U.S. patent application number 16/578679 was filed with the patent office on 2020-03-19 for agent for treating or preventing glaucoma including a sulfonamide compound and another drug.
This patent application is currently assigned to SANTEN PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is SANTEN PHARMACEUTICAL CO., LTD.. Invention is credited to Tomoko KIRIHARA, Masatsugu NAKAMURA, Atsushi SHIMAZAKI.
Application Number | 20200085804 16/578679 |
Document ID | / |
Family ID | 49914503 |
Filed Date | 2020-03-19 |
![](/patent/app/20200085804/US20200085804A1-20200319-C00001.png)
United States Patent
Application |
20200085804 |
Kind Code |
A1 |
KIRIHARA; Tomoko ; et
al. |
March 19, 2020 |
AGENT FOR TREATING OR PREVENTING GLAUCOMA INCLUDING A SULFONAMIDE
COMPOUND AND ANOTHER DRUG
Abstract
A composition for preventing or treating glaucoma or ocular
hypertension including a combination of isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl) aminomethyl}
pyridin-2-ylamino) acetate and at least one other drug for
preventing or treating glaucoma or ocular hypertension, with the
proviso that tafluprost is excluded.
Inventors: |
KIRIHARA; Tomoko;
(Ikoma-shi, JP) ; SHIMAZAKI; Atsushi; (Ikoma-shi,
JP) ; NAKAMURA; Masatsugu; (Ikoma-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SANTEN PHARMACEUTICAL CO., LTD. |
Osaka |
|
JP |
|
|
Assignee: |
SANTEN PHARMACEUTICAL CO.,
LTD.
Osaka
JP
|
Family ID: |
49914503 |
Appl. No.: |
16/578679 |
Filed: |
September 23, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15132768 |
Apr 19, 2016 |
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16578679 |
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13939381 |
Jul 11, 2013 |
9339496 |
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15132768 |
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61671219 |
Jul 13, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5377 20130101;
A61K 31/5377 20130101; A61K 31/444 20130101; A61K 45/06 20130101;
A61K 31/4178 20130101; A61K 31/498 20130101; C07D 401/14 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 31/5575 20130101; A61K
2300/00 20130101; A61K 31/444 20130101; A61K 31/551 20130101; A61K
31/498 20130101; A61K 31/5575 20130101; A61K 31/225 20130101; A61K
31/542 20130101; A61K 31/542 20130101 |
International
Class: |
A61K 31/444 20060101
A61K031/444; C07D 401/14 20060101 C07D401/14; A61K 45/06 20060101
A61K045/06; A61K 31/498 20060101 A61K031/498; A61K 31/5377 20060101
A61K031/5377; A61K 31/542 20060101 A61K031/542; A61K 31/5575
20060101 A61K031/5575; A61K 31/225 20060101 A61K031/225; A61K
31/4178 20060101 A61K031/4178; A61K 31/551 20060101
A61K031/551 |
Claims
1. A preventive or therapeutic agent for glaucoma or ocular
hypertension, comprising a combination of isopropyl
(6-{[4-(pyrazol-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. The preventive or therapeutic agent according to claim 1,
wherein the other preventive or therapeutic drug for glaucoma or
ocular hypertension is one or more preventive or therapeutic agents
selected from the group consisting of a nonselective
sympathomimetic drug, an .alpha..sub.2-receptor agonist, an
.alpha..sub.1-receptor antagonist, a .beta.-receptor antagonist, a
parasympathomimetic drug, a carbonic anhydrase inhibitor, a
prostaglandin and a Rho-kinase inhibitor.
3. The preventive or therapeutic agent according to claim 2,
wherein the nonselective sympathomimetic drug is dipivefrin.
4. The preventive or therapeutic agent according to claim 2,
wherein the .alpha..sub.2-receptor agonist is brimonidine or
apraclonidine.
5. The preventive or therapeutic agent according to claim 2,
wherein the .alpha..sub.1-receptor antagonist is bunazosin.
6. The preventive or therapeutic agent according to claim 2,
wherein the .beta.-receptor antagonist is timolol, befunolol,
carteolol, nipradilol, betaxolol, levobunolol or metipranolol.
7. The preventive or therapeutic agent according to claim 2,
wherein the parasympathomimetic drug is pilocarpine.
8. The preventive or therapeutic agent according to claim 2,
wherein the carbonic anhydrase inhibitor is dorzolamide,
brinzolamide or acetazolamide.
9. The preventive or therapeutic agent according to claim 2,
wherein the prostaglandin is isopropyl unoprostone, latanoprost,
travoprost or bimatoprost.
10. The preventive or therapeutic agent according to claim 2,
wherein the Rho-kinase inhibitor is
(R)-trans-N-(pyridin-4-yl)-4-(1-aminoethyl) cyclohexanecarboxamide,
(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)
benzamide, 1-(5-isoquinolinesulfonyl)homopiperazine or
1-(5-isoquinolinesulfonyl)-2-methylpiperazine.
11. An intraocular pressure lowering agent comprising a combination
of isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}p-
yridine-2-ylamino)acetate with one or more other preventive or
therapeutic drugs for glaucoma or ocular hypertension, with the
proviso that tafluprost is excluded.
12. The intraocular pressure lowering agent according to claim 11,
wherein the other preventive or therapeutic drug for glaucoma or
ocular hypertension is one or more preventive or therapeutic agents
selected from the group consisting of a nonselective
sympathomimetic drug, an .alpha..sub.2-receptor agonist, an
.alpha..sub.1-receptor antagonist, a .beta.-receptor antagonist, a
parasympathomimetic drug, a carbonic anhydrase inhibitor, a
prostaglandin and a Rho-kinase inhibitor.
13. The intraocular pressure lowering agent according to claim 12,
wherein the nonselective sympathomimetic drug is dipivefrin.
14. The intraocular pressure lowering agent according to claim 12,
wherein the .alpha..sub.2-receptor agonist is brimonidine or
apraclonidine.
15. The intraocular pressure lowering agent according to claim 12,
wherein the .alpha..sub.1-receptor antagonist is bunazosin.
16. The intraocular pressure lowering agent according to claim 12,
wherein the .beta.-receptor antagonist is timolol, befunolol,
carteolol, nipradilol, betaxolol, levobunolol or metipranolol.
17. The intraocular pressure lowering agent according to claim 12,
wherein the parasympathomimetic drug is pilocarpine.
18. The intraocular pressure lowering agent according to claim 12,
wherein the carbonic anhydrase inhibitor is dorzolamide,
brinzolamide or acetazolamide.
19. The intraocular pressure lowering agent according to claim 12,
wherein the prostaglandin is isopropyl unoprostone, latanoprost,
travoprost or bimatoprost.
20. The intraocular pressure lowering agent according to claim 12,
wherein the Rho-kinase inhibitor is
(R)-trans-N-(pyridin-4-yl)-4-(1-aminoethyl) cyclohexanecarboxamide,
(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)
benzamide, 1-(5-isoquinolinesulfonyl)homopiperazine or
1-(5-isoquinolinesulfonyl)-2-methylpiperazine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 15/132,768, filed Apr. 19, 2016, which is a Continuation of
U.S. application Ser. No. 13/939,381, filed Jul. 11, 2013, now U.S.
Pat. No. 9,339,496, issued May 17, 2016, which claims the benefit
of U.S. Provisional Application No. 61/671,219, filed Jul. 13,
2012, the entire contents of all of which are incorporated by
reference herein.
TECHNICAL FIELD
[0002] 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-y-
lamino) acetate with other preventive or therapeutic drug for
glaucoma or ocular hypertension.
BACKGROUND ART
[0003] 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.
[0004] In the pharmacotherapy, a drug such as a sympathomimetic
drug (a nonselective stimulant such as dipivefrin or an
.alpha..sub.2-receptor agonist such as brimonidine), a
sympatholytic drug (a .beta.-receptor antagonist such as timolol,
befunolol, carteolol, nipradilol, betaxolol, levobunolol or
metipranolol, or an .alpha..sub.1-receptor antagonist such as
bunazosin hydrochloride), a parasympathomimetic drug (such as
pilocarpine), a carbonic anhydrase inhibitor (such as
acetazolamide), 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 (BVT-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 that a sulfonamide compound having high EP2
receptor selectivity and a potent EP2 agonistic activity is
promising as a therapeutic drug for glaucoma.
[0005] 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 reports the combined
administration of a sympatholytic drug with a prostaglandin. WO
2002/38158 discloses a method of treating glaucoma by the combined
administration of several drugs having an intraocular pressure
lowering effect to eyes. WO 2004/019951 reports the combined
administration of a Rho-kinase inhibitor with a prostaglandin, and
WO 2004/045644 reports the combined administration of a Rho-kinase
inhibitor with a .beta.-receptor antagonist.
[0006] However, there have been no reports specifically disclosing
a combination of isopropyl
(6-{[4-(pyrazol-1-yl)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.
SUMMARY OF THE INVENTION
Problems that the Invention is to Solve
[0007] 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.
Means for Solving the Problems
[0008] 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-yl)benzyl](pyridin-3-ylsulfonyl)
aminomethyl}pyridin-2-ylamino)acetate with other preventive or
therapeutic agent for glaucoma or ocular hypertension, the
intraocular 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.
[0009] (1) A preventive or therapeutic agent for glaucoma or ocular
hypertension, comprising a combination of isopropyl
(6-{[4-(pyrazol-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).
[0010] (2) 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 one or more other
preventive or therapeutic drugs for glaucoma or ocular hypertension
(with the proviso that tafluprost is excluded).
[0011] (3) The preventive or therapeutic agent or the 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
.alpha..sub.2-receptor agonist, an .alpha..sub.1-receptor
antagonist, a .beta.-receptor antagonist, a parasympathomimetic
drug, a carbonic anhydrase inhibitor, a prostaglandin and a
Rho-kinase inhibitor.
[0012] (4) The preventive or therapeutic agent or the intraocular
pressure lowering agent according to the above (3), wherein the
nonselective sympathomimetic drug is dipivefrin.
[0013] (5) The preventive or therapeutic agent or the intraocular
pressure lowering agent according to the above (3) or (4), wherein
the .alpha..sub.2-receptor agonist is brimonidine or
apraclonidine.
[0014] (6) The preventive or therapeutic agent or the intraocular
pressure lowering agent according to any one of the above (3) to
(5), wherein the .alpha..sub.1-receptor antagonist is
bunazosin.
[0015] (7) The preventive or therapeutic agent or the intraocular
pressure lowering agent according to any one of the above (3) to
(6), wherein the .beta.-receptor antagonist is timolol, befunolol,
carteolol, nipradilol, betaxolol, levobunolol or metipranolol.
[0016] (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.
[0017] (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.
[0018] (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.
[0019] (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-yl)-4-(1-aminoethyl) cyclohexanecarboxamide,
(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)-benzamide,
1-(5-isoquinolinesulfonyl)homopiperazine or
1-(5-isoquinolinesulfonyl)-2-methylpiperazine.
[0020] Incidentally, from the above-described respective
configurations (1) to (11), one or more configurations can be
arbitrarily selected and combined.
[0021] Herein after in the specification, "the other preventive or
therapeutic drugs for glaucoma or ocular hypertension" means "the
other preventive or therapeutic drugs for glaucoma or ocular
hypertension except for tafluprost"
Advantage of the Invention
[0022] By the combined administration of isopropyl
(6-{[4-(pyrazol-1-yl)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.
MODE FOR CARRYING OUT THE INVENTION
[0023] 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}pyridin-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.
##STR00001##
[0024] The present compound in the invention can be synthesized by
the method described in WO 2009/113600 or WO 2010/113957.
[0025] 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.
[0026] 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 two other
preventive or therapeutic drugs for glaucoma or ocular
hypertension.
[0027] 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 .alpha..sub.2-receptor agonist, an
.alpha..sub.1-receptor antagonist, a .beta.-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 .beta.-receptor antagonist,
a carbonic anhydrase inhibitor and a prostaglandin, and more
preferably a .beta.-receptor antagonist and a carbonic anhydrase
inhibitor, or a .beta.-receptor antagonist and a prostaglandin.
[0028] Specific examples of the nonselective sympathomimetic drug
include dipivefrin. Specific examples of the .alpha..sub.2-receptor
agonist include brimonidine and apraclonidine. Specific examples of
the .alpha..sub.1-receptor antagonist include bunazosin. Specific
examples of the .beta.-receptor antagonist include timolol,
befunolol, carteolol, nipradilol, betaxolol, levobunolol and
metipranolol. Specific examples of the parasympathomimetic drug
include pilocarpine. Specific examples of the carbonic anhydrase
inhibitor include dorzolamide, brinzolamide and acetazolamide.
[0029] Specific examples of the prostaglandin include
prostaglandins disclosed in JP-A-59-1418 (particularly, a natural
prostaglandin such as prostaglandin F2.alpha.), 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
PGF2.alpha. or a PGF2.alpha. derivative, more preferably isopropyl
unoprostone, latanoprost, travoprost or bimatoprost.
[0030] 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 ROK.alpha. (ROCK-II), p160ROCK (ROK.beta., 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-yl)-4-(1-aminoethyl)
cyclohexanecarboxamide and
(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-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-yl)-(1H-indazol-5-yl)amine disclosed
in WO 01/56988, Rho-kinase inhibitors such as
(1-benzylpiperidin-4-yl)-(1H-indazol-5-yl)amine disclosed in WO
02/100833, Rho-kinase inhibitors such as
N-[2-(4-fluorophenyl)-6,7-dimethoxy-4-quinazolinyl]-N-(1H-indazol-5-yl)am-
ine disclosed in WO 02/076976, Rho-kinase inhibitors such as
N-4-(1H-indazol-5-yl)-6,7-dimethoxy-N-2-pyridin-4-yl-quinazolin-2,4-diami-
ne disclosed in WO 02/076977, and Rho-kinase inhibitors such as
4-methyl-5-(2-methyl-[1,4]diazepan-1-sulfonyl)isoquinoline
disclosed in WO 99/64011. Among these, particularly,
(R)-trans-N-(pyridin-4-yl)-4-(1-aminoethyl) cyclohexanecarboxamide,
(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)
benzamide, 1-(5-isoquinolinesulfonyl)homopiperazine or
1-(5-isoquinolinesulfonyl)-2-methylpiperazine is preferred.
[0031] In the case where the present compound is combined with 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.
[0032] 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, polygalacturonic acid, stearic acid,
tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, lauryl sulfate, methyl sulfate,
napthalenesulfonic 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-(methylamino)-2-D-sorbitol,
2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine,
N,N-bis(phenylmethyl)-1,2-ethanediamine or the like.
[0033] 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 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.
[0034] 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.
[0035] 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 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) may be concomitantly administered, or a
combination drug obtained by mixing all of the components may be
formed.
[0036] 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.
[0037] 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,
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 DuoTrav (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.
[0038] 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.
[0039] 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. 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 edetate. Examples of the preservative include benzalkonium
chloride and paraben.
[0040] 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.
[0041] 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.
[0042] 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
disintegrant include carboxymethyl cellulose calcium and
low-substituted 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.
[0043] 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.
[0044] 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 .mu.g,
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 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.
[0045] 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 .mu.g. More specifically, in the case of dipivefrin, a daily
dose of from 2 to 3000 .mu.g 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.
[0046] The dose of the .alpha..sub.2-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 .mu.g. More specifically, in the case of brimonidine, a daily
dose of from 2 to 1000 .mu.g is generally used and in the case of
apraclonidine, a daily dose of from 20 to 3000 .mu.g 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 .alpha..sub.2-receptor agonists, the dose thereof can be
determined on the basis of the same criteria. The concentration of
the .alpha..sub.2-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 1
w/v % can be instilled once or several times per day.
[0047] The dose of the .alpha..sub.1-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 .mu.g. More specifically, in the case of bunazosin, a daily
dose of from 2 to 3000 .mu.g 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
.alpha..sub.1-receptor antagonists, the dose thereof can be
determined on the basis of the same criteria. The concentration of
the .alpha..sub.1-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.
[0048] The dose of the .beta.-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 .mu.g.
More specifically, in the case of timolol, a daily dose of from 5
to 1500 .mu.g is generally used, in the case of befunolol, a daily
dose of from 10 to 2000 .mu.g is generally used, in the case of
carteolol, a daily dose of from 10 to 5000 .mu.g is generally used,
in the case of nipradilol, a daily dose of from 10 to 1250 .mu.g is
generally used, in the case of betaxolol, a daily dose of from 50
to 1000 .mu.g is generally used, in the case of levobunolol, a
daily dose of from 5 to 5000 .mu.g is generally used, and in the
case of metipranolol, a daily dose of from 5 to 5000 .mu.g 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 .beta.-receptor antagonists, the dose thereof
can be determined on the basis of the same criteria. The
concentration of the .beta.-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 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 befunolol, 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 levobunolol, 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.
[0049] The dose of the parasympathomimetic 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 5 to 300000 .mu.g.
More specifically, in the case of pilocarpine, a daily dose of from
5 to 200000 .mu.g 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.
[0050] 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 10 to
10000 .mu.g. More specifically, in the case of dorzolamide, a daily
dose of from 10 to 10000 .mu.g is generally used and in the case of
brinzolamide, a daily dose of from to 5000 .mu.g 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 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 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.
[0051] 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 .mu.g. More
specifically, in the case of latanoprost, a daily dose of from 1 to
5 .mu.g is generally used, in the case of isopropyl unoprostone, a
daily dose of from 30 to 300 .mu.g is generally used, in the case
of bimatoprost, a daily dose of from 2 to 30 .mu.g is generally
used, and in the case of travoprost, a daily dose of from 0.5 to 5
.mu.g 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 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.
[0052] 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 .mu.g, 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 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.
[0053] 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.
[0054] 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
[0055] 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.
Preparation Example 1
TABLE-US-00001 [0056] 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
TABLE-US-00002 [0057] 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.
Preparation Example 3
TABLE-US-00003 [0058] 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
TABLE-US-00004 [0059] 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. Purified water q.s.
Preparation Example 5
TABLE-US-00005 [0060] 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
TABLE-US-00006 [0061] 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 Diluted
hydrochloric acid q.s. Sodium hydroxide q.s. Purified water
q.s.
Preparation Example 7
TABLE-US-00007 [0062] 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
TABLE-US-00008 [0063] 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
Benzalkonium chloride 0.005 g Diluted hydrochloric acid q.s. Sodium
hydroxide q.s. Purified water q.s.
Preparation Example 9
TABLE-US-00009 [0064] 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
TABLE-US-00010 [0065] 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 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
TABLE-US-00011 [0066] 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
TABLE-US-00012 [0067] Eye Drop (in 100 mL) Present compound 0.01 g
Brimonidine tartrate 0.1 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 13
TABLE-US-00013 [0068] 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
TABLE-US-00014 [0069] Eye Drop (in 100 mL) Present compound 0.01 g
Bunazosin hydrochloride 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 15
TABLE-US-00015 [0070] 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
TABLE-US-00016 [0071] Ophthalmic Ointment (in 100 g) Present
compound 0.01 g Timolol maleate 0.5 g Liquid paraffin 10.0 g White
petrolatum q.s.
Preparation Example 17
TABLE-US-00017 [0072] 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
TABLE-US-00018 [0073] Ophthalmic Ointment (in 100 g) Present
compound 0.01 g Latanoprost 0.005 g Liquid paraffin 10.0 g White
petrolatum q.s.
[0074] 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.
Pharmacological Tests
Example 1
[0075] In order to study the usefulness of the combination of the
present compound with a .beta.-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
[0076] 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
[0077] 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 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.
(3) Preparation of Physiological Saline
[0078] Commercially available physiological saline (trade name:
Otsuka Normal Saline, obtained from Otsuka Pharmaceutical Factory,
Inc.) was used as such.
(4) Preparation of Timolol Solution
[0079] A commercially available timolol eye drop was used as
such.
(Test Method)
[0080] 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)
[0081] Present compound solution: a 0.001 w/v % present compound
solution (instillation amount: 50 .mu.L)
[0082] Timolol solution: a timolol eye drop (trade name: Timoptol
(registered trademark) eye drop (0.5%), in which the active
ingredient is timolol maleate having an equivalent timolol content
of 0.5 w/v %; instillation amount: 50 .mu.L)
[0083] 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
[0084] (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.
[0085] (2) Intraocular pressure was measured immediately before
administering the test compound solution, and the measured
intraocular pressure was defined as initial intraocular
pressure.
[0086] (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.
[0087] (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.
[2] Single Administration of Present Compound
[0088] 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
[0089] 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
[0090] 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)
[0091] 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 (.DELTA.IOP) from the initial intraocular pressure of the
control group and .DELTA.IOP of each individual.
TABLE-US-00019 TABLE 1 Intraocular pressure lowering degree (change
relative to average of control group) Administration group at 4
hours after instillation (mmHg) Control group 0.0 Present compound
single 1.6 administration group Timolol single 2.3 administration
group Present compound and 6.4 timolol concomitant administration
group
[0092] 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, i.e., the present compound
administration 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.
[0093] From the above results, it was found that by combining the
present compound with a .beta.-receptor antagonist, a synergistic
intraocular pressure lowering effect is obtained.
Example 2
[0094] In order to study the usefulness of a combination of the
present compound with a prostaglandin, an intraocular pressure
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
[0095] 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
[0096] 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.
(3) Preparation of Physiological Saline
[0097] Commercially available physiological saline (trade name:
Otsuka Normal Saline, obtained from Otsuka Pharmaceutical Factory,
Inc.) was used as such.
(4) Preparation of Latanoprost Solution
[0098] A commercially available latanoprost eye drop was used as
such.
(Test Method)
[0099] 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)
[0100] Present compound solution: a 0.0006 w/v % present compound
solution (instillation amount: 20 .mu.L)
[0101] Latanoprost solution: a latanoprost eye drop (trade name:
Xalatan (registered trademark) eye drop (0.005%), (instillation
amount: 20 .mu.L))
[0102] Experimental animal: Cynomolgus monkey (sex: male, six
monkeys per group)
(Administration Method and Measurement Method)
[1] Concomitant Administration of Present Compound and
Latanoprost
[0103] (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.
[0104] (2) Intraocular pressure was measured immediately before
administering the test compound solution, and the measured
intraocular pressure was defined as initial intraocular
pressure.
[0105] (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.
[0106] (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
[0107] 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
solution.
[3] Single Administration of Latanoprost
[0108] 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
[0109] 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)
[0110] 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 (MOP) from the initial intraocular pressure of the control
group and MOP of each individual.
TABLE-US-00020 TABLE 2 Intraocular pressure lowering degree (change
relative to average of control group) Administration group at 8
hours after instillation (mmHg) Control group 0.0 Present compound
single 1.6 administration group Latanoprost single 1.5
administration group Present compound and 3.3 latanoprost
concomitant administration group
[0111] 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.
[0112] From the above results, it was found that by combining the
present compound with a prostaglandin, a synergistic intraocular
pressure lowering effect is obtained.
Example 3
[0113] In order to study the usefulness of a combination of the
present compound with an .alpha..sub.2-receptor agonist, an
intraocular pressure lowering effect when the present compound and
brimonidine were concomitantly administered to experimental animals
(monkeys with normal intraocular pressure) was examined.
(Preparation of Test Compound Solution)
(1) Preparation of Base
[0114] 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
[0115] 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.
[0116] Then, an appropriate amount of purified water was added
thereto to make the total volume 100 mL.
(3) Preparation of Physiological Saline
[0117] Commercially available physiological saline (trade name:
Otsuka Normal Saline, obtained from Otsuka Pharmaceutical Factory,
Inc.) was used as such.
(4) Preparation of Brimonidine Solution
[0118] A commercially available brimonidine eye drop was used as
such.
(Test Method)
[0119] An intraocular pressure lowering effect when the present
compound and brimonidine were concomitantly administered was
examined. As comparison subjects, intraocular pressure lowering
effects when the present compound or brimonidine was administered
singly were also examined. As a control, the base and physiological
saline were administered.
(Drugs and Animals Used in Test)
[0120] Present compound solution: a 0.0006 w/v % present compound
solution (instillation amount: 20 .mu.L)
[0121] Brimonidine solution: a brimonidine eye drop (trade name:
ALPHAGAN (registered trademark) P (0.15%), (instillation amount: 20
.mu.L))
[0122] Experimental animal: Cynomolgus monkey (sex: male, six
monkeys per group)
(Administration Method and Measurement Method)
[1] Concomitant Administration of Present Compound and
Brimonidine
[0123] (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.
[0124] (2) Intraocular pressure was measured immediately before
administering the test compound solution, and the measured
intraocular pressure was defined as initial intraocular
pressure.
[0125] (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.
[0126] (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
[0127] 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.
[3] Single Administration of Brimonidine
[0128] 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
[0129] 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)
[0130] 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 (MOP) from the initial intraocular pressure of the control
group and MOP of each individual.
TABLE-US-00021 TABLE 3 Intraocular pressure lowering degree (change
relative to average of control group) Administration group at 2
hours after instillation (mmHg) Control group 0.0 Present compound
single 2.6 administration group Brimonidine single 1.8
administration group Present compound and 5.3 brimonidine
concomitant administration group
[0131] 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.
[0132] From the above results, it was found that by combining the
present compound with an .alpha..sub.2-receptor agonist, a
synergistic intraocular pressure lowering effect is obtained.
Example 4
[0133] 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 experimental
animals (monkeys with normal intraocular pressure) was
examined.
(Preparation of Test Compound Solution)
(1) Preparation of Base
[0134] 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
[0135] 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.
(3) Preparation of Physiological Saline
[0136] Commercially available physiological saline (trade name:
Otsuka Normal Saline, obtained from Otsuka Pharmaceutical Factory,
Inc.) was used as such.
(4) Preparation of Brinzolamide Suspension
[0137] A commercially available brinzolamide eye drop was used as
such.
(Test Method)
[0138] 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)
[0139] Present compound solution: a 0.0006 w/v % present compound
solution (instillation amount: 20 .mu.L)
[0140] Brinzolamide suspension: a brinzolamide ophthalmic
suspension (trade name: Azopt (registered trademark) Ophthalmic
Suspension (1%), (instillation amount: 20 .mu.L))
[0141] 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
[0142] (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.
[0143] (2) Intraocular pressure was measured immediately before
administering the test compound solution, and the measured
intraocular pressure was defined as initial intraocular
pressure.
[0144] (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.
[0145] (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
[0146] 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.
[3] Single Administration of Brinzolamide
[0147] 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
[0148] 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 brinzolamide
suspension.
(Results and Discussion)
[0149] 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 (.DELTA.IOP) from the initial intraocular pressure of the
control group and .DELTA.IOP of each individual.
TABLE-US-00022 TABLE 4 Intraocular pressure lowering degree (change
relative to average of control group) Administration group at 4
hours after instillation (mmHg) Control group 0.0 Present compound
single 2.5 administration group Brinzolamide single 1.6
administration group Present compound and 3.2 brinzolamide
concomitant administration group
[0150] 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.
[0151] 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.
* * * * *