|MIT KUDO TORI TRONOMIAUS 20170368075A1 ETA MALI ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0368075 A1 SAWAI (43 ) Pub . Date : Dec . 28 , 2017 (54 ) COMPOSITION (52 ) U .S . CI. CPC ...... A61K 31 /551 (2013 . 01 ) ; C08L 23 / 12 ( 71 ) Applicant: KOWA COMPANY, LTD ., Nagoya - shi ( 2013 .01 ); A61K 31 /5575 ( 2013 .01 ); A61K ( JP ) 45 / 06 ( 2013 .01 ) ; A61K 9 /0048 ( 2013 .01 ) ; A61K 31 /502 ( 2013 .01 ) ; A6IK 31 / 18 (72 ) Inventor : Isamu SAWAI, Fuji - shi ( JP ) ( 2013 . 01 ) ; A61K 9 /08 (2013 . 01 ) ; A61K ( 73) Assignee: KOWA COMPANY, LTD ., Nagoya- shi 2300 /00 (2013 . 01 ) ( JP ) (57 ) ABSTRACT (21 ) Appl. No. : 15/ 534 , 875 A technique is provided for reducing the discoloration of an (22 ) PCT Filed : Dec. 11 , 2015 aqueous composition containing a halogenated derivative during high - temperature preservation . An aque ( 86 ) PCT No. : PCT/ JP2015 /084803 ous composition comprising a compound represented by $ 371 (c ) ( 1 ) , Formula ( 1 ) : ( 2 ) Date : Jun . 9 , 2017 (30 ) Foreign Application Priority Data Dec . 12 , 2014 ( JP ) ...... 2014 -252182 HN Publication Classification " s = O X ( 51 ) Int. Cl. CH3 A6IK 31/ 551 ( 2006 . 01 ) A61K 31/ 5575 ( 2006 . 01 ) A61K 9 /08 ( 2006 . 01 ) A61K 9 /00 ( 2006 . 01) A61K 31/ 502 ( 2006 . 01 ) A61K 31/ 18 ( 2006 .01 ) wherein X represents a halogen atom , CO8L 23/ 12 ( 2006 . 01 ) or a salt thereof, or a solvate of the compound or the salt A61K 45 / 06 ( 2006 . 01 ) thereof, and a . US 2017 /0368075 A1 Dec . 28 , 2017

COMPOSITION CITATION LIST TECHNICAL FIELD Patent Literature [0007 ] [ Patent Literature 1 ] JP - B -4212149 [0001 ] The present invention relates to an aqueous com [0008 ] [Patent Literature 2 ] W02006 / 115244 position and the like . 0009 ] [ Patent Literature 31 W02006 / 068208 10010 ] [Patent Literature 4 ] JP - B - 5557408 BACKGROUND ART [0011 ] [Patent Literature 5 ] W02012/ 105674 [ 0002 ] It is known that halogenated isoquinoline deriva tives such as ripasudil (chemical name: 4 - fluoro - 5 - {[ (2S ) SUMMARY OF THE INVENTION 2 -methyl - 1 , 4 -diazepan - 1 - yl] sulfonyl } isoquinoline ) repre sented by the following structural formula : Technical Problem [0012 ] An ophthalmic agent is generally a composition containing water ( aqueous composition ). To produce a preparation of a halogenated isoquinoline derivative , ripa HN sudil , as an ophthalmic agent or the like , the present inventor initially prepared an aqueous composition containing ripa S = OF sudil and the preservation stability was investigated , and as H a result the aqueous composition was revealed to be disad cH: vantageously discolored over time due to high - temperature preservation . [0013 ] 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 [ 0003] and 4 -bromo - 5 - { [( 2S ) -2 -methyl - 1, 4 -diazepan - 1 derivative during high -temperature preservation . yl] sulfonyl } isoquinoline represented by the following struc tural formula : Solution to Problem [0014 ] Thus, the present inventors conducted extensive research to solve the above- described problem , and found that further incorporation of a prostaglandin such as bimato HN prost and in an aqueous composition containing a halogenated isoquinoline derivative such as ripasudil can S = O Br reduce the discoloration during high - temperature preserva tion , thus completing the present invention . CH3 [0015 ]. In summary, the present invention provides an aqueous composition comprising a compound represented by Formula ( 1)

[0004 ] 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 HN diseases. Specifically , these halogenated isoquinoline derivatives have been reported to be useful, for example , for s = 0 X the prevention or treatment of , glau coma, and the like (Patent Literature 3 , for example ) , or for CH3 the prevention or treatment of ocular fundus diseases such as age -related macular degeneration and the like ( Patent Lit erature 4 , for example ) . [0005 ] Hence , it is extremely useful to establish a tech nique for producing stable preparations of these halogenated [0016 ] wherein X represents a halogen atom , isoquinoline derivatives as ophthalmic agents , for example . [0017 ] or a salt thereof, or a solvate of the compound or [0006 ] Patent Literature 5 describes a combination of the salt thereof, and a prostaglandin . ripasudil ( ( S ) - ( - ) - 1 - ( 4 - fluoro - 5 - isoquinolinesulfonyl) - 2 [0018 ] Further, the present invention provides a method methyl- 1 , 4 -homopiperazine ) or a salt thereof or a solvate of for reducing discoloration of an aqueous composition , the ripasudil or the salt thereof, and a prostaglandin such as method comprising the step of incorporating a prostaglandin latanoprost. However, Patent Literature 5 only discloses that in an aqueous composition comprising a compound repre a solution containing 0 . 4 % ripasudil and an con sented by Formula ( 1 ) or a salt thereof, or a solvate of the taining 0 .05 % latanoprost were sequentially instilled in one compound or the salt thereof. eye of a cynomolgus monkey , and an aqueous composition containing both of these components , storing the same in a Effects of Invention container, and the preservation stability over time, etc ., are [0019 ] In accordance with the present invention , the dis not disclosed at all. coloration of an aqueous composition containing a haloge US 2017 /0368075 A1 Dec . 28 , 2017 nated isoquinoline derivative such as ripasudil during high [ 0033 ] [ 11 ] The pharmaceutical preparation according to temperature preservation can be reduced . [ 10 ] , wherein the polyolefin -based resin is polyethylene or polypropylene . DESCRIPTION OF EMBODIMENTS [0034 ] [ 12 ] The pharmaceutical preparation according to [ 10 ] or [ 11 ] , wherein the container made of polyolefin -based [0020 ] The present specification discloses , although is in resin is a container for eye drops . no way limited to , the following embodiments of invention , [0035 ] [ 13 ] A method for reducing discoloration of an by way of example . aqueous composition , the method comprising the step of [ 0021] [ 1 ] An aqueous composition comprising a com incorporating a prostaglandin in an aqueous composition pound represented by Formula ( 1) : comprising a compound represented by Formula ( 1 ) or a salt thereof, or a solvate of the compound or the salt thereof. [0036 ] [ 14 ] The method according to [ 13 ] , wherein the ( 1) compound represented by Formula ( 1 ) is ripasudil . [0037 ] [ 15 ] The method according to [ 13 ] or [ 14 ], wherein =O the prostaglandin is one or more selected from the group Z consisting of isopropyl , , , SEO X , latanoprost, a salt of isopropyl unoprostone , a salt of tafluprost, a salt of travoprost , a salt of bimatoprost, a salt of latanoprost , a solvate of isopropyl unoprostone or the salt thereof, a solvate of tafluprost or the salt thereof, a solvate of travoprost or the salt thereof, a solvate of bimato prost or the salt thereof , and a solvate of latanoprost or the salt thereof [ 0022 ] wherein X represents a halogen atom , [0038 ] [ 16 ] The method according to [ 13 ] or [ 14 ], wherein [0023 ] or a salt thereof, or a solvate of the compound or the prostaglandin is one or more selected from the group the salt thereof, and a prostaglandin . consisting of tafluprost , travoprost, bimatoprost, latanoprost , [0024 ] [ 2 ] The aqueous composition according to [ 1 ] , a salt of tafluprost, a salt of travoprost, a salt of bimatoprost , wherein the compound represented by Formula ( 1 ) is ripa a salt of latanoprost, a solvate of tafluprost or the salt thereof , sudil . a solvate of travoprost or the salt thereof , a solvate of [0025 ] [ 3 ] The aqueous composition according to [ 1 ] or bimatoprost or the salt thereof, and a solvate of latanoprost [ 2 ] , wherein the prostaglandin is one or more selected from or the salt thereof. the group consisting of isopropyl unoprostone, tafluprost, [0039 ] [ 17 ] The method according to any of [ 13 ] to [ 16 ] , travoprost , bimatoprost, latanoprost , and salts thereof, as wherein the aqueous composition is an ophthalmic agent. well as solvates thereof. 10040 ] [ 18 ] The method according to [ 17 ] , wherein the [0026 ] [ 4 ] The aqueous composition according to [ 1 ] or ophthalmic agent is an eye drop . [ 2 ] , wherein the prostaglandin is one or more selected from [0041 ] [ 19 ] The method according to any of [ 13 ] to [ 18 ], the group consisting of tafluprost , travoprost, bimatoprost , wherein the aqueous composition is a prophylactic and /or therapeutic agent for a disease selected from the group latanoprost, and salts thereof, as well as solvates thereof. consisting of ocular hypertension , , and ocular [0027 ] [ 5 ] The aqueous composition according to any of fundus diseases . [ 19 to [4 ], being an ophthalmic agent. [ 0042 ] [ 20 ] The method according to any of [ 13 ] to [ 19] , [ 0028 ] [6 ] The aqueous composition according to [ 5 ] , wherein the aqueous composition further contains one or being an eye drop . more selected from the group consisting of al receptor [0029 ] [7 ] The aqueous composition according to any of blockers , a2 receptor agonists , ß blockers , carbonic anhy [ 19 to [6 ] , being a prophylactic and / or therapeutic agent for drase inhibitors , sympathomimetics , parasympathomimet a disease selected from the group consisting of ocular ics , calcium antagonists , and cholinesterase inhibitors. hypertension , glaucoma, and ocular fundus diseases . [0043 ] [ 21 ] The method according to any of [13 ] to [19 ], [ 0030 ] [ 8 ] The aqueous composition according to any of wherein the aqueous composition further contains one or [ 19 to [ 7 ] , further containing one or more selected from the more selected from the group consisting of nipradilol, dor group consisting of al receptor blockers , a2 receptor ago zolamide , , , a salt of nipradilol, a salt of nists , B blockers , carbonic anhydrase inhibitors , sympath , a salt of brinzolamide , a salt of timolol, a omimetics , parasympathomimetics , calcium antagonists , solvate of nipradilol or the salt thereof, a solvate of dorzo and cholinesterase inhibitors . lamide or the salt thereof, a solvate of brinzolamide or the [0031 ] [ 9] The aqueous composition according to any of salt thereof, and a solvate of timolol or the salt thereof. [ 19 to [ 7 ] , further containing one or more selected from the [0044 ] [ 22 ] The method according to any of [ 13 ] to [ 21 ] , group consisting of nipradilol, dorzolamide , brinzolamide , further comprising the step of housing the aqueous compo timolol, a salt of nipradilol, a salt of dorzolamide , a salt of sition in a container made of polyolefin -based resin . brinzolamide , a salt of timolol, a solvate of nipradilol or the [0045 ] [ 23 ] The method according to [22 ], wherein the salt thereof, a solvate of dorzolamide or the salt thereof, a polyolefin -based resin is polyethylene or polypropylene . solvate of brinzolamide or the salt thereof , and a solvate of [0046 ] [ 24 ] Themethod according to [22 ] or [23 ], wherein timolol or the salt thereof. the container made of polyolefin - based resin is a container [ 0032 ] [ 10 ] A pharmaceutical preparation obtained by for eye drops . housing the aqueous composition according to any of [ 19 to [0047 ] [25 ] A method for suppressing crystal precipitation [ 9 ] in a container made of polyolefin -based resin . of an aqueous composition , the method comprising the step US 2017 /0368075 A1 Dec . 28 , 2017 of incorporating a prostaglandin in an aqueous composition nitrate , hydrofluoride, and hydrobromate ; and organic acid comprising a compound represented by Formula ( 1 ) or a salt salts such as acetate , tartrate , lactate , citrate , fumarate , thereof, or a solvate of the compound or the salt thereof . maleate , succinate , methanesulfonate , ethanesulfonate , ben [0048 ] [26 ] The method according to [25 ], wherein the zenesulfonate , toluenesulfonate , naphthalenesulfonate , and compound represented by Formula ( 1 ) is ripasudil . camphorsulfonate , with hydrochloride being preferred . [ 0049 ] [ 27 ] The method according to [ 25 ] or [26 ] , wherein [0059 ] The compound represented by Formula ( 1 ) or a salt the prostaglandin is one or more selected from the group thereofmay also be in the form of a hydrate or a solvate such consisting of isopropyl unoprostone , tafluprost, travoprost , as an alcohol solvate , and is preferably in the form of a bimatoprost, latanoprost , a salt of isopropyl unoprostone , a hydrate . salt of tafluprost , a salt of travoprost , a salt of bimatoprost, [0060 ] Specific examples of the compound represented by a salt of latanoprost, a solvate of isopropyl unoprostone or Formula ( 1 ) or a salt thereof or a solvate of the compound the salt thereof, a solvate of tafluprost or the salt thereof, a or the salt thereof include : solvate of travoprost or the salt thereof, a solvate of bimato [ 0061 ] ripasudil ( chemical name: 4 - fluoro - 5 - { [ ( 2S ) - 2 prost or the salt thereof, and a solvate of latanoprost or the methyl- 1 , 4 - diazepan - 1 -yl ] sulfonyllisoquinoline ) or a salt salt thereof. thereof or a solvate of ripasudil or the salt thereof; and [ 0050 ] [28 ] The method according to [ 25 ] or [ 26 ], wherein [ 0062 ] 4 - bromo - 5 - { [ (2S ) - 2 -methyl - 1 , 4 - diazepan - 1 - yl] the prostaglandin is one or more selected from the group sulfonyl isoquinoline or a salt thereof or a solvate of consisting of tafluprost , travoprost , bimatoprost, latanoprost 4 - bromo - 5 - { [ (2S ) - 2 -methyl - 1 , 4 - diazepan - 1 -yl ] sulfonylliso a salt of tafluprost , a salt of travoprost , a salt of bimatoprost , quinoline or the salt thereof. a salt of latanoprost, a solvate of tafluprost or the salt thereof, [0063 ] The compound represented by Formula ( 1) or a salt a solvate of travoprost or the salt thereof, a solvate of thereof or a solvate thereof is preferably ripasudil or a salt bimatoprost or the salt thereof , and a solvate of latanoprost thereof or a solvate of ripasudil or the salt thereof, or or the salt thereof. 4 -bromo - 5 - {[ (2S )- 2 -methyl - 1, 4 -diazepan - 1 -yl ] [0051 ] [ 29 ] The method according to any of [ 25 ] to [ 28 ], sulfonyl } isoquinoline or a salt thereof or a solvate of wherein the aqueous composition is an ophthalmic agent. 4 -bromo - 5 - { [ ( 2S ) - 2 -methyl - 1 , 4 - diazepan - 1 - yl ] [0052 ] [ 30 ] The method according to [29 ], wherein the sulfonyl } isoquinoline or the salt thereof, more preferably ophthalmic agent is an eye drop . ripasudil or a salt thereof or a solvate of ripasudil or the salt [ 0053 ] [ 31 ] The method according to any of [ 25 ] to [ 30 ] , thereof, still more preferably ripasudil or a hydrochloride wherein the aqueous composition is a prophylactic and /or thereof or a hydrate of ripasudil or the hydrochloride thereof, therapeutic agent for a disease selected from the group and particularly preferably a ripasudil hydrochloride hydrate consisting of ocular hypertension , glaucoma, and ocular (ripasudil monohydrochloride dihydrate ) represented by the fundus diseases. following structural formula : [ 0054 ] [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 al receptor blockers , a2 receptor agonists , ß blockers, carbonic anhy UN drase inhibitors, sympathomimetics , parasympathomimet ics , calcium antagonists , and cholinesterase inhibitors . S = OF [0055 ] [33 ] The method according to any of [ 25 ] to [ 31 ] , wherein the aqueous composition further contains one or CH3 more selected from the group consisting of nipradilol, dor zolamide, brinzolamide , timolol , a salt of nipradilol, a salt of ON •HCI •2H20 . dorzolamide , a salt of brinzolamide , a salt of timolol, a solvate of nipradilol or the salt thereof, a solvate of dorzo lamide or the salt thereof, a solvate of brinzolamide or the [0064 ] The compound represented by Formula ( 1 ) or a salt salt thereof, and a solvate of timolol or the salt thereof. thereof or a solvate of the compound or the salt thereof is [0056 ] Examples of the halogen atom in Formula ( 1 ) known and can be produced using a known method . Spe include a fluorine atom , a chlorine atom , and a bromine cifically , ripasudil or a salt thereof or a solvate of ripasudil atom . In Formula ( 1 ) , a fluorine atom or a bromine atom is or the salt thereof can be produced using the method preferred as the halogen atom , and a fluorine atom is described in WO1999/ 020620 or WO2006 /057397 , for particularly preferred . example . 4 -Bromo - 5 - { [( 2S ) -2 -methyl - 1, 4 -diazepan - 1 -yl ] [0057 ] Further, in Formula ( 1) , the carbon atom forming sulfonyl } isoquinoline or a salt thereof or a solvate of the homopiperazine ring substituted with the methyl group 4 - bromo- 5 - { [ (2S ) - 2 -methyl - 1 ,4 - diazepan - 1 - yl] sulfonylliso is an asymmetric carbon atom . As a result , stereoisomerism quinoline or the salt thereof can be produced using the occurs. The compound represented by Formula ( 1 ) includes method described in WO2006 / 115244 , for example . all the stereoisomers , and may be a single stereoisomer or a [ 0065 ] The content of the compound represented by For mixture of various stereoisomers at any given ratio . Pre mula ( 1 ) or a salt thereof or a solvate of the compound or the ferred as the compound represented by Formula ( 1 ) is a Salt thereof in the aqueous composition is not particularly compound having the S configuration as the absolute con limited , and may be determined as appropriate , in consid figuration . eration of the target disease , or the sex , age, or symptomsof [0058 ] The salt of the compound represented by Formula the patient, for example . From the viewpoint of achieving ( 1 ) is not particularly limited as long as it is a pharmaco excellent pharmacological action , however , the content of logically acceptable salt , and specific examples of the salt the compound represented by Formula ( 1 ) or a salt thereof include inorganic acid salts such as hydrochloride , sulfate , or a solvate of the compound or the salt thereof is preferably US 2017 /0368075 A1 Dec . 28 , 2017

0 .01 to 10 wiv % , more preferably 0 . 02 to 8 w / v , and point of discoloration - reducing action and/ or crystal precipi particularly preferably 0 .04 to 6 w / v % , calculated as the free tation - suppressing action , the content of the prostaglandin is form of the compound represented by Formula ( 1 ) , based on preferably 0 .00005 to 1 . 0 w / v % , more preferably 0 .00025 the total volume of the aqueous composition . In particular , to 0 . 25 w / v % , and particularly preferably 0 .00075 to 0 . 075 when ripasudil is used as the compound represented by w /v % baSed on the total volume of the aqueous composi Formula ( 1 ) , from the viewpoint of achieving excellent tion . pharmacological action , the content of ripasudil or a salt [0071 ] While the content ratio by mass of the prostaglan thereof or a solvate of ripasudil or the salt thereof is din to the compound represented by Formula ( 1 ) or a salt preferably 0 .05 to 5 w / v % , more preferably 0 . 1 to 3 w / v % , thereof or a solvate of the compound or the salt thereof in the and particularly preferably 0 . 15 to 2 w / v % , calculated as the aqueous composition is not particularly limited , from the free form , based on the total volume of the aqueous com viewpoint of discoloration - reducing action and /or crystal position . precipitation - suppressing action , the content ratio by mass [0066 ] As used herein , the " prostaglandin ” means a pros of the prostaglandin is preferably 0 . 0001 to 4 parts by mass , taglandin or a derivative thereof, and specific examples of more preferably 0 .00125 to 1 .25 parts by mass , and particu such include isopropyl unoprostone (chemi larly preferably 0 .005 to 0 . 5 parts by mass, with respect to cal name: ( + ) - isopropyl ( Z ) - 7 - [ ( 1R , 2R , 3R , 5S ) - 3 , 5 - dihy 1 part by mass of the compound represented by Formula ( 1 ) droxy - 2 - ( 3 -oxodecyl ) cyclopentyl] hept - 5 - enoate ), tafluprost calculated as the free form . In particular, when the com ( chemical name: 1 -methylethyl (5Z ) - 7 - [ ( 1R , 2R , 3R , 5S ) - 2 pound represented by Formula ( 1 ) or a salt thereof or a [ (1E )- 3 ,3 -difluoro -4 -phenoxy - 1 -butenyl ] - 3, 5 -dihydroxycy solvate of the compound or the salt thereof is ripasudil or a clopentyl] - 5 -heptenoate ), travoprost (chemical name: iso salt thereof or a solvate of ripasudil or the salt thereof, from propyl (5Z ) - 7 - ( ( 1R , 2R , 3R , 5S ) - 3 , 5 - dihydroxy - 2 - [ ( 1E , 3R ) the viewpoint of discoloration - reducing action and / or crystal 3 -hydroxy - 4 - [ 3 - ( trifluoromethyl ) phenoxy ] but- 1 - enyl] precipitation - suppressing action , the content ratio by mass cyclopentyl) hept -5 -enoate ), bimatoprost (chemical name: of the prostaglandin is preferably 0 . 0005 to 2 parts by mass , (52 )- 7 - { (1R , 2R , 3R , 5S )- 3 ,5 -dihydroxy - 2 - [( 1E , 3S )- 3 -hy more preferably 0 .0025 to 0 .75 parts by mass , and particu droxy - 5 -phenylpent - 1- en - 1- yl] cyclopentyl } - N - ethylhept- 5 larly preferably 0 .0075 to 0 .25 parts by mass , with respect enamide) , latanoprost ( chemical name: ( + ) - isopropyl ( Z ) - 7 to 1 part by mass of ripasudil or a salt thereof or a solvate [ ( 1R , 2R , 3R , 5S ) - 3 , 5 - dihydroxy - 2 - [ ( 3R ) - 3 -hydroxy - 5 of ripasudil or the salt thereof calculated as the free form . phenylpentyl] cyclopentyl ] - 5 - heptenoate ) , pharmaceutically [0072 ] In particular, when the prostaglandin is tafluprost acceptable salts thereof, and solvates of such a compound or or a salt thereof or a solvate of tafluprost or the salt thereof , pharmaceutically acceptable salt thereof with water , an from the viewpoint of discoloration - reducing action and /or alcohol, or the like , and these can be used singly or in crystal precipitation -suppressing action , the content of taflu combination of two or more . prost or a salt thereof or a solvate of tafluprost or the salt [ 0067 ] Preferred as the prostaglandin is one or more thereof is preferably 0 . 0001 to 0 .02 w / v % , more preferably selected from the group consisting of tafluprost , travoprost , 0 . 0005 to 0 .01 w / v % , and particularly preferably 0 .001 to bimatoprost , latanoprost, a salt of tafluprost , a salt of travo 0 .005 w / v % , calculated as the free form of tafluprost, based prost , a salt of bimatoprost , a salt of latanoprost , a solvate of on the total volume of the aqueous composition . tafluprost or the salt thereof, a solvate of travoprost or the [0073 ] While the content ratio by mass of tafluprost or a salt thereof, a solvate of bimatoprost or the salt thereof, and salt thereof or a solvate of tafluprost or the salt thereof to the a solvate of latanoprost or the salt thereof. compound represented by Formula ( 1 ) or a salt thereof or a 10068 ] Each of these prostaglandins is known , and may be solvate of the compound or the salt thereof in the aqueous produced using a known method , or a commercially avail composition is not particularly limited , from the viewpoint able product may be used . of discoloration - reducing action and /or crystal precipitation [ 0069] The prostaglandin has reducing action for discol suppressing action , the content ratio by mass of tafluprost or oration during high - temperature preservation , and in addi a salt thereof or a solvate of tafluprost or the salt thereof is tion suppressing action for crystal precipitation during low preferably 0 . 0001 to 0 .025 parts by mass, more preferably temperature preservation . As specifically disclosed in Test 0 .0007 to 0 .015 parts by mass , and particularly preferably Example 2 , it was found that, although the aqueous com - 0 . 002 to 0 . 005 parts by mass , calculated as the free form , position containing the compound represented by Formula with respect to 1 part by mass of the compound represented ( 1 ) typified by ripasudil or a salt thereof or a solvate of the by Formula ( 1 ) calculated as the free form . In particular, compound or the salt thereof can suffer from crystal pre - when the compound represented by Formula ( 1 ) or a salt cipitation during low -temperature preservation , further thereof or a solvate of the compound or the salt thereof is incorporation of latanoprost in the aqueous composition ripasudil or a salt thereof or a solvate of ripasudil or the salt suppresses crystal precipitation during low - temperature thereof , from the viewpoint of discoloration - reducing action preservation in comparison with the case where the aqueous and / or crystal precipitation - suppressing action , the content composition does not contain latanoprost. Accordingly, the ratio by mass of tafluprost or a salt thereof or a solvate of aqueous composition containing the compound represented tafluprost or the salt thereof is preferably 0 .0005 to 0 .02 by Formula ( 1 ) or a salt thereof or a solvate of the compound parts by mass , more preferably 0 .001 to 0 .01 parts by mass , or the salt thereof and the prostaglandin undergoes reduced and particularly preferably 0 . 003 to 0 . 004 parts by mass , discoloration during high - temperature preservation , and in calculated as the free form , with respect to 1 part by mass of addition is suppressed from crystal precipitation during ripasudil or a salt thereof or a solvate of ripasudil or the salt low - temperature preservation , and thus has an advantage of thereof calculated as the free form . excellent preservation stability . [0074 ] When the prostaglandin is travoprost or a salt [ 0070 ] While the content of the prostaglandin in the aque thereof or a solvate of travoprost or the salt thereof, from the ous composition is not particularly limited , from the view viewpoint of discoloration - reducing action and /or crystal US 2017 /0368075 A1 Dec . 28 , 2017 precipitation - suppressing action , the content of travoprost or part by mass of ripasudil or a salt thereof or a solvate of a salt thereof or a solvate of travoprost or the salt thereof is ripasudil or the salt thereof calculated as the free form . preferably 0 . 0001 to 0 . 05 w / v % , more preferably 0 .0005 to 10078 ]. Further, when the prostaglandin is latanoprost or a 0 .01 w / v % , and particularly preferably 0 . 001 to 0 .005 w / v salt thereof or a solvate of latanoprost or the salt thereof, % , calculated as the free form of travoprost, based on the from the viewpoint of discoloration -reducing action and /or total volume of the aqueous solution . crystal precipitation - suppressing action , the content of [0075 ] While the content ratio by mass of travoprost or a latanoprost or a salt thereof or a solvate of latanoprost or the salt thereof or a solvate of travoprost or the salt thereof to the salt thereof is preferably 0 . 0001 to 0 . 1 w / v % , more pref compound represented by Formula ( 1 ) or a salt thereof or a erably 0 .0005 to 0 .05 w / v % , and particularly preferably solvate of the compound or the salt thereof in the aqueous 0 .001 to 0 .01 w / v % , calculated as the free form , based on composition is not particularly limited , from the viewpoint the total volume of the aqueous composition . of discoloration -reducing action and / or crystal precipitation [0079 ] While the content ratio by mass of latanoprost or a suppressing action , the content ratio by mass of travoprost or salt thereof or a solvate of latanoprost or the salt thereof to a salt thereof or a solvate of travoprost or the salt thereof is the compound represented by Formula ( 1 ) or a salt thereof preferably 0 . 00025 to 0 .03 parts by mass, more preferably or a solvate of the compound or the salt thereof in the 0 .00075 to 0 . 07 parts by mass , and particularly preferably aqueous composition is not particularly limited , from the viewpoint of discoloration - reducing action and / or crystal 0 .0025 to 0 . 03 parts by mass , calculated as the free form , precipitation -suppressing action , the content ratio by mass with respect to 1 part by mass of the compound represented of latanoprost or a salt thereof or a solvate of latanoprost or by Formula ( 1 ) calculated as the free form . In particular, the salt thereof is preferably 0 .0005 to 0 . 1 parts by mass , when the compound represented by Formula ( 1 ) or a salt more preferably 0 .0025 to 0 .04 parts by mass , and particu thereof or a solvate thereof is ripasudil or a salt thereof or a larly preferably 0 . 0075 to 0 .03 parts by mass, calculated as solvate of the compound or the salt thereof, from the the free form , with respect to 1 part by mass of the viewpoint of discoloration - reducing action and /or crystal compound represented by Formula ( 1) calculated as the free precipitation - suppressing action , the content ratio by mass form . In particular , when the compound represented by of travoprost or a salt thereof or a solvate of travoprost or the Formula ( 1 ) or a salt thereof or a solvate of the compound salt thereof is preferably 0 . 0005 to 0 . 1 parts by mass , more or the salt thereof is ripasudil or a salt thereof or a solvate preferably 0 . 001 to 0 .05 parts by mass, and particularly of ripasudil or the salt thereof, from the viewpoint of preferably 0 .005 to 0 .02 parts by mass , calculated as the free discoloration - reducing action and / or crystal precipitation form , with respect to 1 part by mass of ripasudil or a salt suppressing action , the content ratio by mass of latanoprost thereof or a solvate of ripasudil or the salt thereof calculated or a salt thereof or a solvate of latanoprost or the salt thereof as the free form . is preferably 0 .001 to 0 . 05 parts by mass, more preferably [0076 ] When the prostaglandin is bimatoprost or a salt 0 .005 to 0 .02 parts by mass , and particularly preferably 0 .01 thereof or a solvate of bimatoprost or the salt thereof, from to 0 . 015 parts by mass, calculated as the free form , with the viewpoint of discoloration - reducing action and /or crystal respect to 1 part by mass of ripasudil or a salt thereof or a precipitation -suppressing action , the content of bimatoprost solvate of ripasudil or the salt thereof calculated as the free or a salt thereof or a solvate of bimatoprost or the salt thereof form . is preferably 0 .001 to 0 .5 w /v % , more preferably 0 .005 to [0080 ] As used herein , the “ aqueous composition " means 0 . 1 w / v % , and particularly preferably 0 .01 to 0 . 05 w / v % , a composition containing at least water, which may be in the calculated as the free form of bimatoprost, based on the total form of a liquid ( solution or suspension ) or a semi- solid volume of the aqueous composition . ( ointment) , for example , and preferably in the form of a [0077 ] While the content ratio by mass of bimatoprost or liquid . As the water in the composition , purified water , water a salt thereof or a solvate of bimatoprost or the salt thereof for injection , or sterile purified water, for example , can be to the compound represented by Formula ( 1) or a salt thereof used . or a solvate of the compound or the salt thereof in the 10081 ] While the content of water in the aqueous compo aqueous composition is not particularly limited , from the sition is not particularly limited , it is preferably 5 mass % or viewpoint of discoloration - reducing action and / or crystal more, more preferably 20 mass % or more , still more precipitation - suppressing action , the content ratio by mass preferably 50 mass % or more , even more preferably 90 of bimatoprost or a salt thereof or a solvate of bimatoprost mass % or more, and particularly preferably 90 to 99 . 8 mass or the salt thereof is preferably 0 . 001 to 2 parts by mass , % . more preferably 0 .0075 to 0 .75 parts by mass, and particu [ 0082] The aqueous composition can be prepared into larly preferably 0 .025 to 0 . 3 parts by mass , calculated as the various dosage forms in accordance with known methods free form , with respect to 1 part by mass of the compound described in the General Rules for Preparations in the represented by Formula ( 1 ) calculated as the free form . In Japanese Pharmacopoeia 16th Edition , for example . particular, when the compound represented by Formula ( 1 ) Examples of dosage forms include injections, inhalation or a salt thereof or a solvate of the compound or the salt solutions, eye drops , eye ointments , ear drops, nasal drops, thereof is ripasudil or a salt thereof or a solvate of ripasudil enemas , liquids for external use , sprays , ointments , gels , oral or the salt thereof, from the viewpoint of discoloration liquids , and syrups. From the viewpoint of advantageously reducing action and /or crystal precipitation -suppressing utilizing the pharmacological action of the compound rep action , the content ratio by mass of bimatoprost or a salt resented by Formula ( 1 ), the dosage form is an ophthalmic thereof or a solvate of bimatoprost or the salt thereof is agent, which specifically is preferably an eye drop or an eye preferably 0 .005 to 1 parts by mass , more preferably 0 .01 to ointment, and is particularly preferably an eye drop . 0 . 5 parts by mass , and particularly preferably 0 . 05 to 0 . 1 0083 ] The aqueous composition may contain , in addition parts by mass, calculated as the free form , with respect to 1 to the components described above , additives used in drugs, US 2017 /0368075 A1 Dec . 28 , 2017

quasi drugs , and the like , in accordance with the dosage phosphate hydrate , potassium dihydrogenphosphate , sodium form . Examples of such additives include inorganic salts , dihydrogenphosphate , sodium dihydrogenphosphate mono isotonic agents , chelating agents , stabilizers , pH regulators , hydrate , sodium hyaluronate, glucose, and 1- menthol . antiseptics, antioxidants, thickeners, surfactants , solubiliz ers , suspending agents , cooling agents , dispersants , preser [ 0086 ] The aqueous composition may further contain , in addition to the components described above , othermedicinal vatives , oily bases, emulsion bases , and water - soluble bases. components in accordance with the target disease and the [ 0084 ] Specific examples of these additives include ascor like . Examples of such medicinal components include al bic acid , potassium aspartate , sodium bisulfite , alginic acid , receptor blockers including bunazosin or a salt thereof or a sodium benzoate , benzyl benzoate , epsilon - aminocaproic solvate of bunazosin or the salt thereof, such as bunazosin acid , fennel oil, ethanol , ethylene- vinyl acetate copolymer , hydrochloride ; a2 receptor agonists including sodium edetate , tetrasodium edetate , potassium chloride , or a salt thereof or a solvate of brimonidine or the salt calcium chloride hydrate , sodium chloride, magnesium thereof, such as brimonidine tartrate , and or a chloride , hydrochloric acid , alkyl diaminoethylglycine salt thereof or a solvate of apraclonidine or the salt thereof; hydrochloride solution , carboxyvinyl polymer , dried sodium B blockers including or a salt thereof or a solvate sulfite , dried sodium carbonate , d - camphor , dl - camphor , of carteolol or the salt thereof, such as carteolol hydrochlo xylitol, citric acid hydrate , sodium citrate hydrate , glycerin , ride , nipradilol or a salt thereof or a solvate of nipradilol or gluconic acid , L - glutamic acid , monosodium L - glutamate , the salt thereof, timolol or a salt thereof or a solvate of creatinine, chlorhexidine gluconate solution , chlorobutanol, timolol or the salt thereof, such as timololmaleate , sodium dihydrogenphosphate dihydrate , geraniol, sodium or a salt thereof or a solvate of betaxolol or the salt thereof, chondroitin sulfate , acetic acid , potassium acetate , sodium such as betaxolol hydrochloride , or a salt acetate hydrate, titanium oxide , gellan gum , dibutylhydroxy thereof or a solvate of levobunolol or the salt thereof , such toluene , potassium bromide , benzododecinium bromide , tar as levobunolol hydrochloride , or a salt thereof or taric acid , sodium hydroxide , polyoxyl 45 stearate , purified a solvate of befunolol or the salt thereof, and lanolin , D -sorbitol , sorbitol solution , taurine , sodium bicar or a salt thereof or a solvate of metipranolol or the salt bonate , sodium carbonate hydrate , sodium thiosulfate thereof ; carbonic anhydrase inhibitors including dorzol hydrate , thimerosal, tyloxapol, sodium dehydroacetate , tro amide or a salt thereof or a solvate of dorzolamide or the salt metamol, concentrated glycerin , mixed tocopherol concen thereof , such as dorzolamide hydrochloride , brinzolamide or trate , white petrolatum , mentha water, mentha oil , benzalko a salt thereof or a solvate of brinzolamide or the salt thereof , nium chloride concentrated solution 50 , ethyl or a salt thereof or a solvate of acetazolamide parahydroxybenzoate , butyl parahydroxybenzoate , propyl or the salt thereof, dichlorphenamide or a salt thereof or a parahydroxybenzoate, methylparahydroxybenzoate , solvate of dichlorphenamide or the salt thereof, and meth sodium hyaluronate , human serum albumin , hydroxyethyl azolamide or a salt thereof or a solvate of or cellulose , hydroxypropyl cellulose , hypromellose , glacial the salt thereof; sympathomimetics including or acetic acid , sodium pyrosulfite , phenylethyl alcohol, glu a salt thereof or a solvate of dipivefrine or the salt thereof, cose , propylene glycol, bergamot oil , benzalkonium chlo such as dipivefrine hydrochloride , and epinephrine or a salt ride, benzalkonium chloride solution , benzyl alcohol, ben thereof or a solvate of epinephrine or the salt thereof, such zethonium chloride, benzethonium chloride solution , borax , as epinephrine , epinephrine borate , or epinephrine hydro boric acid , povidone , polyoxyethylene ( 200 ) polyoxypro chloride ; parasympathomimetics including distigmine bro pylene glycol (70 ), sodium polystyrene sulfonate , polysor mide or a salt thereof or a solvate of distigmine bromide or bate 80 , polyoxyethylene hydrogenated castor oil 60 , par the salt thereof, or a salt thereof or a solvate of tially hydrolyzed polyvinyl alcohol, d - borneol, macrogol pilocarpine or the salt thereof, such as pilocarpine , pilo 4000 , macrogol 6000 , D -mannitol , anhydrous citric acid , carpine hydrochloride , or pilocarpine nitrate , and anhydrous sodium monohydrogen phosphate , anhydrous or a salt thereof or a solvate of carbachol or the salt thereof; sodium dihydrogen phosphate , methanesulfonic acid , meth calcium antagonists including lomerizine or a salt thereof or ylcellulose , 1- menthol , monoethanolamine , aluminum a solvate of lomerizine or the salt thereof, such as lomerizine monostearate , polyethylene glycol monostearate , eucalyptus hydrochloride ; and cholinesterase inhibitors including oil, potassium iodide , sulfuric acid , oxyquinoline sulfate , demecarium or a salt thereof or a solvate of demecarium or liquid paraffin , borneo camphor, phosphoric acid , dibasic the salt thereof, or a salt thereof or a solvate sodium phosphate hydrate , potassium dihydrogenphosphate , of echothiophate or the salt thereof, and or a sodium dihydrogenphosphate, sodium dihydrogenphosphate salt thereof or a solvate of physostigmine or the salt thereof. monohydrate , malic acid , and petrolatum . One or more of these medicinal components can be incor [0085 ] Examples of preferred additives include potassium porated . chloride , calcium chloride hydrate , sodium chloride , mag nesium chloride , glycerin , acetic acid , potassium acetate , [0087 ] Preferred as the other medicinal components is one sodium acetate hydrate, tartaric acid , sodium hydroxide , or more selected from the group consisting of nipradilol, sodium bicarbonate , sodium carbonate hydrate , concen dorzolamide, brinzolamide , timolol, a salt of nipradilol, a trated glycerin , hydroxyethyl cellulose, hydroxypropyl cel salt of dorzolamide , a salt of brinzolamide , a salt of timolol, lulose , hypromellose , borax , boric acid , povidone, polysor a solvate of nipradilol or the salt thereof, a solvate of bate 80 , polyoxyethylene hydrogenated castor oil , dorzolamide or the salt thereof, a solvate ofbrinzolamide or polyethylene glycol monostearate , partially hydrolyzed the salt thereof, and a solvate of timolol or the salt thereof. polyvinyl alcohol, macrogol 4000 , macrogol 6000 , anhy [ 0088 ] The pH of the aqueous composition is not particu drous citric acid , anhydrous sodium monohydrogen phos larly limited , but is preferably 4 to 9 , more preferably 4 .5 to phate , anhydrous sodium dihydrogen phosphate , methylcel - 8 , and particularly preferably 5 to 7 . The osmotic pressure lulose , monoethanolamine , phosphoric acid , dibasic sodium ratio of the aqueous composition relative to physiological US 2017 /0368075 A1 Dec . 28 , 2017

saline is not particularly limited , but is preferably 0 .6 to 3 , polyethylene ( including linear low density polyethylene ) , and particularly preferably 0 .6 to 2 . high - density polyethylene , and medium - density polyethyl [0089 ] The aqueous composition is preferably stored in a ene ), polypropylene , cyclic polyolefins , poly ( 4 -methylpen container, from the viewpoint of preservation stability and tene ) , polytetrafluoroethylene , ethylene propylene copoly portability , and the like . As used herein , the " container " mer, ethylene - a - olefin copolymer , ethylene -acrylic acid means a package for directly storing the aqueous composi copolymer, ethylene -methacrylic acid copolymer , ethylene tion . The container is a concept that includes all of the vinylacetate copolymer , and ethylene -ethyl acrylate copoly " well -closed container ” , “ tight container” , and “ hermetic mer. These polyolefin - based resins can be used singly or in container" defined in the General Notices in the Japanese combination of two or more . As the polyolefin -based resin , Pharmacopoeia 16th Edition . polyethylene, polypropylene , or a cyclic polyolefin is pre [0090 ] The form of the container is not particularly limited ferred , and polyethylene or polypropylene is more preferred , as long as it can store an aqueous composition , and may be and polypropylene is particularly preferred , from the view selected or set as appropriate , depending on the dosage form , point of reducing the discoloration . for example . Specific examples of such forms of the con [0095 ] As used herein , the expression “ made of poly tainer include containers for injections, containers for inha olefin -based resin ” means that the polyolefin - based resin is lations, containers for sprays, bottle - shaped containers , included in at least a portion of the material, and “ made of tubular containers , containers for eye drops, containers for polyolefin - based resin ” also includes , for example , a mixture nasal drops, containers for ear drops, and bag containers . of two or more resins (polymer alloy ) , which are a poly The container may be further packaged in a box , a bag, or olefin -based resin and other resins . the like. 10096 ] A substance that prevents transmission of ultravio [0091 ] The material of the container is not particularly let light, such as an ultraviolet absorber or an ultraviolet limited , and may be selected as appropriate depending on the scattering agent, is preferably further mixed into the con form of the container. Specific examples of materials include tainer made of polyolefin - based resin . This improves pho glass , plastics , cellulose , pulp , rubber, and metals , and tostability of the compound represented by Formula ( 1 ) . preferably a plastic from the viewpoint of processability, Specific examples of such substances, for example , specific squeezability, and durability . The resin for a container made examples of ultraviolet scattering agents include titanium of a plastic is preferably a thermoplastic resin . Examples of oxide and zinc oxide. Examples of ultraviolet absorbers such resins include polyolefin -based resins such as low include benzotriazole -based ultraviolet absorbers such as density polyethylene ( including linear low -density polyeth 2 - ( 2H - benzotriazol- 2 - yl) - p - cresol ( for example , Tinuvin P : ylene ) , high - density polyethylene ,medium - density polyeth BASF Corporation ), 2 - ( 2H -benzotriazol - 2 - yl) - 4 , 6 - bis ( 1 ylene, polypropylene, and cyclic polyolefins; polyester methyl - 1 -phenylethyl ) phenol ( for example , Tinuvin 234 : based resins such as polyethylene terephthalate , BASF Corporation ), 2 -( 3 ,5 -di - t - butyl - 2 -hydroxyphenyl ) polybutylene terephthalate, polyethylene naphthalate , poly benzotriazole ( for example , Tinuvin 320 : BASF Corpora butylene naphthalate , and poly ( 1 ,4 -cyclohexylene dimeth tion ), 2 -[ 5 -chloro ( 2H )- benzotriazol - 2 - yl )- 4 -methyl -6 - ( tert ylene terenaphthalate ); polyphenylene ether -based resins ; butyl) phenol ( for example, Tinuvin 326 : BASF polycarbonate -based resins ; polysulfone -based resins; poly Corporation ), 2 - ( 3 , 5 - di- t -butyl - 2 - hydroxyphenyl) - 5 - chlo amide -based resins ; polyvinyl chloride resins; and styrene robenzotriazole ( for example , Tinuvin 327 : BASF Corpora based resins. A mixture of these resins (polymer alloy ) may tion ), 2 -( 2H -benzotriazol - 2 -yl ) -4 , 6 -di - tert -pentylphenol ( for also be used . example , Tinuvin PA328 : BASF Corporation ) , 2 - ( 2H -ben [0092 ] While the material of the container is not particu zotriazol- 2 -yl ) - 4 - ( 1 , 1 , 3 , 3 - tetramethylbutyl) phenol ( for larly limited , from the viewpoint of discoloration - reducing example , Tinuvin 329 : BASF Corporation ) , 2 , 2 ' -methylen action , it is preferably a polyolefin -based resin , and particu ebis [6 -( 2H -benzotriazol - 2 -yl ) - 4 -( 1, 1 ,3 , 3 - tetramethylbutyl) larly preferably polypropylene . As described in Test phenol ( for example, Tinuvin 360 : BASF Corporation ), a Examples below , discoloration is particularly prominently reaction product of methyl 3 -( 3 -( 2H -benzotriazol - 2 -yl ) - 5 reduced in the case of a container made of polyolefin -based tert- butyl - 4 - hydroxyphenyl) propionate and polyethylene resin . glycol 300 ( for example , Tinuvin 213: BASF Corporation ), [0093 ] As used herein , the “ container made of polyolefin 2 - ( 2H -benzotriazol - 2 -yl ) -6 -dodecyl - 4 - methylphenol ( for based resin ” means a container in which at least a portion example , Tinuvin 571: BASF Corporation ) , 2 - ( 2 -hydroxy that contacts the aqueous composition is “ made of poly 3 ', 5 -di - t -amylphenyl ) benzotriazole , 2 -[ 2' - hydroxy -3 ' -( 3 " , olefin -based resin ” . Accordingly , a container in which , for 4 " , 5 " ,6 " -tetrahydrophthalimidomethyl ) -5 '- methylphenyl ] example , a polyolefin layer is provided as the inner layer that benzotriazole, and 2 , 2 ' -methylenebis [ 4 - ( 1 , 1 , 3 , 3 contacts the aqueous composition and a different resin tetramethylbutyl) - 6 - (2H -benzotriazol - 2 - yl) phenol] ; material or the like is , for example , laminated on the outer [0097 ] cyanoacrylate -based ultraviolet absorbers such as side of the inner layer also corresponds to the " container 2 ,2 -bis { [ 2 -cyano - 3 , 3 -diphenylacryloyloxy ] made of polyolefin -based resin ”. The polyolefin -based resin methyl} propane - 1 , 3 - diyl= bis( 2 - cyano - 3 , 3 - diphenylacry is not particularly limited herein , and may be a polymer of late ) ( for example , Uvinul 3030 FF : BASF Corporation ), a single monomer (homopolymer ) or a copolymer of a ethyl 2 -cyano - 3, 3 -diphenylacrylate ( for example , Uvinul plurality of monomers (copolymer ). In the case of a copo 3035 : BASF Corporation ), and 2 - ethylhexyl 2 - cyano - 3 , lymer, the mode of polymerization is not particularly lim 3 - diphenylacrylate ( for example , Uvinul 3039 : BASF ited , and may be random polymerization or block polymer Corporation ); triazine- based ultraviolet absorbers such as ization . Further, the stereoregularity ( tacticity ) of the 2 - ( 4 ,6 - diphenyl - 1 , 3 , 5 - triazin - 2 - yl) - 5 - [ (hexyl ) oxyl - phe polyolefin -based resin is not particularly limited . nol ( for example , Tinuvin 1577 ED : BASF Corporation ) ; [0094 ] Specific examples of such polyolefin -based resins benzophenone -based ultraviolet absorbers such as include polyethylene (more specifically , such as low -density octabenzone ( for example, Chimassorb 81 : BASF Cor US 2017 /0368075 A1 Dec . 28 , 2017

poration ), 2 , 2' - dihydroxy - 4 ,4 -dimethoxybenzophenone resented by Formula ( 1 ) , and the - low ( for example , Uvinul 3049 : BASF Corporation ), 2 , 2 - 4 , ering action of the prostaglandin . This is preferred because 4 ' -tetrahydrobenzophenone ( for example , Uvinul 3050 : the intraocular pressure - lowering action of the compound BASF Corporation ), oxybenzone , hydroxymethoxyben represented by Formula ( 1 ) and the intraocular pressure zophenonesulfonic acid , sodium hydroxymethoxybenzo lowering action of the prostaglandin are combined to pro phenone sulfonate , dihydroxydimethoxybenzophenone , duce excellent intraocular pressure - lowering action , which sodium dihydroxydimethoxybenzophenone disulfonate , leads to achievement of excellent prophylactic and / or thera dihydroxybenzophenone , and tetrahydroxybenzophe peutic action for ocular hypertension or glaucoma . More none ; cinnamate -based ultraviolet absorbers such as specifically , examples of types of glaucoma include primary methyl. diisopropylcinnamate , cinoxate , glyceryl mono open -angle glaucoma, normal- tension glaucoma, hyperse 2 -ethylhexanoate di- p -methoxycinnamate , isopropyl cretion glaucoma, acute closed -angle glaucoma, chronic p -methoxycinnamate - diisopropyl cinnamate ester mix closed - angle glaucoma, plateau iris syndrome, combined ture , 2 - ethylhexyl p -methoxycinnamate , and benzyl cin mechanism glaucoma, steroid - induced glaucoma , capsular namate ; benzoate -based ultraviolet absorbers such as glaucoma, pigmentary glaucoma, amyloid - associated glau p - aminobenzoic acid , ethyl p -aminobenzoate , glyceryl coma, neovascular glaucoma, and malignant glaucoma. p - aminobenzoate, amyl p - dimethylaminobenzoate , 2 - eth [0103 ] Further, as disclosed in JP - B - 5557408 , the phar ylhexyl p - dimethylaminobenzoate, and ethyl 4 - [ N , N -di maceutical preparation may be used as a prophylactic or ( 2 -hydroxypropyl ) amino ] benzoate ; salicylate - based therapeutic agent for ocular fundus diseases ( lesions that ultraviolet absorbers such as ethylene glycol salicylate , mainly develop in the retina and /or choroidea ; specifically , octyl salicylate , dipropylene glycol salicylate , phenyl for example , hypertensive or arteriosclerotic ocular fundus salicylate , homomenthyl salicylate, and methyl salicylate ; abnormalities, central retinal artery occlusion , retinal vein guaiazulene ; 2 - ethylhexyl dimethoxybenzylidene diox occlusion such as central retinal vein occlusion or branch oimidazolidine propionate ; 2 ,4 , 6 - tris [4 - (2 - ethylhexyloxy retinal vein occlusion , , diabetic macular carbonyl )anilino ] 1 ,3 , 5 - triazine ; p -hydroxyanisole ; 4 - tert edema, diabetic maculopathy , Eales disease , congenital reti butyl -41 -methoxydibenzoylmethane ; nal vascular abnormalities such as Coats disease , von Hippel phenylbenzimidazole sulfonate ; and hexyl 2 - ( 4 -diethyl disease , pulseless disease , macular diseases ( such as central amino - 2 - hydroxybenzoyl) benzoate . serous chorioretinopathy, cystoid macular edema, age - re [ 0098 ] When a substance that prevents transmission of lated macular degeneration , macular hole , myopic macular ultraviolet light is mixed into the container , the proportion of degeneration , vitreoretinal interface maculopathy, drug - re the substance to be incorporated varies depending on the lated maculopathy , or heredomacular degeneration ) , retinal type of the substance and the like, but it may be 0 .001 to 50 detachment such as rhegmatogenous, tractional, exudative , mass % , for example , preferably 0 . 002 to 25 mass % , and or the like, retinitis pigmentosa, or retinopathy of prematu particularly preferably about 0 .01 to 10 mass % , in the rity ) based on the action of the compound represented by container . Formula ( 1 ). More preferably , the pharmaceutical prepara [0099 ] The inside of the container is preferably visible tion may be used as a prophylactic or therapeutic agent for (observable ) by the naked eye . When the inside is visible , diabetic retinopathy, diabetic macular edema , or age - related the following advantages are produced . For example , the macular degeneration . presence or absence of any foreign matter can be inspected [0104 ] When the aqueous composition or pharmaceutical in the manufacturing steps of the pharmaceutical prepara preparation is used as a prophylactic and / or therapeutic tion , and the residual amount of the contents (aqueous agent for an eye disease (preferably , a disease selected from composition ) can be examined by a user of the pharmaceu the group consisting of ocular hypertension , glaucoma, and tical preparation . The visibility may be ensured in at least a ocular fundus diseases, particularly preferably a disease portion of the surface of the container (for example , even if selected from the group consisting of ocular hypertension the side surface of a container for eye drops cannot be seen and glaucoma ) , the aqueous composition or pharmaceutical through due to the presence of a shrinkable film or the like , preparation may be administered about one to three times it can be determined as visible if the bottom surface of the per day container is visible .) . If the inside is visible through a portion of the surface of the container , then the aqueous composition EXAMPLES in the container is visible . [0100 ] The means for storing the aqueous composition [0105 ] The present invention will be described next in into the container is not particularly limited , and the con more detail with reference to examples ; however , the inven tainer may be filled with the aqueous composition using a tion is in no way limited to these examples. conventional method , in accordance with the form of the [0106 ] In the following test examples, ripasudil monohy container and the like . drochloride dihydrate can be produced in accordance with [0101 ] The disease targeted by the aqueous composition or the method described in WO2006 /057397 , for example . the pharmaceutical preparation is not particularly limited , and may be selected as appropriate depending on the phar Test Example 1 macological action or the like of the compound represented by Formula ( 1 ) . Preservation Test [0102 ] Specifically , the aqueous composition or pharma [0107 ] Aqueous compositions of Example 1 and Com ceutical preparation can be used , for example, as a prophy parative Example 1 containing the components in the quan lactic or therapeutic agent for ocular hypertension or glau tities per 100 mL shown in Table 1 were prepared in coma, based on the Rho kinase inhibitory action or accordance with a conventionalmethod , and each housed in intraocular pressure - lowering action of the compound rep a container made of polypropylene. US 2017 /0368075 A1 Dec . 28 , 2017

[ 0108 ]. The resulting aqueous compositions were pre compound or the salt thereof, discoloration (yellowing ) is served at 80° C . for 1 week . The degree of discoloration relatively difficult to occur even after preservation at high ( yellowing ) after the preservation was evaluated by measur temperature , and excellent preservation stability can be ing the color difference ( AYI) of the aqueous compositions achieved . before and after the preservation using a color difference meter ( spectrophotometer, CM - 700d : Konica Minolta Sens ing , Inc . ) . Test Example 3 [010 ] The results are shown in Table 1 . Preservation Test No. TABLE 1 [0116 ] Aqueous compositions of Example 3 and Com Example 1 Comparative Example 1 parative Example 2 containing the components in the quan Ripasudil 0 . 9792 g ( 0 . 8 g as the 0 . 9792 g (0 . 8 g as the tities per 100 mL shown in Table 3 were prepared in Monohydrochloride free form ) free form ) Dihydrate accordance with a conventional method . Bimatoprost 0 . 06 g Anhydrous Sodium 0 . 4 g 0 . 4 g [0117 ] Each of the resulting aqueous compositions was Dihydrogen Phosphate preserved at - 5° C . , during which the presence or absence of Glycerin 2 . 136 g 2 . 136 g crystal precipitation was visually evaluated periodically to Benzalkonium 0 . 002 mL 0 .002 mL determine for which aqueous composition earlier crystal Chloride Concentrated Solution 50 precipitation would be observed . The aqueous composition Sodium Hydroxide q . s . (pH 6 .0 ) q. s . (pH 6 . 0 ) for which earlier crystal precipitation was not observed was Purified Water Total Amount 100 mL Total Amount 100 mL rated as “ b ” , and the aqueous composition for which earlier ??? 0 . 9 6 . 0 crystal precipitation was observed was rated as “ d ” . [0110 ] As shown in the results set forth in Table 1 , it was [0118 ] The results are shown in Table 3 . revealed that when bimatoprost is further incorporated in the aqueous composition containing ripasudil, the AYI value is TABLE 3 significantly lowered in comparison with the case where the Example 3 Comparative Example 2 aqueous composition does not contain bimatoprost, and discoloration after high - temperature preservation is reduced . Ripasudil 0 .9792 g ( 0 . 8 g as the 0 .9792 g ( 0 . 8 g as the Monohydrochloride free form ) free form ) Test Example 2 Dihydrate Latanoprost 0 .01 g Anhydrous Sodium 0 . 4 g 0 . 4 g Preservation Test No . 2 Dihydrogen Phosphate [ 0111] An aqueous composition of Example 2 containing Benzalkonium 0 .002 mL 0 .002 mL the components in the quantities per 100 mL shown in Table Chloride Concentrated Solution 50 2 was prepared in accordance with a conventional method , Sodium Hydroxide q. s. (pH 6 . 0 ) q . s . (pH 6 . 0 ) and stored in a container made of polypropylene . Purified Water Total Amount 100 mL Total Amount 100 mL [ 0112 ] The resulting aqueous composition was preserved Crystal Precipitation b at 80° C . for 1 week , and the degree of discoloration ( yellowing ) after the preservation was evaluated using the same method as in Test Example 1 . 0119 ] As shown in the results set forth in Table 3 , it was [0113 ] The results are shown in Table 2 . revealed thatwhen latanoprost is further incorporated in the aqueous composition containing ripasudil, crystal precipita TABLE 2 tion during low - temperature preservation is suppressed in Example 2 comparison with the case where the aqueous composition does not contain latanoprost . Ripasudil Monohydrochloride Dihydrate 0. 9792 g ( 0 . 8 g as the free form ) Latanoprost 0 .01 g 10120 ] The foregoing test results revealed that when a Anhydrous Sodium Dihydrogen 0 . 4 g Phosphate prostaglandin typified by latanoprost is further incorporated Benzalkonium Chloride Concentrated 0 .002 mL in the aqueous composition containing the compound rep Solution 50 resented by Formula ( 1 ) typified by ripasudil or a salt thereof Sodium Hydroxide q .s . (pH 6 . 0 ) or a solvate of the compound or the salt thereof, precipitation Purified Water Total Amount 100 mL ??? 0 . 9 of crystals is relatively difficult to occur even after preser vation at low temperature , and excellent preservation sta [0114 ] As shown in the results set forth in Table 2 , the AYI bility can be achieved . value was similarly low when latanoprost is further incor porated in the aqueous composition containing ripasudil . Production Examples 1 to 27 [ 0115 ] The foregoing results of Test Examples 1 and 2 revealed that when a prostaglandin typified by bimatoprost [0121 ] Aqueous compositions containing the components and latanoprost is further incorporated in the aqueous com in the quantities ( amounts ( g ) per 100 mL of the aqueous position containing the compound represented by Formula composition ) shown in Tables 4 to 6 can be produced in ( 1 ) typified by ripasudil or a salt thereof or a solvate of the accordance with a conventional method . US 2017 /0368075 A1 Dec . 28 , 2017 10

TABLE 4 Production Production Production Production Production Production Production Production Production Exam Exam Exam Exam Exam Exam Exam Exam Exam ple 1 ple 2 ple 3 ple 4 ple 5 ple 6 ple 7 ple 8 ple 9 RipasudilMonohydrochloride 0 . 2 0 . 2 0 .. 2 0 . 44 0 . 4 0 .4 0 . 8 0 . 8 0 . 8 Dihydrate (as the amount of the free form ) Latanoprost 0 . 005 0 . 005 0 . 005 Bimatoprost 0 .03 0 . 03 Travoprost 0 .004 Tafluprost 12:1118-III 0 .0015 1:1133113119190 .003 Sodium Chloride 0 . 3 0 . 3 Glycerin Propylene Glycol 1 S111-111 Potassium Chloride -| AI 322| Boric Acid Borax 1211|laillsIII 1 Sodium Dihydrogenphosphate 1111111 0 . 4 11:11831-1113|Š111381311111326 $ 0 . 4 Monohydrate Dibasic Sodium Phosphate 1 q . s . Hydrate 1 delcol Anhydrous Sodium Intell 1 q . s . Monohydrogen Phosphate Potassium 0 . 4 Dihydrogenphosphate lladelII Sodium Hydroxide igent q . s . q . s . Trometamol Hydrochloric Acid q . s . Citric Acid Hydrate 3 0 . 1 Sodium Acetate Hydrate | 0 . 1 | Sodium Edetate 0 . 1 Benzalkonium Chloride 0 .001 0 . 001 0 . 005 0 .01 0 . 001 0 . 005 III1111311122 Benzethonium Chloride 0 . 01 Methyl Parahydroxybenzoate 0 .01 0 . 01 Propyl Parahydroxybenzoate 0 .01 0 . 01 Chlorobutanol 131| | 2 Polysorbate 80 11L 0 . 3 0 . 3 0 . 3 Polyoxyethylene Castor | 0 . 3 0 . 3 0 . 3 Oil 60 Polyethylene Glycol - 1 . 5 1. 5 1. 5 - 1 . 5 Monostearate Purified Water Total Total Total Total Total Total Total Total Total Amount Amount Amount Amount 9111111111011Amount Amount 11911031931112Amount Amount Amount 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 mL pH 5 5 6 6 6 . 5 6 . 5 4 . 5 4 . 5 4 .

TABLE 5 T Production Production Production Production Production Production Production Production Production Exam - Exam - Exam Exam - Exam - Exam - Exam - Exam - Exam ple 10 ple 11 ple 12 ple 13 ple 14 ple 15 ple 16 ple 17 ple 18 Ripasudil Monohydrochloride 0 . 2 0 . 2 0. 2 0 .4 0 . 4 0 .4 0 .8 0 .8 0 . 8 Dihydrate (as the amount of the free form ) Latanoprost 0 . 005 0 .005 0 .005 Bimatoprost 0 .03 Travoprost 0 .004 Tafluprost 0 . 0015 0 . 003 - 11 Sodium Chloride 065 0 . 3 0 . 3 Glycerin - Propylene Glycol Potassium Chloride -1 Boric Acid |58 1 . 0 |-1011III Borax III11510|1181 q . s . Sodium Dihydrogenphosphate |11911alI :11188113911IT! Monohydrate -1121III Dibasic Sodium Phosphate | Hydrate 10111 Anhydrous Sodium | 2221211ILI Monohydrogen Phosphate Potassium | Dihydrogenphosphate US 2017 /0368075 A1 Dec . 28 , 2017

TABLE 5 - continued Production Production Production Production Production Production Production Production Production Exam - Exam - Exam - Exam - Exam - Exam - Exam - Exam - Exam ple 10 ple 11 ple 12 112ple 13 ple 14 ple 15 ple 16 ple 17 ple 18 Sodium Hydroxide q . s . Trometamol Hydrochloric Acid q . s . q . s . q . s . Citric Acid Hydrate 13 0 . 1 Sodium Acetate Hydrate 0 . 1 0 . 1 Sodium Edetate 0 . 1 Benzalkonium Chloride 0 .001 0 .005 0 .001 0 .005 0 .001 0 .005 Benzethonium Chloride 0 .01 Methyl Parahydroxybenzoate 11011111118811110 . 01 111al11832 0 .01 Propyl Parahydroxybenzoate 0 .01 0 . 01 Chlorobutanol BITEL111311 |110 0 . 2 0 . 2 Polysorbate 80 1EL 0 .3 0 . 3 Polyoxyethylene Castor 0 . 3 113313111|12 0 . 3 Oil 60 Polyethylene Glycol | — 1 . 5 1 . 5 1 . 5 1 . 5 Monostearate Purified Water Total Total Total Total Total Total Total Total Total Amount Amount3111311111181 Amount Amount Amount Amount Amount Amount Amount 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 mL PH 5 5 6 6 11131111311111:6 . 5 6 . 5 111311321331119111:4 . 5 4 .5 4 TABLE 6 1 Production Production Production Production Production Production Production Production Production Exam - Exam - Exam - Exam - Exam - Exam - Exam - Exam - Exam ple 19 ple 20 ple 21 ple 22 ple 23 ple 24 ple 25 ple 26 ple 27 12: | Ripasudil Monohydrochloride 0 . 2 00 . 2 00 . 2 2 0 . 44 0 . 4 0 . 4 0 . 8 0 . 8 8 0 . 8 Dihydrate (as the amount of the free form ) Latanoprost 0 .005 0 .005 0 .005 Bimatoprost 0 . 03 0 .03 Travoprost 0 . 004 Tafluprost 0 . 0015 0 . 003 Sodium Chloride 0 .65 0 . 3 0 . 3 Glycerin 0 . 5 Propylene Glycol 0 .5 Potassium Chloride !|-L11 Boric Acid |- Borax Sodium Dihydrogenphosphate Monohydrate Tallll T-IIII Dibasic Sodium Phosphate DELLL| IIIIII Hydrate |lllluent Anhydrous Sodium l Monohydrogen Phosphate |12 Potassium l Dihydrogenphosphate Sodium Hydroxide BL1333|LUBILL333 Trometamol 1 . 5 12 1 . 5 Hydrochloric Acid q .s . q . s . Citric Acid Hydrate 0 . 1 - 0 . 1 Sodium Acetate Hydrate — 0 . 1 0. 1 Sodium Edetate | 0 . 1 1133113111III199113315311111110 . 1 Benzalkonium Chloride 0 . 001 0 .005 0 . 001 0 .005 0. 01 0 . 001 0 .005 Benzethonium Chloride 0 .01 Methyl Parahydroxybenzoate 0 . 01 0 .01 Propyl Parahydroxybenzoate 0 . 01 0 . 01 | EELISILIELI Chlorobutanol 0 .2 0 . 2 Polysorbate 80 0. 3 0 . 3 0 . 3 Polyoxyethylene Castor 0 . 3 0 . 3 Oil 60 IL ila Polyethylene Glycol 1 . 5 1 . 5 — 1 . 5 1 . 5 Monostearate Purified Water Total Total Total Total Total Total Total Total Total Amount Amount Amount Amount Amount Amount Amount Amount Amount 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 mL PH 5 5 6 6 6 6 . 55 6 . 5 4 . 55 44 . 55 4 . US 2017 /0368075 A1 Dec . 28 , 2017 12

Production Examples 28 to 54 2 . The aqueous composition according to claim 1, wherein the compound represented by Formula ( 1 ) is ripa [0122 ] Aqueous compositions of Production Examples 28 sudil . to 54 can be produced in accordance with a conventional 3 . The aqueous composition according to claim 1 , method as in Production Examples 1 to 27 , except that wherein the prostaglandin is one or more selected from the instead of ripasudil monohydrochloride dihydrate , an equal group consisting of tafluprost, travoprost , bimatoprost, amount of 4 -bromo - 5 - { [ (2S ) - 2 -methyl - 1 , 4 -diazepan - 1 - yl ] latanoprost, a salt of tafluprost , a salt of travoprost , a salt of sulfonyl } isoquinoline is used . bimatoprost , a salt of latanoprost, a solvate of tafluprost or the salt thereof, a solvate of travoprost or the salt thereof, a Production Examples 55 to 108 solvate of bimatoprost or the salt thereof, and a solvate of [0123 ] Pharmaceutical preparations of Production latanoprost or the salt thereof . Examples 55 to 108 can be produced in accordance with a 4 . A pharmaceutical preparation obtained by storing the conventional method by storing the aqueous compositions aqueous composition according to claim 1 in a container of Production Examples 1 to 54 in a container made of made of a polyolefin -based resin . polypropylene for eye drops . 5 . The pharmaceutical preparation according to claim 4 , wherein the polyolefin -based resin is polypropylene . Production Examples 109 to 162 6 . A method for reducing discoloration of an aqueous [0124 ] Pharmaceutical preparations of Production composition , the method comprising incorporating a pros Examples 109 to 162 can be produced in accordance with a taglandin in an aqueous composition comprising a com conventional method by storing the aqueous compositions pound represented by Formula ( 1 ) : of Production Examples 1 to 54 in a container made of polyethylene for eye drops.

INDUSTRIAL APPLICABILITY HN [ 0125 ] In accordance with the present invention , aqueous compositions or pharmaceutical preparations having excel lent preservation stability can be provided , which can be ' S = O X advantageously used in the pharmaceutical industry , for example . 1 . An aqueous composition comprising : ( i) a compound represented by Formula ( 1 ): wherein X represents a halogen atom , ( 1 ) or a salt thereof, or a solvate of the compound or the salt thereof. 7 . The method according to claim 6 , wherein the com pound represented by Formula ( 1 ) is ripasudil . SEO X 8 . The method according to claim 6 , wherein the prosta glandin is one or more selected from the group consisting of tafluprost, travoprost , bimatoprost, latanoprost, a salt of tafluprost, a salt of travoprost, a salt of bimatoprost, a salt of latanoprost, a solvate of tafluprost or the salt thereof, a solvate of travoprost or the salt thereof, a solvate of bimato wherein X represents a halogen atom , prost or the salt thereof, and a solvate of latanoprost or the or a salt thereof, or a solvate of the compound or the salt salt thereof. thereof, and ( ii ) a prostaglandin . * * * * *