[Technical Field]
[0001]
The present invention relates to an aqueous composition and the like.
[Background Art] [0002]
It is known that halogenated isoquinoline derivatives such as ripasudil (chemical name: 4-fluoro-5 { [ (2S) -2 -methyl-l^-diazepan-l-yl] sulfonyljisoquinoline) -^represented by the following structural-formula; [0003]
[0004]
and 4~bromo-5-{ [ (2S)-2-methyl-1,4-diazepan-l-yl]sulfonyljisoquinoline represented by the following structural formula:
[0005]
[0006]
have pharmacological action such as Rho kinase inhibitory action (Patent Literatures 1 and 2, for example), and thus, are usable for the prevention or treatment of eye diseases. Specifically, these halogenated isoquinoline derivatives have been reported to be useful, for example, for the prevention or treatment of ocular hypertension, glaucoma, and the like
(Patent Literature 3, for example), or for the prevention
or treatment of ocular fundus diseases such as age-
related macular degeneration and the like (Patent
Literature 4, for example).
[0007]
Hence, it is extremely useful to establish a technique for producing stable preparations of these halogenated isoquinoline derivatives as ophthalmic agents, for example.
[0008]
Patent Literature 5 describes a combination of ripasudil ((S)-{-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-l,4-homopiperazine) or a salt thereof, and nipradilol as a p blocker. However, Patent Literature 5 only discloses that a solution containing 1% ripasudil
and an eye drop containing 0.25% nipradilol were sequentially instilled in one eye of a rabbit, and does not disclose at all an aqueous composition containing both of these components, storing such a composition in a container, the preservation stability over time, and the like.
[Citation List]
[Patent Literature]
[0009]
[Patent Literature 1] JP-B-4212149
[Patent Literature 2] WO2006/115244
[Patent Literature 3] WO2006/068208
[Patent Literature 4] JP-B-5557408
[Patent Literature 5} JP-A-2£X)-6-348028
[Summary of Invention]
[Technical Problem]
[0010]
An ophthalmic agent is generally a composition containing water {aqueous composition). To produce a preparation of a halogenated isoquinoline derivative, ripasudil, as an ophthalmic agent or the like, the present inventors initially prepared an aqueous composition containing ripasudil and the preservation stability was investigated, and as a result the aqueous composition was revealed to be disadvantageously discolored over time during high-temperature preservation.
Accordingly, it is an object of the present invention to provide a technique for reducing the discoloration of an aqueous composition containing a halogenated isoquinoline derivative during high-temperature preservation.
[Solution to Problem]
[0011]
Thus, the present inventors conducted extensive research to solve the above-described problem, and found that further incorporation of a (3 blocker such as carteolol and nipradilol in an aqueous composition containing a halogenated isoquinoline derivative such as ripasudil can reduce the discoloration during high-temperature preservation, thus completing the present invention.
[0012]
In summary, the present invention provides an aqueous composition comprising a compound represented by Formula (1):
[0013]
[0014]
wherein X represents a halogen atom,
or a salt thereof, or a solvate of the compound or
the salt thereof, and a p blocker.
Further, the present invention provides a method for reducing discoloration of an aqueous composition, the method comprising the step of incorporating a p blocker in an aqueous composition comprising a compound represented by Formula (1) or a salt thereof, or a solvate of the compound or the salt thereof.
[Effects of Invention]
[0015]
In accordance with the present invention, the discoloration of an aqueous composition containing a
halogenated isoquinoline derivative such as ripasudil
during high-temperature preservation can be reduced.
[Description of Embodiments] [0016]
The present specification discloses, although is in no way limited to, the following embodiments of invention, by way of example.
[1] An aqueous composition comprising a compound represented by Formula (1): [0017]
[0018]
wherein X represents a halogen atom,
or a salt thereof, or a solvate of the compound, or
the salt thereof, and a p blocker.
[2] The aqueous composition according to [1], wherein the compound represented by Formula (1) is ripasudil.
[3] The aqueous composition according to [1] or [2], wherein the—p blocker is one or more selected f-r^om—the group consisting of carteolol, timolol, nipradilol, betaxolol, levobunolol, befunolol, metipranolol, a salt of carteolol, a salt of timolol, a salt of nipradilol, a salt of betaxolol, a salt of levobunolol,. a salt of befunolol, a salt of metipranolol, a solvate of carteolol or the salt thereof, a solvate of timolol or the salt thereof, a solvate of nipradilol or the salt thereof, a solvate of betaxolol or the salt thereof, a solvate of levobunolol or the salt thereof, a solvate of befunolol or the salt thereof, and a solvate of metipranolol or the salt thereof.
[4] The aqueous composition according to [1] or [2], wherein the p blocker is one or more selected from the
group consisting of carteolol, timolol, nipradilol, a salt of carteolol, a salt of timolol, a salt of nipradilol, a solvate of carteolol or the salt thereof, a solvate of timolol or the salt thereof, and a solvate of nipradilol or the salt thereof.
[5] The aqueous composition according to any of [1] to [4], being an ophthalmic agent.
[6] The aqueous composition according to [5], being an eye drop.
[7] The aqueous composition according to any of [1] to [6], being a prophylactic and/or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma, and ocular fundus diseases. [0019]
L8] The aqueous composition according^^to. any of [1]
to [7], further containing one or more selected from the
group consisting of al receptor blockers, a2 receptor agonists, carbonic anhydrase inhibitors, prostaglandins, sympathomimetics, parasympathomimetics, calcium antagonists, and cholinesterase inhibitors.
[9] The aqueous composition according to any of [1] to [7] , further containing one or more selected from the group consisting of latanoprost, dorzolamide, brinzolamide, a salt of latanoprost, a salt of dorzolamide,. a salt of brinzolamide, a solvate of latanoprost or the salt thereof, a solvate of dorzolamide or the salt thereof, and a solvate of brinzolamide or the salt thereof.
[0020]
[10] A pharmaceutical preparation obtained by storing the aqueous composition according to any of [1] to [9] in a container made of polyc-lefin-based resin.
[11] The pharmaceutical preparation according to [10], wherein the polyolefin-based resin is polyethylene or polypropylene.
[12] The pharmaceutical preparation according to [10] or [11], wherein the container made of polyolefin-based resin is a container for eye drops. [0021]
[13] A method for reducing discoloration of an aqueous composition, the method comprising the step of incorporating a p blocker in an aqueous composition .comprising a compound represented by-_£ormula (1) or a salt thereof, or a solvate of the compound or the salt thereof,
[14] The method according to [13], wherein the compound represented by Formula (1) is ripasudil.
[15] The method according to [13] or [14], wherein
the p blocker is one or more selected from the group consisting of carteolol, timolol, nipradilol, betaxolol, levobunolol, befunolol, metipranolol, a salt of carteolol, a salt of timolol, a salt of nipradilol, a salt of betaxolol, a salt of levobunolol, a salt of befunolol, a salt of metipranolol, a solvate of carteolol or the salt thereof, a solvate of timolol or the salt thereof, a solvate of nipradilol or the salt thereof, a solvate of
betaxolol or the salt thereof, a solvate of levobunolol or the salt thereof, a solvate of befunolol or the salt thereof, and a solvate of metipranolol or the salt thereof.
[16] The method according to [13] or [14], wherein
the fi blocker is one or more selected from the group consisting of carteolol, timolol, nipradilol, a salt of carteolol, a salt of timolol, a salt of nipradilol, a solvate of carteolol or the salt thereof, a solvate of timolol or the salt thereof, and a solvate of nipradilol or the salt thereof.
[17] The method according to any of [13] to [16], wherein the aqueous composition is an ophthalmic agent.
[18] The method according to [17], wherein the ophthalmic agent is an eye drop-,—
[19] The method according to any of [13] to [18], wherein the aqueous composition is a prophylactic and/or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma, and ocular fundus diseases. [0022]
[20] The method according to any of [13] to [19], wherein the aqueous composition further contains one or more selected from the group consisting of ccl receptor blockers, a2 receptor agonists, carbonic anhydrase inhibitors, prostaglandins, sympathomimetics, parasympathomimetics, calcium antagonists, and cholinesterase inhibitors.
[21] The method according to any of [13] to [19], wherein the aqueous composition further contains one or more selected from the group consisting of latanoprost, dorzolamide, brinzolamide, a salt of latanoprost, a salt of dorzolamide, a salt of brinzolamide, a solvate of latanoprost or the salt thereof, a solvate of dorzolamide or the salt thereof, and a solvate of brinzolamide or the salt thereof. [00231
[22] The method according to any of [13] to [21], further comprising the step of storing the aqueous composition in a container made of polyolefin-based resin.
[23] The method according to [22], wherein the polyolefin-based resin is polyethylene or polypropylene.
[24] The method according to [22] or [23] , wherein the container made of polyolefin-based resin is a container for eye drops. [0024]
[25] A method for suppressing crystal precipitation of an aqueous composition, the method comprising the step of incorporating a p blocker in an aqueous composition-containing a compound represented by Formula (1) or a salt thereof, or a solvate of the compound or the salt thereof.
[26] The method according to [25] ,. wherein the compound represented by Formula (1) is ripasudil.
[27] The method according to [25] or [26] , wherein the (3 blocker is one or more selected from the group
consisting of carteolol, timolol, nipradilol, betaxolol, levobunolol, befunolol, metipranolol, a salt of carteolol, a salt of timolol, a salt of nipradilol, a salt of betaxolol, a salt of levobunolol, a salt of befunolol, a salt of metipranolol, a solvate of carteolol or the salt thereof, a solvate of timolol or the salt thereof, a solvate of nipradilol or the salt thereof, a solvate of betaxolol or the salt thereof, a solvate of levobunolol or the salt thereof, a solvate of befunolol or the salt thereof, and a solvate of metipranolol or the salt thereof.
[28] The method according to [25] or [26] , wherein
the (3 blocker is one or more selected from the group consisting of carteolol, timolol, nipradilol, a salt of
carteolol, a salt—o£-timolol, a salt of nipradilol, a
solvate of carteolol or the salt thereof, a solvate of timolol or the salt thereof, and a solvate of nipradilol or the salt thereof.
[29] The method according to any of [25] to [28] , wherein the aqueous composition is an ophthalmic agent.
[30] The method according to [29] , wherein the ophthalmic agent is an eye drop.
[31] The method according to any of [25] to [30] , wherein the aqueous composition is a prophylactic and/or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma, and ocular fundus diseases. [0025]
[32] The method according to any of [25] to [31], wherein the aqueous composition further contains one or more selected from the group consisting of
KW0288 - 23 -
Examples of the halogen atom in Formula (1) include a fluorine atom, a chlorine atom, and a bromine atom. In Formula (1), a fluorine atom or a bromine atom is preferred as the halogen atom, and a fluorine atom is particularly preferred.
Further, in Formula (1), the carbon atom forming the
homopiperazine ring substituted with the methyl group is
an asymmetric carbon atom. As a result, stereoisomerism
occurs. The compound represented by Formula (1) includes
all the stereoisomers, and may be a single stereoisomer
or a mixture of various stereoisomers at any given ratio,
Preferred as the compound represented by Formula (1) is a
compound having the S configuration as the absolute
configuration.
[0042]
The salt of the compound represented by Formula (1) is not particularly limited as long as it is a pharmacologically acceptable salt, and specific examples of the salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromate; and organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate, with hydrochloride being preferred.
The compound represented by Formula (1) or a salt thereof may also be in the form of a hydrate or a solvate
KW02 8 8
- 24 -
such as an alcohol solvate, and is preferably in the form of a hydrate. [0043]
Specific examples of the compound represented by Formula (1) or a salt thereof or a solvate of the compound or the salt thereof include:
ripasudil (chemical name: 4-fluoro-5-{ [ (2S)-2-methyl-l,4~diazepan-l-yl]sulfonyl}isoquinoline) or a salt thereof or a solvate of ripasudil or the salt thereof; and
4-bromo-5-{[(2S)-2-methyl-l,4-diazepan-l-
yl]sulfonyl}isoquinoline or a salt thereof or a solvate
of 4-bromo-5-{[(2S)-2-methyl-l,4~diazepan-l-
yl]sulfonyljisoquinoline or the salt thereof.
[0044]
The compound represented by Formula (1) or a salt thereof or a solvate of the compound or the salt thereof is preferably ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, or 4~bromo-5-{ [ (2S)-2-methyl-l,4-diazepan-l-yl] sulfonyl}isoquinoline or a salt thereof or a solvate of 4-bromo-5-{[(2S)-2-methyl-l,4-diazepan-1-yl]sulfonyl}isoquinoline or the salt thereof, more preferably ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, still more preferably ripasudil or a hydrochloride thereof or a hydrate of ripasudil or the hydrochloride thereof, and particularly preferably a ripasudil hydrochloride hydrate (ripasudil
KW0288
- 25 -
monohydrochloride dihydrate) represented by the following
structural formula:
[0045]
^N
HCI -2H20
[0046]
[0047]
The compound represented by Formula (1) or a salt thereof or. a solvate of the compound or the salt thereof is known and can be produced using a fcnown method. Specifically-,- ripasudil or a salt thereof or a sol-vate of ripasudil or the salt thereof can be produced using the method described in WO1999/020620 or WO2006/057397, for example. 4-Bromo-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyljisoquinoline or a salt thereof or a solvate of 4-bromo-5-{[(2S)-2-methyl-1,4-diazepan-l-yl]sulfonyljisoquinoline or the salt thereof can be produced using the method described in WO2Q06/115244, for example.
[0048]
The content of the compound represented by Formula
(1) or a salt thereof or a solvate of the compound or the salt thereof in the aqueous composition is not particularly limited, and may be determined as
KW0288 - 26 -
appropriate, in consideration of the target disease, or the sex, age, or symptoms of the patient, for example. From the viewpoint of achieving excellent pharmacological action, however, the content of the compound represented by Formula (1) or a salt thereof or a solvate of the compound or the salt thereof is preferably 0,01 to 10 w/v%, more preferably 0.02 to 8 w/v%, and particularly preferably 0.04 to 6 w/v%, calculated as the free form of the compound represented by Formula (!), based on the total volume of the aqueous composition. In particular, when ripasudil is used as the compound represented by Formula (1), from the viewpoint of achieving excellent pharmacological action, the content of ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof is preferably 0.05 to 5 w/v%, more preferably 0.1 to 3 w/v%, and particularly preferably 0.15 to 2 w/v%, calculated as the free form, based on the total volume of the aqueous composition. [0049]
As used herein, the "p blocker" is not particularly limited as long as it has p-blocking action, and specific examples of such p blockers include carteolol, timolol, nipradilol, betaxolol, levobunolol, befunolol, metipranolol, pharmaceutically acceptable salts thereof, and solvates of such a compound or pharmaceutically acceptable salt thereof with water, an alcohol, or the like, and these can be used singly or in combination of
KW028 8 - 27 -
two or more. The pharmaceutically acceptable salt is not particularly limited, and specific examples of the pharmaceutically acceptable salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromate; and organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate.
Preferred as the p blocker is one or more selected from the group consisting of carteolol, timolol, nipradilol, a salt of carteolol, a salt of timolol, a salt of nipradilol, a solvate of carteolol or the salt thereof, a solvate of timolol or the salt thereof, and a .solvate of nipradilol or the salt thereof, more preferred is one or more selected from the group consisting of carteolol hydrochloride (chemical name: 5-[(2RS)-3-(1,1-dimethylethyl)amino-2-hydroxypropyloxy]-3,4-dihydroquinolin-2(1H)-one monohydrochloride), timolol maleate (chemical name: (2S)-1-[(1,1-dimethylethyl)amino] -3-(4-morpholin-4-yl-l,2,5-thiadiazol-3-yloxy)propan-2-ol monomaleate), and nipradilol (chemical name: 3,4-dihydro-8-(2-hydroxy-3-isopropylamino)propoxy-3-nitroxy-2H-l-benzopyran), and particularly preferred is one or more selected from the group consisting of carteolol hydrochloride and nipradilol.
KW0288
- 28 -
Each of these p blockers is known, and may be produced using a known method, or a commercially available product may be used. [0050]
The p blocker has reducing action for discoloration during high-temperature preservation, and in addition suppressing action for crystal precipitation during low-temperature preservation. As specifically disclosed in Test Examples 2, 3, and 4, it was found that, although the aqueous composition containing the compound represented by Formula (1) typified by ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof can suffer from crystal precipitation during low-temperature preservation, further incorporation of carteolol, timolol, or niprad.i 1 ol_in the aqueous composition suppresses crystal precipitation during low-temperature preservation in comparison with the case where the aqueous composition does not contain any of them. Accordingly, the aqueous composition containing the compound represented by Formula (1) or a salt thereof or a solvate of the compound or the salt thereof and the p blocker undergoes reduced discoloration during high-temperature preservation, and crystal precipitation duiing low-temperature preservation is also suppressed, and thus has an advantage of excellent preservation stability. [0051}
KW0288 - 29 -
While the content of the p blocker in the aqueous composition is not particularly limited, from the viewpoint of discoloration-reducing action and/or crystal
precipitation-suppressing action, the content of the p blocker is preferably 0.01 to 10 w/v%, more preferably 0.04 to 4 w/v%, and particularly preferably 0.075 to 2.5 w/v% based on the total volume of the aqueous composition
While the content ratio by mass of the p blocker to the compound represented by Formula (1) or a salt thereof or a solvate of the compound or the salt thereof in the aqueous composition is not particularly limited, from the viewpoint of discoloration-reducing action and/or crystal precipitation-suppressing action, the content ratio by mass of the p blocker is preferably 0.02 to 30 parts by mass, more preferably 0..2_to 15 parts by mass, and particularly preferably 0.5 to 10 parts by mass, with respect to 1 part by mass of the compound represented by Formula (1) calculated as the free form. In particular, when the compound represented by Formula (1) or a salt thereof or a solvate of the compound or the salt thereof is ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, from the viewpoint of discoloration-reducing action and/or crystal precipitation-suppressing action, the content ratio by mass of the p blocker is preferably 0.005 to 20 parts by mass, more preferably 0.005 to 12.5 parts by mass, and particularly preferably 0.25 to 7-5 parts by mass, with respect to 1 part by mass
KW0288 - 30 -
of ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, calculated as the free form. [0052]
In particular, when the |3 blocker is carteolol or a salt thereof or a solvate of carteolol or the salt thereof, from the viewpoint of discoloration-reducing action and/or crystal precipitation-suppressing action, the content of carteolol or a salt thereof or a solvate of carteolol or the salt thereof is preferably 0.1 to 5 w/v%, more preferably 0.5 to 3 w/v%, and particularly preferably 1 to 2 w/v%, calculated as the free form of carteolol, based on the total volume of the aqueous composition.
While" the content ratio by mass of carteolol or a salt thereof or a solvate of carteolol or the salt thereof to the compound represented by Formula <1) or a salt thereof or a solvate of the compound or the salt thereof in the aqueous composition is not particularly limited, from the viewpoint of discoloration-reducing action and/or crystal precipitation-suppressing action, the content ratio by mass of carteolol or a salt thereof or a solvate of carteolol or the salt thereof is preferably 0.25 to 20 parts by mass, more preferably 0.75 to 12.5 parts by mass, and particularly preferably 1.5 to 7.5 parts by mass, calculated as the free form, with respect to 1 part by mass of the compound represented by Formula (1) calculated as the free form. In particular, when the compound represented by Formula (1) or a salt
KW0288 - 31 -
thereof or a solvate of the compound or the salt thereof is ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, from the viewpoint of discoloration-reducing action and/or crystal precipitation-suppressing action, the content ratio by mass of carteolol or a salt thereof or a solvate of carteolol or the salt thereof is preferably 0.5 to 15 parts by mass, more preferably 1 to 10 parts by mass, and particularly preferably 2 to 5 parts by mass, calculated as the free form, with respect to 1 part by mass of ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, calculated as the free form. [0053]
When the p blocker is timolol or a salt thereof or a solvate thereof-^ from the viewpoint of discoloration-— reducing action and/or crystal precipitation-suppressing action, the content of timolol or a salt thereof or a solvate of timolol or the salt thereof is preferably 0.01 to 5 w/v%, more preferably 0.02 to 2 w/v%, preferably 0.05 to 0.75 w/v%, and particularly preferably 0.25 to 0.5 w/v%, calculated as the free form of timolol, based on the total volume of the aqueous composition.
While the content ratio by mass of timolol or a salt thereof or a solvate of timolol or the salt thereof to the compound represented by Formula (1) or a salt thereof or a solvate of the compound or the salt thereof in the aqueous composition is not particularly limited, from the viewpoint of discoloration-reducing action and/or crystal
KW0288 - 32 -
precipitation-suppressing action, the content ratio by mass of timolol or a salt thereof or a solvate of timolol or the salt thereof is preferably 0.05 to 6 parts by mass, more preferably 0.3 to 4 parts by mass, and particularly preferably 0.6 to 2 parts by mass, calculated as the free form, with respect to 1 part by mass of the compound represented by Formula (1), calculated as the free form. In particular, when the compound represented by Formula
(1) or a salt thereof or a solvate of the compound or the salt thereof is ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, from the viewpoint of discoloration-reducing action and/or crystal precipitation-suppressing action, the content ratio by mass of timolol or a salt thereof or a solvate of timolol or the__s_a.lt thereof is preferably 0.01 to 5 parts by mass, more preferably 0.1 to 3 parts by mass, and particularly preferably 0.5 to 1.5 parts by mass, calculated as the free form, with respect to 1 part by mass of ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, calculated as the free form.
[0054]
Further, when the J3 blocker is nipradilol or a salt thereof or a solvate of nipradilol or the salt thereof, from the viewpoint of discoloration-reducing action and/or crystal precipitation-suppressing action, the content of nipradilol or a salt thereof or a solvate of nipradilol or the salt thereof is preferably 0.05 to 2 w/v%, more preferably 0.1 to 1 w/v%, and particularly
KW0288 - 33 -
preferably 0.3 to 0.5 w/v%, calculated as the free form of nipradilol, based on the total volume of the aqueous composition.
While the content ratio by mass of nipradilol or a salt thereof or a solvate of nipradilol or the salt thereof to the compound represented by Formula (1) or a salt thereof or a solvate of the compound or the salt thereof in the aqueous composition is not particularly limited, from the viewpoint of discoloration-reducing action and/or crystal precipitation-suppressing action, the content ratio by mass of nipradilol or a salt thereof or a solvate of nipradilol or the salt thereof is preferably 0.025 to 5 parts by mass, more preferably 0.075 to 2 parts by mass, and particularly preferably 0.25 to 1 parts by mass, calculated as the—free form of nipradilol or a salt thereof or a solvate of nipradilol or the salt thereof, with respect to 1 part by mass of the compound represented by Formula (1) calculated as the free form. In particular, when the compound represented by Formula (1) or a salt thereof or a solvate of the compound or the salt thereof is ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, from the viewpoint of discoloration-reducing action and/or crystal precipitation-suppressing action, the content ratio by mass of nipradilol or a salt thereof or a solvate of nipradilol or the salt thereof is preferably 0.05 to 3 parts by mass, more preferably 0.1 to 1.5 parts by mass, and particularly preferably 0.5 to 0.75 parts by
KW0288
- 34 -
mass, calculated as the free form, with respect to 1 part by mass of ripasudil or a salt thereof or a solvate of ripasudil or the salt thereof, calculated as the free form. [0055]
It is preferred to further incorporate an amino compound in the aqueous composition (in particular, the aqueous composition containing timolol or a salt thereof or a solvate of timolol or the salt thereof as a p blocker). As disclosed in Test Example 5 below, incorporation of an amino compound was found to provide the aqueous composition with excellent crystal precipitation-suppressing effect when the aqueous composition is preserved at low temperature over a long period.
The "amino compound" is a compound having an amino group or a salt thereof, and not particularly limited herein as long as it has been confirmed to be basically safe for administration to a human body, and specific examples of such amino compounds include aspartic acid, sodium aspartate, ethyl aminobenzoate, alanine, arginine, arginine hydrochloride, epsilon-aminocaproic acid, ethylenediamine, glycine, glucosamine hydrochloride, glutamine, glutamic acid, glutamic acid hydrochloride, potassium glutamate, sodium glutamate, cystine, cysteine, cysteine hydrochloride, taurine, trometamol, urea, histidine, histidine hydrochloride, phenylalanine,
KW0288 - 35 -
phenprobamate, methionine, monoethanolamine, lysine, lysine hydrochloride, and leucine, and these can be used singly or in combination of two or more. Each of them is a known compound, and can be produced using a known method, or a commercially available product can be used.
Preferred as the amino compound is epsilon-aminocaproic acid, glutamic acid, sodium glutamate, taurine, trometamol, or monoethanolamine. [0056]
The content of the amino compound in the aqueous composition is not particularly limited, and may be determined on the basis of the contents of the compound represented by Formula (1) or a salt thereof or a solvate
of the compound or the salt thereof and the p blocker (in particular, timolol or a salt thereof or a solvate of timolol or the salt thereof) in the aqueous composition determined as appropriate, in consideration of the target disease, or the sex, age, or symptoms of the patient, for example, and crystal precipitation-suppressing effect intended. From the viewpoint of achieving excellent crystal precipitation-suppressing action, the content of the amino compound is preferably 0.01 to 20 w/v%, more preferably 0.2 to 10 w/v%, and particularly preferably 0.25 to 1.5 w/v% based on the total volume of the aqueous composition. When monoethanolamine is used as the amino compound, the content of monoethanolamine is preferably 0.05 to 5 w/v%, more preferably 0.1 to 2 w/v%, and
KW0288 - 36 -
particularly preferably 0.5 to 1 w/v% based on the total volume of the aqueous composition. [0057]
