|MIT KUDO TORI USTRONOMIA 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 isoquinoline 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 prostaglandin . 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 latanoprost 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 ocular hypertension , 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 eye drop 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 unoprostone , tafluprost , travoprost, SEO X bimatoprost , 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 , glaucoma, 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