U.S. patent application number 15/742705 was filed with the patent office on 2018-07-19 for prophylactic and/or therapeutic agent containing pyridylaminoacetic acid compound.
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, Najam A. SHARIF, Atsushi SHIMAZAKI.
Application Number | 20180200239 15/742705 |
Document ID | / |
Family ID | 57685038 |
Filed Date | 2018-07-19 |
United States Patent
Application |
20180200239 |
Kind Code |
A1 |
KIRIHARA; Tomoko ; et
al. |
July 19, 2018 |
PROPHYLACTIC AND/OR THERAPEUTIC AGENT CONTAINING PYRIDYLAMINOACETIC
ACID COMPOUND
Abstract
The object of the present invention is to find a new application
of isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}p-
yridin-2-ylamino)acetate or a salt thereof. Isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof is useful as a therapeutic agent
for a disease involving a greatly elevated intraocular
pressure.
Inventors: |
KIRIHARA; Tomoko;
(lkoma-shi, Nara, JP) ; SHIMAZAKI; Atsushi;
(Osaka-shi, Osaka, JP) ; SHARIF; Najam A.;
(Emeryville, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SANTEN PHARMACEUTICAL CO., LTD. |
Osaka-shi, Osaka |
|
JP |
|
|
Assignee: |
SANTEN PHARMACEUTICAL CO.,
LTD.
Osaka-shi, Osaka
JP
|
Family ID: |
57685038 |
Appl. No.: |
15/742705 |
Filed: |
July 7, 2016 |
PCT Filed: |
July 7, 2016 |
PCT NO: |
PCT/JP2016/070110 |
371 Date: |
January 8, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 27/06 20180101;
A61P 27/02 20180101; A61K 31/444 20130101; A61K 9/0048
20130101 |
International
Class: |
A61K 31/444 20060101
A61K031/444; A61K 9/00 20060101 A61K009/00; A61P 27/06 20060101
A61P027/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 9, 2015 |
JP |
2015-137968 |
Claims
1. A prophylactic and/or therapeutic agent for a disease involving
a greatly elevated intraocular pressure, comprising isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof.
2. The prophylactic and/or therapeutic agent according to claim 1,
wherein the disease involving a greatly elevated intraocular
pressure is acute primary angle closure, primary angle closure
glaucoma, secondary angle closure glaucoma, or acute intraocular
pressure elevation.
3. The prophylactic and/or therapeutic agent according to claim 1,
comprising 0.001 to 0.03% (w/v) of the isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or the salt thereof.
4. The prophylactic and/or therapeutic agent according to claim 1,
which does not comprise any other prophylactic and/or therapeutic
agent for glaucoma or ocular hypertension than isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof.
5. An eye drop, comprising the prophylactic and/or therapeutic
agent according to claim 1.
6. Isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof for the use of preventing and/or
treating a disease involving a greatly elevated intraocular
pressure.
7. Isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof according to claim 6, wherein the
disease involving a greatly elevated intraocular pressure is acute
primary angle closure, primary angle closure glaucoma, secondary
angle closure glaucoma, or acute intraocular pressure
elevation.
8. An eye drop, comprising isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof according to claim 6.
9.-13. (canceled)
14. A method for preventing and/or treating a disease involving a
greatly elevated intraocular pressure, comprising administering
isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof to patients with said disease
which has to be prevented and/or treated.
15. The method according to claim 14, wherein the disease involving
a greatly elevated intraocular pressure is acute primary angle
closure, primary angle closure glaucoma, secondary angle closure
glaucoma, or acute intraocular pressure elevation.
16. The method according to claim 14, wherein the administration
amount of the isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or the salt thereof is 0.001 to 0.03% (w/v).
17. The method according to claim 14, wherein any other
prophylactic and/or therapeutic agent for glaucoma or ocular
hypertension than isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}p-
yridin-2-ylamino)acetate or a salt thereof is not administered.
18. The method according to claim 14, wherein the administration is
instillation.
Description
TECHNICAL FIELD
[0001] The present invention relates to a prophylactic and/or
therapeutic agent containing isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof.
BACKGROUND ART
[0002] Glaucoma is an eye disease in which an elevated intraocular
pressure due to various causes may damage the tissues (retina,
optic nerve, and the like) inside the eyeball and lead to visual
loss. In general, intraocular pressure-lowering therapies have been
employed as treatment methods for glaucoma, and representative
intraocular pressure-lowering therapies include drug therapies,
laser therapies, surgical therapies, and the like.
[0003] Here, for treating some types of glaucoma, for example,
primary angle closure glaucoma, a treatment of rapidly lowering the
greatly elevated intraocular pressure has been conducted by
intravenous administration, oral administration, or the like of
acetazolamide before radical treatment such as iridotomy. However,
it cannot be said that this treatment is sufficient in terms of
safety and efficacy, and there has been a demand for a new drug
therapy which is safer, and which lowers the greatly elevated
intraocular pressure more rapidly.
[0004] Isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate is a compound represented by the following formula
(1) and described in Patent Literature 1 as one of the numerous
pyridylaminoacetic acid compounds:
##STR00001##
[0005] In addition, it is stated that these pyridylaminoacetic acid
compounds have EP2 agonist action (Patent Literature 2), and are
expected to have intraocular pressure-lowering activity, and may be
used as a therapeutic agent for glaucoma (Patent Literature 1).
[0006] Moreover, Patent Literatures 3 and 4 state that a
combination of the compound represented by the above-described
formula (1) with another therapeutic agent for glaucoma such as
timolol increases the intraocular pressure-lowering activity. Note
that the entire contents described in Patent Literatures 1 to 4 are
incorporated herein by reference.
[0007] However, there has been no report on the point that the
compound represented by the above-described formula (1) or a salt
thereof can lower a greatly elevated intraocular pressure rapidly
and safely.
CITATION LIST
Patent Literature
[0008] [Patent Literature 1] United States Patent Application
Publication No. 2012/0190852 [0009] [Patent Literature 2] United
States Patent Application Publication No. 2011/0054172 [0010]
[Patent Literature 3] United States Patent Application Publication
No. 2014/0018396 [0011] [Patent Literature 4] United States Patent
Application Publication No. 2014/0018350
SUMMARY OF INVENTION
[0012] An object of the present invention is to find a new
medicinal use of the above-described compound represented by the
formula (1) or a salt thereof.
[0013] To achieve the above-described object, the present inventors
have conducted intensive studies, and found that isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof (hereinafter, also referred to as
"the present compound") lowers a greatly elevated intraocular
pressure safely and rapidly. This finding has led to the completion
of the present invention.
[0014] Specifically, the present invention relates to the
following.
[1] A prophylactic and/or therapeutic agent for a disease involving
a greatly elevated intraocular pressure, comprising isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof. [2] The prophylactic and/or
therapeutic agent according to the above-described item [1],
wherein
[0015] the disease involving a greatly elevated intraocular
pressure is acute primary angle closure, primary angle closure
glaucoma, secondary angle closure glaucoma, or acute intraocular
pressure elevation.
[3] The prophylactic and/or therapeutic agent according to the
above-described item [1] or [2], comprising 0.001 to 0.03% (w/v) of
the isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}p-
yridin-2-ylamino)acetate or the salt thereof. [4] The prophylactic
and/or therapeutic agent according to anyone of the above-described
items [1] to [3], which does not comprise any other prophylactic
and/or therapeutic agent for glaucoma or ocular hypertension than
isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof. [5] An eye drop, comprising the
prophylactic and/or therapeutic agent according to any one of the
above-described items [1] to [4]. [6] Isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof for the use of preventing and/or
treating a disease involving a greatly elevated intraocular
pressure. [7] Isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}p-
yridin-2-ylamino)acetate or a salt thereof according to the
above-described item [6], wherein the disease involving a greatly
elevated intraocular pressure is acute primary angle closure,
primary angle closure glaucoma, secondary angle closure glaucoma,
or acute intraocular pressure elevation. [8] An eye drop,
comprising isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof according to the above-described
item [6] or [7]. [9] Use of isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof for preparing a prophylactic
and/or therapeutic agent for a disease involving a greatly elevated
intraocular pressure. [10] The use according to the above-described
item [9], wherein the disease involving a greatly elevated
intraocular pressure is acute primary angle closure, primary angle
closure glaucoma, secondary angle closure glaucoma, or acute
intraocular pressure elevation. [11] The use according to the
above-described item [9] or [10], comprising 0.001 to 0.03% (w/v)
of the isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or the salt thereof. [12] The use according to any
one of the above-described items [9] to [11], which does not use
any other prophylactic and/or therapeutic agent for glaucoma or
ocular hypertension than isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof. [13] The use according to anyone
of the above-described items [9] to [12], wherein the prophylactic
and/or therapeutic agent is an eye drop. [14] A method for
preventing and/or treating a disease involving a greatly elevated
intraocular pressure, comprising administering isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof to patients with said disease
which has to be prevented and/or treated. [15] The method according
to the above-described item [14], wherein the disease involving a
greatly elevated intraocular pressure is acute primary angle
closure, primary angle closure glaucoma, secondary angle closure
glaucoma, or acute intraocular pressure elevation. [16] The method
according to the above-described item [14] or [15], wherein the
administration amount of the isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or the salt thereof is 0.001 to 0.03% (w/v). [17]
The method according to any one of the above-described items [14]
to [16], wherein any other prophylactic and/or therapeutic agent
for glaucoma or ocular hypertension than isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof is not administered. [18] The
method according to any one of the above-described items [14] to
[17], wherein the administration is instillation.
[0016] Note that it is possible to combine any two or more selected
from the above-described configurations [1] to [5]. It is possible
to combine any two or more selected from the above-described
configurations [6] to [8], and the explanations regarding
"prophylactic and/or therapeutic agent" in this specification may
also be applied to these embodiments regarding said "isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof." It is also possible to combine
any two or more selected from the above-described configurations
[9] to [13], and the explanations regarding "prophylactic and/or
therapeutic agent" in this specification may also be applied to
these embodiments regarding said "use." It is also possible to
combine any two or more selected from the above-described
configurations [14] to [18], and the explanations regarding
"prophylactic and/or therapeutic agent" in this specification may
also be applied to these embodiments regarding said "method."
DESCRIPTION OF EMBODIMENTS
[0017] Hereinafter, embodiments of the present invention are
described in detail. Note that, in the following description, the
"prophylactic and/or therapeutic agent" of the present invention is
simply referred to as "therapeutic agent", unless otherwise
noted.
[0018] Isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof contained in the therapeutic agent
of the present invention can be produced according to the method
described in United States Patent Application Publication No.
2012/0190852 (Patent Literature 1), an ordinary method in the
technical field, or the like.
[0019] The salt of isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate contained in the therapeutic agent of the present
invention is not particularly limited, as long as the salt is
pharmacologically acceptable. Specifically, the salt may be an
inorganic acid salt such as hydrochloric acid salt, hydrobromic
acid salt, hydroiodic acid salt, nitric acid salt, sulfuric acid
salt, or phosphoric acid salt; an organic acid salt such as acetic
acid salt, trifluoroacetic acid salt, benzoic acid salt, oxalic
acid salt, malonic acid salt, succinic acid salt, maleic acid salt,
fumaric acid salt, tartaric acid salt, citric acid salt,
methanesulfonic acid salt, ethanesulfonic acid salt,
trifluoromethanesulfonic acid salt, benzenesulfonic acid salt,
p-toluenesulfonic acid salt, glutamic acid sal, or aspartic acid
salt; or the like. The salt is preferably a hydrochloric acid salt
or a trifluoroacetic acid salt.
[0020] The content of isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or the salt thereof in the therapeutic agent of the
present invention is not particularly limited. In the case of an
eye drop, the lower limit of the content is preferably 0.0003%
(w/v), more preferably 0.001 (w/v), further preferably 0.0013%
(w/v), and particularly preferably 0.0015% (w/v). Meanwhile, the
upper limit of the content is preferably 0.03% (w/v), more
preferably 0.01% (w/v), further preferably 0.005% (w/v),
particularly preferably 0.003% (w/v), and especially preferably
0.0027% (w/v). More specifically, the content is preferably 0.0003
to 0.03% (w/v), more preferably 0.001 to 0.01% (w/v), further
preferably 0.001 to 0.005% (w/v), particularly preferably 0.001 to
0.003% (w/v), especially preferably 0.0013 to 0.003% (w/v), and
still further preferably 0.0015 to 0.0027% (w/v). More
specifically, the content is preferably 0.0010% (w/v), 0.0011%
(w/v), 0.0012% (w/v), 0.0013% (w/v), 0.0014% (w/v), 0.0015% (w/v),
0.0016% (w/v), 0.0017% (w/v), 0.0018% (w/v), 0.0019% (w/v), 0.0020%
(w/v), 0.0021% (w/v), 0.0022% (w/v), 0.0023% (w/v), 0.0024% (w/v),
0.0025% (w/v), 0.0026% (w/v), 0.0027% (w/v), 0.0028% (w/v), 0.0029%
(w/v), 0.0030% (w/v), 0.005% (w/v), 0.01% (w/v), or 0.03% (w/v), or
the content is preferably in a range having an upper limit or a
lower limit selected from any of these amounts. Here, the term "%
(w/v)" means the mass (g) of an active ingredient (the present
compound here) or an additive (surfactant or the like) contained
per 100 mL of the eye drop. For example, 0.01% (w/v) of the present
compound means that the content of the present compound per 100 mL
of the eye drop is 0.01 g.
[0021] Note that, when a salt of isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate is contained, this content means that the content of
isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}p-
yridin-2-ylamino)acetate, which is the free form of the salt, is
within the above-described range.
[0022] If necessary, additives can be used in the therapeutic agent
of the present invention. As the additives, for example, a
surfactant, a buffering agent, a tonicity adjusting agent, a
stabilizer, an antiseptic agent, an antioxidant, a high-molecular
weight polymer, and the like can be added.
[0023] In the therapeutic agent of the present invention, a
surfactant usable as an additive for pharmaceuticals can be
blended, as appropriate.
[0024] Examples of the surfactant include polyoxyethylene castor
oils, polyoxyethylene hardened castor oils, polyoxyethylene
sorbitan fatty acid esters, vitamin E TPGS, polyoxyethylene fatty
acid esters, polyoxyethylene polyoxypropylene glycols, sucrose
fatty acid esters, and the like.
[0025] More specifically, as the polyoxyethylene castor oils,
various polyoxyethylene castor oils having different degrees of
polymerization of ethylene oxide can be used. The degree of
polymerization of ethylene oxide is preferably 5 to 100, more
preferably 20 to 50, particularly preferably 30 to 40, and most
preferably 35. Specific examples of the polyoxyethylene castor oils
include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15
castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, and the
like, and polyoxyl 35 castor oil is the most preferable.
[0026] As the polyoxyethylene hardened castor oils, various
polyoxyethylene hardened castor oils having different degrees of
polymerization of ethylene oxide can be used. The degree of
polymerization of ethylene oxide is preferably 10 to 100, more
preferably 20 to 80, particularly preferably 40 to 70, and most
preferably 60. Specific examples of the polyoxyethylene hardened
castor oils include polyoxyethylene hardened castor oil 10,
polyoxyethylene hardened castor oil 40, polyoxyethylene hardened
castor oil 50, polyoxyethylene hardened castor oil 60, and the
like, and polyoxyethylene hardened castor oil 60 is the most
preferable.
[0027] The polyoxyethylene sorbitan fatty acid esters include
polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene
sorbitan monolaurate, polyoxyethylene sorbitan trioleate,
polysorbate 65, and the like, and polysorbate 80 is the most
preferable.
[0028] Vitamin E TPGS is also referred to as tocopherol
polyethylene glycol 1000 succinate.
[0029] The polyoxyethylene fatty acid esters include polyoxyl 40
stearate, and the like.
[0030] The polyoxyethylene polyoxypropylene glycols include
polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene
(42) polyoxypropylene (67) glycol, polyoxyethylene (54)
polyoxypropylene (39) glycol, polyoxyethylene (196)
polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene
(20) glycol, and the like.
[0031] The sucrose fatty acid esters include sucrose stearate and
the like.
[0032] When a surfactant is blended in the therapeutic agent of the
present invention, the content of the surfactant can be adjusted,
as appropriate, according to the type of the surfactant and the
like. Specifically, the lower limit is preferably 0.001% (w/v),
more preferably 0.01% (w/v), further preferably 0.1% (w/v),
particularly preferably 0.5% (w/v), and most preferably 0.8% (w/v).
The upper limit is preferably 10% (w/v), more preferably 5% (w/v),
further preferably 4% (w/v), particularly preferably 3% (w/v)), and
most preferably 2% (w/v). More specifically, the content is
preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v),
further preferably 0.1 to 4% (w/v), particularly preferably 0.5 to
3% (w/v), and most preferably 0.8 to 2% (w/v).
[0033] In the therapeutic agent of the present invention, a
buffering agent usable as an additive for pharmaceuticals can be
blended, as appropriate.
[0034] Examples of the buffering agent include phosphoric acid,
salts thereof, boric acid, salts thereof, citric acid, salts
thereof, acetic acid, salts thereof, carbonic acid, salts thereof,
tartaric acid, salts thereof, .epsilon.-aminocaproic acid,
trometamol, and the like. More specifically, the salts of
phosphoric acid include sodium phosphate, sodium dihydrogen
phosphate, disodium hydrogen phosphate, potassium phosphate,
potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and
the like; the salts of boric acid include borax, sodium borate,
potassium borate, and the like; the salts of citric acid include
sodium citrate, disodium citrate, trisodium citrate, and the like;
the salts of acetic acid include sodium acetate, potassium acetate,
and the like; the salts of carbonic acid include sodium carbonate,
sodium hydrogen carbonate, and the like; the salts of tartaric acid
include sodium tartrate, potassium tartrate, and the like.
Especially, boric acid, salts thereof, citric acid, and salts
thereof are preferable.
[0035] When a buffering agent is blended in the therapeutic agent
of the present invention, the content of the buffering agent can be
adjusted, as appropriate, according to the type of the buffering
agent and the like, and is preferably 0.001 to 10% (w/v), more
preferably 0.01 to 5% (w/v), further preferably 0.1 to 3% (w/v),
and most preferably 0.2 to 2% (w/v).
[0036] In the therapeutic agent of the present invention, a
tonicity adjusting agent usable as an additive for pharmaceuticals
can be blended, as appropriate.
[0037] Examples of the tonicity adjusting agent include ionic
tonicity adjusting agents, nonionic tonicity adjusting agents, and
the like.
[0038] The ionic tonicity adjusting agents include sodium chloride,
potassium chloride, calcium chloride, magnesium chloride, and the
like. The nonionic tonicity adjusting agents include glycerin,
propylene glycol, sorbitol, mannitol, and the like. When a tonicity
adjusting agent is blended in the therapeutic agent of the present
invention, the content of tonicity adjusting agent can be adjusted,
as appropriate, according to the type of the tonicity adjusting
agent and the like, and is preferably 0.01 to 10% (w/v), more
preferably 0.02 to 7% (w/v), further preferably 0.1 to 5% (w/v),
particularly preferably 0.5 to 4% (w/v), and most preferably 0.8 to
3% (w/v).
[0039] In the therapeutic agent of the present invention, a
stabilizer usable as an additive for pharmaceuticals can be
blended, as appropriate.
[0040] Examples of the stabilizer include edetic acid, monosodium
edetate, disodium edetate, tetrasodium edetate, sodium citrate, and
the like, and disodium edetate is particularly preferable. The
sodium edetates may be hydrates. When a stabilizer is blended in
the therapeutic agent of the present invention, the content of the
stabilizer can be adjusted, as appropriate, according to the type
of the stabilizer and the like, and is preferably 0.001 to 1%
(w/v), more preferably 0.005 to 0.5% (w/v), and most preferably
0.01 to 0.1% (w/v).
[0041] In the therapeutic agent of the present invention, an
antiseptic agent usable as an additive for pharmaceuticals can be
blended, as appropriate.
[0042] Examples of the antiseptic agents include benzalkonium
chloride, benzalkonium bromide, benzethonium chloride, sorbic acid,
potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate,
chlorobutanol, and the like. When an antiseptic agent is blended in
the therapeutic agent of the present invention, the content of the
antiseptic agent can be adjusted, as appropriate, according to the
type of the antiseptic agent and the like, and is preferably 0.0001
to 1% (w/v), more preferably 0.0005 to 0.1% (w/v), further
preferably 0.001 to 0.05% (w/v), and most preferably 0.005 to
0.010% (w/v).
[0043] In the therapeutic agent of the present invention, an
antioxidant usable as an additive for pharmaceuticals can be
blended, as appropriate.
[0044] Examples of the antioxidant include ascorbic acid,
tocopherols, dibutylhydroxytoluene, butylhydroxyanisole, sodium
erythorbate, propyl gallate, sodium sulfite, and the like. When an
antioxidant is blended in the therapeutic agent of the present
invention, the content of the antioxidant can be adjusted, as
appropriate, according to the type of the antioxidant and the like,
and is preferably 0.0001 to 1% (w/v), more preferably 0.0005 to
0.1% (w/v), and most preferably 0.001 to 0.05% (w/v).
[0045] In the therapeutic agent of the present invention, a
high-molecular weight polymer usable as an additive for
pharmaceuticals can be blended, as appropriate.
[0046] Examples of the high-molecular weight polymer include methyl
cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose,
hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxy
methyl cellulose sodium salt, hydroxypropyl methyl cellulose
acetate succinate, hydroxypropyl methyl cellulose phthalate,
carboxymethyl ethyl cellulose, cellulose acetate phthalate,
polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer,
polyethylene glycol, and the like.
[0047] When a high-molecular weight polymer is blended in the
therapeutic agent of the present invention, the content of the
high-molecular weight polymer can be adjusted, as appropriate,
according to the type of the high-molecular weight polymer and the
like, and is preferably 0.001 to 5% (w/v), more preferably 0.01 to
1% (w/v), and most preferably 0.1 to 0.5% (w/v).
[0048] The pH of the therapeutic agent of the present invention is
preferably 4.0 to 8.0, more preferably 4.5 to 7.5, particularly
preferably 5.0 to 7.0, and most preferably 5.5 to 6.5. To the
therapeutic agent of the present invention, a pH adjusting agent
for adjusting the pH may be added such as hydrochloric acid,
phosphoric acid, citric acid, acetic acid, sodium hydroxide,
potassium hydroxide, or the like.
[0049] The therapeutic agent of the present invention can be stored
in containers produced from various materials. For example, a
container made of polyethylene, polypropylene, or the like can be
used. The therapeutic agent of the present invention is preferably
stored in a polyethylene container from the viewpoints of the ease
of instillation (hardness of the container), the stability of the
present compound, and the like.
[0050] The dosage form of the therapeutic agent of the present
invention is not particularly limited, as long as the dosage form
is usable for pharmaceuticals. Specifically, the dosage form may be
an eye drop, an ophthalmic injection, an ophthalmic ointment, or
the like, and is particularly preferably an eye drop. These dosage
forms of these drugs can be produced according to ordinary methods
in the technical field. In addition, a solvent or dispersion medium
used when the therapeutic agent of the present invention is a
liquid agent is preferably water.
[0051] The therapeutic agent of the present invention may contain
or may be used in combination with one or more, preferably 1 to 3,
and more preferably 1 or 2 prophylactic and/or therapeutic agents
for glaucoma or ocular hypertension other than the present
compound. The other prophylactic and/or therapeutic agents for
glaucoma or ocular hypertension are not particularly limited.
Specifically, the other prophylactic and/or therapeutic agents are
preferably therapeutic agents for glaucoma and the like which are
commercially available or under development, more preferably
commercially available therapeutic agents for glaucoma and the
like, and particularly preferably commercially available
therapeutic agents for glaucoma and the like which have different
mechanisms of action from that of the present compound. More
specifically, the other prophylactic and/or therapeutic agents
include nonselective sympathomimetics, .alpha..sub.2 receptor
agonists, .alpha..sub.1 receptor blockers, .beta. receptor
blockers, parasympathomimetics, carbonic anhydrase inhibitors,
prostaglandins, Rho kinase inhibitors, and the like.
[0052] A specific example of the nonselective sympathomimetics is
dipivefrine. Specific examples of the .alpha..sub.2 receptor
agonists include brimonidine and apraclonidine. A specific example
of the .alpha..sub.1 receptor blocker is bunazosin. Specific
examples of the .beta. receptor blockers include timolol,
befunolol, carteolol, nipradilol, betaxolol, levobunolol, and
metipranolol. A specific example of the parasympathomimetics is
pilocarpine. Specific examples of the carbonic anhydrase inhibitors
include dorzolamide, brinzolamide, and acetazolamide. Specific
examples of the prostaglandins include latanoprost, isopropyl
unoprostone, bimatoprost, and travoprost. A specific example of the
Rho kinase inhibitors is ripasudil.
[0053] In an embodiment, the therapeutic agent of the present
invention does not contain any other prophylactic and/or
therapeutic agent for glaucoma or ocular hypertension than
isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof.
[0054] In an embodiment, the therapeutic agent of the present
invention is not used in combination with any other prophylactic
and/or therapeutic agent for glaucoma or ocular hypertension than
isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate or a salt thereof.
[0055] The therapeutic agent of the present invention can be
administered orally or parenterally. No special technique is
required to prepare pharmaceutical preparations of the therapeutic
agent, and the pharmaceutical preparations can be prepared by using
commonly used techniques. The dosage forms for the administration
include eye drops, ophthalmic ointments, injections, tablets,
capsules, granules, powders, and the like, and eye drops are
preferable.
[0056] The usage of the therapeutic agent of the present invention
is not particularly limited, as long as the usage is enough to
achieve a desired medicinal effect. A suitable usage can be
selected, as appropriate, according to symptoms of the disease, the
age and body weight of the patient, the dosage form of the agent,
and the like. Specifically, 1 to 5 drops, preferably 1 to 3 drops,
more preferably 1 to 2 drops, and particularly preferably 1 drop of
the therapeutic agent of the present invention can be instilled 1
to 4 times a day, preferably 1 to 3 times a day, more preferably 1
to 2 times a day, and particularly preferably once a day, every day
to every week. It is preferable to instill one drop of the
therapeutic agent of the present invention once a day, every day.
Here, 1 drop is generally approximately 0.01 to approximately 0.1
mL, preferably approximately 0.015 to approximately 0.07 mL, more
preferably approximately 0.02 to approximately 0.05 mL, and
particularly preferably approximately 0.03 mL.
[0057] The therapeutic agent of the present invention is a
prophylactic and/or therapeutic agent for a disease involving a
greatly elevated intraocular pressure, and is a pharmaceutical
preparation used to rapidly reduce or lower the intraocular
pressure.
[0058] In the present invention, the "disease involving a greatly
elevated intraocular pressure" refers to a disease with an
intraocular pressure in a range of, for example, from 25 to 100
mmHg, preferably from 25 to 80 mmHg, more preferably from 30 to 80
mmHg, and further preferably from 40 to 80 mmHg. For such a
disease, it is necessary to rapidly lower the intraocular
pressure.
[0059] The "greatly elevated intraocular pressure" which has to be
treated or prevented by the present invention includes not only the
so-called acute ocular hypertension state as in the case where the
intraocular pressure is rapidly elevated to the above-described
high intraocular pressure range in several weeks, several days, or
several hours, but also the so-called chronic ocular hypertension
state where the above-described greatly elevated intraocular
pressure is reached over a long period of several months or several
years.
[0060] Here, the phrase "rapidly reduce the intraocular pressure"
or "rapidly lower the intraocular pressure" means that the
intraocular pressure is reduced or lowered to a normal level, for
example, in a range from 10 to 25 mmHg and preferably in a range
from 10 to 20 mmHg within, for example, 24 hours, preferably 12
hours, more preferably 6 hours, further preferably 4 hours, and
especially preferably 2 hours. More specifically, it is suitable to
achieve a reduction in intraocular pressure of -1 to -90 mmHg,
preferably -5 to -80 mmHg, more preferably -7 to -70 mmHg, further
preferably -10 to -70 mmHg, and most preferably -10 to -60 mmHg,
for example, within 6 hours, or it is suitable to achieve a
reduction in intraocular pressure of -1 to -90 mmHg, preferably -5
to -80 mmHg, more preferably -7 to -70 mmHg, further preferably -10
to -70 mmHg, and most preferably -10 to -60 mmHg, for example,
within 2 hours. Here, regarding the negative values, for example, a
negative value of "-10 mmHg" means that the intraocular pressure is
reduced by 10 mmHg from that before treatment.
[0061] In the present invention, examples of the "disease involving
a greatly elevated intraocular pressure" include acute primary
angle closure, primary angle closure glaucoma, secondary angle
closure glaucoma, and acute intraocular pressure elevation such as
that caused by inflammation such as uveitis.
[0062] Patients with the above-described disease which has to be
prevented and/or treated include humans and non-human animals, and,
especially, humans and non-human mammals.
EXAMPLES
[0063] Hereinafter, Formulation Examples and results of a
pharmacological test are shown; however, these are provided for
better understanding of the present invention, and do not limit the
scope of the present invention.
FORMULATION EXAMPLES
[0064] Representative Formulation Examples of the therapeutic agent
of the present invention are shown below. Note that, in the
following Formulation Examples, the blended amount of each
component is an amount in 100 mL of the pharmaceutical preparation.
In addition, the present compound A means isopropyl
(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-y-
lamino)acetate.
Formulation Example 1
TABLE-US-00001 [0065] Eye drop (in 100 mL) the present compound A
0.002 g boric acid 0.2 g glycerin 2.0 g polysorbate 80 0.5 g
disodium edetate 0.05 g benzalkonium chloride 0.005 g dilute
hydrochloric acid quantum sufficit sodium hydroxide quantum
sufficit purified water quantum sufficit
Formulation Example 2
TABLE-US-00002 [0066] Eye drop (in 100 mL) the present compound A
0.002 g sodium dihydrogen phosphate 0.2 g glycerin 2.0 g vitamin E
TPGS 0.8 g disodium edetate 0.05 g benzalkonium chloride 0.005 g
dilute hydrochloric acid quantum sufficit sodium hydroxide quantum
sufficit purified water quantum sufficit
Formulation Example 3
TABLE-US-00003 [0067] Eye drop (in 100 mL) the present compound A
0.002 g trisodium citrate 0.2 g glycerin 2.0 g polyoxyethylene
hardened castor oil 60 0.3 g disodium edetate 0.05 g benzalkonium
chloride 0.005 g dilute hydrochloric acid quantum sufficit sodium
hydroxide quantum sufficit purified water quantum sufficit
[0068] Note that, it is possible to obtain a desired agent by
adjusting the types and/or the blended amounts of the present
compound A and/or the additives in any of the above-described
Formulation Examples 1 to 3, as appropriate.
[Pharmacological Test]
[0069] To investigate the usefulness of the present compound A, an
intraocular pressure-lowering effect of the present compound A was
tested in experimental animals (ocular hypertensive monkeys).
Regarding test solutions, a reference solution not containing the
present compound A was used as a control, a solution containing the
present compound A was prepared as Example 1 of the invention of
the present application, and a latanoprost eye drop was prepared as
Comparative Example 1, as shown below.
(Preparation of Test Solutions)
(1) Preparation of Reference Solution
[0070] To 1.7 g of polyoxyl 35 castor oil, 10 mL of a 0.5% (w/v)
disodium edetate/10% (w/v) glycerin solution, 1 mL of a 1% (w/v)
benzalkonium chloride solution, 30 mL of purified water, and 50 mL
of a 2% (w/v) boric acid/0.2% (w/v) sorbic acid solution were added
and dissolved therein. After dissolution was achieved, the pH of
the pharmaceutical preparation was adjusted to about 6.5 by adding
a suitable amount of a sodium hydroxide solution, and the total
volume was adjusted to 100 mL by adding a suitable amount of
purified water. Thus, a reference solution serving as a control was
prepared.
(2) Preparation of Solution of the Present Compound A (Example
1)
[0071] To 2.55 g of polyoxyl 35 castor oil, 0.015 g of the present
compound A, 15 mL of a 0.5% (w/v) disodium edetate/10% (w/v)
glycerin solution, 1.5 mL of a 1% (w/v) benzalkonium chloride
solution, 45 mL of purified water, and 75 mL of a 2% (w/v) boric
acid/0.2% (w/v) sorbic acid solution were added and dissolved
therein. After dissolution was achieved, the pH of the
pharmaceutical preparation was adjusted to about 6.5 by adding a
suitable amount of a sodium hydroxide solution, and then the total
volume was adjusted to 150 mL by adding a suitable amount of
purified water. Thus, a 0.01 w/v % solution of the present compound
A was prepared (Example 1).
(3) Latanoprost Eye Drop (Comparative Example 1)
[0072] A commercially available latanoprost eye drop (Trade Name:
Xalatan.RTM. eye drop 0.005% (w/v), instillation amount: 20 .mu.L)
was used.
[0073] (Preparation of Experimental Animals)
[0074] Laser-induced ocular hypertensive monkeys (Macaca
fascicularis) (sex: male, three groups each consisting of 11
monkeys were prepared in total) were prepared according to the
article of Gaasterland and Kupfer (Gaasterland D and Kupfer C.,
Invest Ophthalmol., 1974, June; 13(6): 455-7).
(Testing Method)
[0075] (1) For local anesthesia, one drop of a 0.4% oxybuprocaine
hydrochloride eye drop (Trade Name: Benoxil.RTM. solution 0.4%) was
instilled to an eye of each of the experimental animals.
[0076] (2) The intraocular pressure was measured immediately before
instillation of one of the test solutions (the above-described
control, Example 1, and Comparative Example 1), and employed as the
initial intraocular pressure.
[0077] (3) To the one eye of each of the experimental animals, 20
.mu.L of one of the test solutions was instilled (the other eye was
not treated).
[0078] (4) After 2 hours, 4 hours, and 6 hours had passed from the
instillation of the test solution, one drop of the 0.4%
oxybuprocaine hydrochloride eye drop was instilled for local
anesthesia to the eye whose intraocular pressure was to be
measured, and then the intraocular pressure was measured. In
addition, the intraocular pressure was measured three times, and
the average value was shown in the results.
[0079] Note that this test on the three groups was carried out as a
three-group, three-period complete-crossover test in which three
types of the test using the control, Example 1, and Comparative
Example 1 were conducted on each of the groups three times in
differed periods (in three periods).
(Results and Discussion) Table 1 shows the average intraocular
pressure reduction (relative to the initial intraocular pressure)
of each of the treated groups at 2 hours, 4 hours, and 6 hours
after the administration.
TABLE-US-00004 TABLE 1 Average intraocular pressure reduction (vs
initial intraocular pressure) (mmHg) 2 hours after 4 hours after 6
hours after Treated group instillation instillation instillation
Control group -0.5 -1.0 -1.6 Example 1- -16.2 -19.3 -19.7 treated
group Comparative -7.4 -8.9 -9.3 Example 1- treated group * In
Table 1, the "negative sign (-)" has such a meaning that, for
example, in the case of -1.0, the intraocular pressure was reduced
by 1.0 from the initial intraocular pressure.
[0080] As is apparent from Table 1, the intraocular
pressure-lowering activity of the present compound A of Example 1
was larger than that in the latanoprost-treated group of
Comparative Example 1, and the present compound A of Example 1
exhibited an excellent intraocular pressure-lowering activity no
later than 2 hours after the administration.
[0081] From the above-described results, it was found that the
present compound A rapidly provided an excellent intraocular
pressure-lowering effect after the administration in the test on
the ocular hypertensive monkeys.
* * * * *