution.
(Results and Discussion)
An intraocular pressure lowering degree (change relative
to the average of the control group) at 4 hours after
instillation for each administration group is shown in Table
1. The intraocular pressure lowering degree (change relative
to the average of the control group) is expressed as an average
of differences for 6 rabbits in each group between an average
of intraocular pressure change (ATOP) from the initial
intraocular pressure of the control group and ATOP of each
individual.
Table 1
39
Date Recue/Date Received 2020-11-16
=
Intraocular pressure lowering degree
Administration group (change relative to average of control group)
at 4 hours after instillation (mmHg)
Control group 0.0
Present compound single administration group 1.6
Timolol single administration group 2.3
Present compound and timolol concomitant
6.4
administration group
As apparent from Table 1, the intraocular pressure
lowering degree (change relative to the average of the control
group) at 4 hours after instillation of the present compound
and timolol concomitant administration group was larger than
that of each drug single administration group, the
present compound a.dministration group or the timolol
administration group, and moreover, the intraocular pressure
lowering degree was larger than the sum of the intraocular
pressure lowering degrees (changes relative to the average of
the control group) at 4 hours after instillation caused by the
single administration of each drug. Accordingly, the effect
of the combination of the present compound with timolol was
synergistic.
From the above results, it was found that by combining
the present compound with a 3-receptor antagonist, a
synergistic intraocular pressure lowering effect is obtained.
Example 2
In order to study the usefulness of a combination of the
present compound with a prostaglandin, an intraocular pressure
40
=
Date Recue/Date Received 2020-11-16
lowering effect when the present compound and latanoprost were
concomitantly administered to experimental animals (monkeys
with normal intraocular pressure) was examined.
(Preparation of Test Compound Solution)
(1) Preparation of Base
To 1.7 g of polyoxyl 35 castor oil, 10 mL of a 0.5% disodium
edetate/10% glycerin solution, 1 mL of a 1% benzalkonium
chloride solution, 30 mL of purified water, and 50 mL of a 2%
boric acid/0.2% sorbic acid solution were added and dissolved.
After confirming that a solution was obtained, an appropriate
amount of a sodium hydroxide solution or diluted hydrochloric
acid was added thereto to adjust the pH of the preparation to
around 6.5. Then, an appropriate amount of purified water was
added thereto to make the total volume 100 mL.
(2) Preparation of Present Compound Solution
To 0.8 g of polyoxyl 35 ca.stor oil, 0.0006 g of the present
compound was added, and then, 10 mL of a 0.5% disodium
edetate/10% glycerin solution, 1 mL of a 1% berizalkonium
chloride solution, 30 mL of purified water, and 50 mL of a 2%
boric acid/0.2% sorbic acid solution were added thereto and
dissolved. Alter confirming that a solution was obtained, an
appropriate amount of a sodium hydroxide solution or diluted
hydrochloric acid was added thereto to adjust the pH of the
preparation to around 6.5. Then, an appropriate amount of
purified water was added thereto to make the total volume 100
41
Date Recue/Date Received 2020-11-16
mL.
(3) Preparation of Physiological Saline
Commercially available physiological saline (trade
name: Otsuka Normal Saline, obtained from Otsuka
Pharmaceutical Factory, Inc.) was used as such.
(4) Preparation of Latanoprost Solution
A commercially available latanoprost eye drop was used
as such.
(Test Method)
An intraocular pressure lowering effect when the present
compound and latanoprost were concomitantly administered was
examined. As comparison subjects, intraocular pressure
lowering effects when the present compound or latanoprost was
administered singly were also examined. As a control, the base
and physiological saline were administered.
(Drugs and Animals Used in Test)
Present compound solution: a 0.0006 w/v% present
compound solution (instillation amount: 20 ii.L)
Latanoprost solution: a latanoprost eye drop (trade
name: Xalatan (registered trademark) eye drop (0.005%) ,
(instillation amount: 20 ILL))
Experimental animal: Cynomolgus monkey (sex: male, six
monkeys per group)
(Administration method and Measurement Method)
[1] Concomitant Administration of Present Compound and
42
=
Date Recue/Date Received 2020-11-16
Latan.oprost
(1) One drop of a 0.4% oxybuprocaine hydrochloride eye
drop (trade name: Benoxil (registered trademark) eye drop
(0.4%) ) was instilled into both eyes of each experimental
animal to effect local anesthesia.
(2) Intraocular pressure was measured immediately before
administering the test compound solution, and the measured
intraocular pressure was defined as initial intraocular
pressure.
(3) The present compound solution was instilled into one
eye of each experimental animal (the other eye was not treated) .
A few minutes later, the latanoprost solution was instilled
into the same eye.
(4) At 2, 4, 6 and 8 hours after instilling the present
compound solution, one drop of the 0.4% oxybuprocaine
hydrochloride eye drop was instilled into the eyes for which
intraocular pressure was to be measured to effect local
anesthesia, and then, intraocular pressure was measured. The
intraocular pressure was measured in triplicate for each eye
to obtain an average of three measurements, which is shown as
the result.
[2] Single Administration of Present Compound
A test was carried out in the same manner as in the
above-described concomitant administration test except that
physiological saline was used in place of the latanoprost
43
Date Recue/Date Received 2020-11-16
solution.
[31 Single Administration of Latanoprost
A test was carried out in the same manner as in the
above-described concomitant administration test except that
the base was used in place of the present compound solution.
[4] Control
A test was carried out in the same manner as in the
above-described concomitant administration test except that
the base was used in place of the present compound solution
and physiological saline was used in place of the latanoprost
solution.
(Results and Discussion)
An intraocular pressure lowering degree (change relative
to the average of the control group) at 8 hours after
instillation for each administration group is shown in Table
2. The intraocular pressure lowering degree (change relative
to the average of the control group) is expressed as an average
of differences for 6 monkeys in each group between an average
of intraocular pressure change (AIOP) from the initial
intraocular pressure of the control group and AICP of each
individual.
Table 2
44
=
Date Recue/Date Received 2020-11-16
Intraocular pressure lowering degree
Administration group (change relative to average of control group)
at 8 hours after instillation (mmHg)
Control group 0.0
Present compound single administration group 1.6
Latanoprost single administration group 1.5
Present compound and latanoprost
3.3
concomitant administration group
As apparent from Table 2, the intraocular pressure
lowering degrees at 8 hours after instillation of the present
compound and latanoprost concomitant administration group was
larger than that of each drug single administration group, i.e.,
the present compound administration group or the latanoprost
administration group, and moreover, was larger than the sum
of the intraocular pressure lowering degrees (changes relative
to the average of the control group) at 8 hours after
instillation caused by the single administration of each drug.
Accordingly, the effect of the combination of the present
compound with latanoprost was synergistic.
From the above results, it was found that by combining
the present compound with a prostaglandin, a synergistic
1
intraocular pressure lowering effect is obtained.
Example 3
In order to study the usefulness of a combination of the
present compound with an az-receptor agonist, an intraocular
pressure lowering effect when the present compound and
brimonidine were concomitantly administered to experimental
Date Recue/Date Received 2020-11-16
animals (monkeys with normal intraocular pressure) was
examined.
(Preparation of Test Compound Solution)
(1) Preparation of Base
To 1.7 g of polyoxyl 35 castor oil, 10 mL of a 0.5% disodiurn
edetate/10% glycerin solution, 1 mL of a 1% benzalkoni-um
chloride solution, 30 mL of purified water, and 50 mL of a 2%
boric acid/0.2% sorbic acid solution were added and dissolved.
After confirming that a solution was obtained, an appropriate
amount of a sodium hydroxide solution or diluted hydrochloric
acid was added thereto to adjust the pH of the preparation to
around 6.5. Then, an appropriate amount of purified water was
added thereto to make the total volume 100 mL.
(2) Preparation of Present Compound Solution
To 0.8 g of polyoxyl 35 castor oil, 0.0006 g of the present
compound was added, and then, 10 mL of a 0.5% disodium
edetate/10% glycerin solution, 1 mL of a 1% benzalkonium
chloride solution, 30 mL of purified water, and 50 mL of a 2%
boric acid/0.2% sorbic acid solution were added thereto and
dissolved. After confirming that a solution was obtained, an
appropriate amount of a sodium hydroxide solution or diluted
hydrochloric acid was added thereto to adjust the pH of the
preparation to around 6.5. Then, an appropriate amount of
purified water was added thereto to make the total volume 100
mL.
46
Date Recue/Date Received 2020-11-16
(3). Preparation of Physiological Saline
Commercially available physiological saline (trade
name: Otsuka. Normal Saline, obtained from Otsuka
Pharmaceutical Factory, Inc.) was used as such.
(4) Preparation of Brimonidine Solution
A commercially available brimonidine eye drop was used
as such.
= (Test Method)
An intraocular pressure lowering effect when the present
compound and brimonidin.e were concomitantly administered was
examined. As comparison subjects, intraocular pressure
lowering effects when the present compound or brimonidin.e was
administered singly were also examined. As a control, the base
and physiological saline were administered.
(Drugs and Animals Used in Test)
Present compound solution: a 0.0006 w/v% present
compound solution (instillation amount: 20 ILL)
Brimonidine solution: a brimonidine eye drop (trade
name: ALPHAGAN (registered trademark) P (0.15%) ,
(instillation amount: 20 !IL))
Experimental animal: Cynomolgus monkey (sex: male, six
monkeys per group)
(Administration Method and Measurement Method)
[1] Concomitant Administration of Present Compound and
Brimonidine
47
Date Recue/Date Received 2020-11-16
(1) One drop of a 0.4% oxybuproca.ine hydrochloride eye
drop (trade name: Benoxil (registered trademark) eye drop
(0.4%) ) was instilled into both eyes of each experimental
animal to effect local anesthesia.
(2) Intraocular pressure was measured immediately before
administering the test compound solution, and the measured
intraocular pressure was defined as initial intraocular
pressure.
(3) The present compound solution was instilled into one
eye of each experimental animal (the other eye was not treated) .
A few minutes later, the brimonidine solution was instilled
into the same eye.
(4) At 2, 4, 6 and 8 hours after instilling the present
compound solution, one drop of the 0.4% oxybuprocaine
hydrochloride eye drop was instilled into the eyes for which
intraocular pressure was to be measured to effect local
anesthesia, and then, intraocular pressure was measured. The
intraocular pressure was measured in triplicate for each eye
to obtain an average of three measurements, which is shown as
the result.
[2] Single Administration of Present Compound
A test was carried out in the same manner as in the
above-described concomitant administration test except that
physiological saline was used in place of the brimonidine
solution.
48
Date Recue/Date Received 2020-11-16
[3] Single Administration of Brimonidine
A test was carried out in the same manner as in the
above-described concomitant administration test except that
the base was used in place of the present compound solution.
[4] Control
A test was carried out in the same manner as in the
above-described concomitant administration test except that
the base was used in place of the present compound solution
and physiological saline was used in place of the brimonidine
solution.
(Results and Discussion)
An intraocular pressure lowering degree (change relative
to the average of the control group) at 2 hours after
instillation for each administration group is shown in Table
3. The intraocular pressure lowering degree (change relative
=
to the average of the control group) is expressed as an average
of differences for 6 monkeys in each group between an average
of intraocular pressure change (AIOP) from the initial
intraocular pressure of the control group and AIOP of each
individual.
Table 3
49
Date Recue/Date Received 2020-11-16
intraocular pressure lowering degree
Administration group (change relative to average of control group)
at 2 hours after instillation (mmHg)
Control group 0.0
Present compound single administration group 2.6
Brimonidine single administration group 1.8
Present compound and brimonidine
5.3
concomitant administration group
As apparent from Table 3, the intraocular pressure
lowering degrees at 2 hours after instillation of the present
compound and brimonidine concomitant administration group was
larger than that of each drug single administration group, i.e. ,
the present compound administration group or the brimonidine
administration group, and moreover, was larger than the sum
=of the intraocular pressure lowering degrees (changes relative
to the average of the control group) at 2 hours after
instillation caused by the single administration of each drug.
Accordingly, the effect of the combination of the present
compound with brimonidine was synergistic.
From the above results, it was found that by combining
the present compound with an a2-receptor agonist, a synergistic
intraocular pressure lowering effect is obtained.
Example 4
In order to study the usefulness of a combination of the
present compound with a carbonic anhydrase inhibitor, an
intraocular pressure lowering effect when the present compound
and brinzolamide were concomitantly administered to
Date Recue/Date Received 2020-11-16
experimental animals (monkeys with normal intraocular
pressure) was examined.
(Preparation of Test Compound Solution)
(1) Preparation of Base
To 1.7 g of polyoxyl 35 castor oil, 10 mL of a 0.5% disodium
edetate/10% glycerin solution, 1 mL of a 1% benzalkonium
chloride solution, 30 mL of purified water, and 50 mr, of a 2%
boric acid/0.2% sorbic acid solution were added and dissolved.
After confirming that a solution was obtained, an appropriate
amount of a sodium hydroxide solution or diluted hydrochloric
acid was added thereto to adjust the pH of the preparation to
around 6.5. Then, an appropriate amount of purified water was
added thereto to make the total volume 100 mL.
(2) Preparation of Present Compound Solution
To 0.8 g of polyoxyl 35 castor oil, 0.0006 g of the presen.t
compound was added, and then, 10 mL of a 0.5% disodium
edetate/10% glycerin solution, 1 mL of a 1% benzalkonium
chloride solution, 30 nth of purified water, and 50 mL of a 2%
boric acid/0.2% sorbic acidrsolution were added thereto and
dissolved. After confirming that a solution was obtained, an
appropriate amount of a sodium hydroxide solution or diluted
hydrochloric acid was added thereto to adjust the pH of the
preparation to around 6.5. Then, an appropriate amount of
purified water was added thereto to make the total volume 100
mL
51
Date Recue/Date Received 2020-11-16
(3) Preparation of Physiological Saline
Commercially available physiological saline (trade
name: Otsuka Normal Saline, obtained from Otsuka.
Pharmaceutical Factory, Inc.) was used as such.
(4) Preparation of brinzolamide suspension
A commercially available brinzolamide eye drop was used
as such.
(Test Method)
An intraocular pressure lowering effect when the present
compound and brinzolamide were concomitantly administered was
examined. As comparison subjects, intraocular pressure
lowering effects when the present compound or brinzolamide was
administered singly were also examined. As a control, the base
and physiological saline were administered.
(Drugs and Animals Used in Test)
Present compound solution: a 0.0006 w/v% present
compound solution (instillation amount: 20 L)
Brinzolamide suspension: a brinzolamide ophthalmic
suspension (trade name: Azopt (registered trademark)
Ophthalmic Suspension (1%) , (instillation amount: 20 ,T, ) )
Experimental animal: Cynomolgus monkey (sex: male, five
or six monkeys per group)
(Administration Method and Measurement Method)
[1] Concomitant Administration of Present Compound and
brinzolamide
52
Date Recue/Date Received 2020-11-16
(1) One drop of a 0.4% oxybuprocaine hydrochloride eye
drop (trade name: Benoxil (registered trademark) eye drop
(0.4%)) was instilled into both eyes of each experimental
animal to effect local anesthesia.
(2) Intraocular pressure was measured immediately before
administering the test compound solution, and the measured
intraocular pressure was defined as initial intraocular
pressure.
(3) The present compound solution was instilled into one
eye of each experimental animal (the other eye was not treated) .
A few minutes later, the brinzolamide suspension was instilled
into the same eye.
(4) At 2, 4, 6 and 8 hours after instilling the present
compound solution, one drop of the 0.4% oxybuprocaine
hydrochloride eye drop was instilled into the eyes for which
intraocular pressure was to be measured to effect local
anesthesia, and then, intraocular pressure was measured. The
intraocular pressure was measured in triplicate for each eye
to obtain an average of three measurements, which is shown as
the result.
[2] Single Administration of Present Compound
A test was carried out in the same manner as in the
above-described concomitant administration test except that
physiological saline was used in place of the brinzolamide
suspension.
53
Date Recue/Date Received 2020-11-16
[3] Single Administration of brinzolamide
A test was carried out in the same manner as in the
above-described concomitant administration test except that
the base was used in place of the present compound solution.
[4] Control
A test was carried out in the same manner as in the
above-described concomitant administration test except that
the base was used in place of the present compound solution
and physiological saline was used in place of the brin.zolamide
suspension.
(Results and Discussion)
An intraocular pressure lowering degree, (change relative
to the average of the control group) at 4 hours after
instillation for each administration group is shown in Table
4. The intraocular pressure lowering degree (change relative
to the average of the control group) is expressed as an average
of differences for 5 or 6 monkeys in each group between an
average of intraocular pressure change (AIOP) from the initial
intraocular pressure of the control group and AIOP of each
individual.
Table 4
54
Date Recue/Date Received 2020-11-16
Intraocular pressure lowering degree
Administration group (change relative to average of control group)
at 4 hours after instillation (mmHg)
Control group 0.0
Present compound single administration group 2.5
Brinzolamide single administration group 1.6 =
Present compound and brinzolamide
3.2
=
concomitant administration group
As apparent from Table 4, the intraocular pressure
lowering degree at 4 hours after instillation of the present
compound and brinzolamide concomitant administration group
was larger than that of each drug single administration group,
i.e., the present compound administration group or the
brinzolamide administration group.
From the above results, it was found that by combining
the present compound with a carbonic anhydrase inhibitor, a
potent intraocular pressure lowering effect is obtained.
Date Recue/Date Received 2020-11-16
