(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`UMA OA AOU CAAATAA
`
`(10) International Publication Number
`WO 2017/204262 Al
`
`= a
`
`WIPO! PCT
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`30 November 2017 (30.11.2017)
`
`KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK, MN, MW, MX, MY, MZ, NA, NG, NL NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW,SA, SC,
`SD, SE, SG, SK, SL, SM,ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG,US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM,KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO,PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`KM,ML, MR, NE, SN, TD, TG).
`
`(51) International Patent Classification:
`A61K 31/46 (2006.01)
`A61K 47/12 (2006.01)
`A6LK 9/08 (2006.01)
`A61K 47/18 (2006.01)
`A61K 47/02 (2006.01)
`A61K 47/26 (2006.01)
`A61K 47/10 (2006.01)
`A61K 47/38 (2006.01)
`
`(21) International Application Number:
`
`PCT/JP2017/019423
`
`(84)
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`24 May 2017 (24.05.2017)
`
`English
`
`English
`
`(30) Priority Data:
`10201604200P
`
`25 May 2016 (25.05.2016)
`
`SG
`
`Published:
`
`with international search report (Art. 21(3))
`
`(71) Applicants: SINGAPORE HEALTH SERVICES PTE
`LTD [SG/SG]; 31 Third Hospital Avenue, #03-03 Bowyer
`Block C, Singapore, 168753 (SG). NANYANG TECH-
`NOLOGICAL UNIVERSITY[SG/SG]; 50 Nanyang Avy-
`enue, Singapore, 639798 (SG). SANTEN PHARMA-
`CEUTICAL CO., LTD. [JP/JP]; 9-19, Shimoshinjo 3-
`chome, Higashiyodogawa-ku, Osaka-shi, Osaka, 5338651
`(JP).
`
`(72) Inventors: TAN, Donald; c/o Singapore Eye Research
`Institute, 11 Third Hospital Ave, 168751 (SG). BEUER-
`MAN, Roger; c/o Singapore Eye Research Institute, 11
`Third Hospital Ave, 168751 (SG). ASADA, Hiroyuki; c/
`o SANTEN PHARMACEUTICAL CO., LTD., 8916-16,
`Takayama-cho, Ikoma-shi, Nara, 6300101 (JP). TAKA-
`HASHI, Kyohei; c/o SANTEN PHARMACEUTICAL
`COo., LTD., 8916-16, Takayama-cho, Tkoma-shi, Nara,
`6300101 GP). SAKANAKA,Koji; c/o SANTEN PHAR-
`MACEUTICAL CO., LTD., 8916-16, Takayama-cho, Iko-
`ma-shi, Nara, 6300101 (IP). MORIMOTO, Takashi; c/
`o SANTEN PHARMACEUTICAL CO., LTD., 8916-16,
`Takayama-cho,
`Ikoma-shi, Nara, 6300101 (JP). FU-
`JISAWA, Toyomi; c/o SANTEN PHARMACFUTICAL
`CO., LTD., 8916-16, Takayama-cho,
`Ikoma-shi, Nara,
`6300101 (JP).
`
`(74)
`
`Agent: SAMEJIMA, Mutsumi et al; AOYAMA &
`PARTNERS, Umeda Hankyu Bldg. Office Tower, 8-1,
`Kakuda-cho, Kita-ku, Osaka-shi, Osaka, 5300017 (JP).
`
`(81) Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AO,AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW,BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU,ID,IL,IN,IR, IS, JP, KE, KG, KH, KN, KP, KR,
`
`wo2017/204262A.IININNINIIINANITATACINNVROAAA (57) Abstract: Disclosed herein is an aqueous composition comprising 0.001 - 0.1 % (w/v) atropine ora salt thereof, a water-soluble
`
`
`
`(54) Title: ATROPINE-CONTAINING AQUEOUS COMPOSITION
`
`polymer, and butter (1), which is at a pH range of 6 or lower, wherein the buffer (1) is at least one selected from the group consisting of
`a phosphate buffer, an aminocarboxylate buffer, a carbonate buffer, an acetate buffer, atartrate buffer, a borate buffer, and trometamol.
`
`
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`

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`WO 2017/204262
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`PCT/JP2017/019423
`
`Description
`Title of Invention: ATROPINE-CONTAINING AQUEOUS COM-
`
`Technical Field
`
`POSITION
`
`[0001]
`
`[0002]
`
`The present invention mainly relates to an aqueous composition that comprises
`atropine or a salt thereof (hereinafter also referred to simply as "atropine”).
`Background Art
`Myopia, a type of refractive error, is a condition of eyes where light coming into an
`eye from a distance is not focused on retina, but focused before retina, which causes
`the image of an object to appearblurred. It is known that myopia is caused by an
`ocular axial length (length from the corneato the retina) that is longer than normal
`(axial myopia) or by excessively high refractive powers of the corneaorthe crystalline
`lens (refractive myopia).
`
`[0003]
`
`Atropine is known to have the property of preventing the elongation of an ocular
`axial length. For example, Patent Literature 1 discloses that a composition comprising
`
`[0004]
`
`less than 0.025% atropine inhibits or prevents myopia progression.
`Onthe other hand, an atropine ophthalmic solution is used as a mydriatic, and also
`reduces accommodation. An atropine ophthalmic solution, when instilled into the eye,
`relaxes the pupillary sphincter muscle of the iris and thus induces mydriasis that causes
`glare, which persists for a period during which the action of the atropine ophthalmic
`solution is maintained, and also reduces accommodation of the crystalline lens to result
`in poornear-acuity. This can be a hindrance in performing daily activities. It would
`
`therefore be highly desirable that a medication for inhibiting or preventing myopia pro-
`gression, should induce a lesser degree of mydriasis and a lesser loss of accom-
`
`modation so as to enhance the quality of life (QOL).
`
`Citation List
`
`Patent Literature
`
`[0005]
`
`[PTL 1] WO 2012/161655
`Summaryof Invention
`
`Technical Problem
`
`[0006]
`
`A purpose of the present invention is to find an aqueous composition comprising
`
`atropine which has a potent action for inhibiting the elongation of eye axial length and
`improvingthe refractive error. The important goalis to find an atropine-containing
`
`aqucous composition that induccs a lesser degree of mydriasis and also a lesser loss of
`accommodation. And, another purpose of the present invention is to find an aqueous
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`composition comprising atropine whose viscosity does not decrease with time and
`wherein atropine or a salt thereofis stable.
`Solution to Problem
`
`[0007]
`
`The present inventors have intensively studied to solve the aforementioned problem
`and consequently have found that an aqueous composition comprising 0.001 - 0.1 %
`(w/v) atropine or a salt thereof, a water-soluble polymer, and buffer (D, which is at a
`
`pH range of 6 or lower, wherein the buffer (1) is at least one selected from the group
`consisting of a phosphate buffer, an aminocarboxylate buffer, a carbonate buffer, an
`
`acctate buffer, a tartrate buffcr, a borate buffer, and tromctamol, surprisingly has a
`potent action for inhibiting the elongation of eye axial length and improving the re-
`fractive error without exacerbating the mydriatic action of atropine. Additionally, the
`present inventors have also found that the above aqueous composition, but which
`comprises no benzalkonium chloride or a limited amount of benzalkonium chloride,
`has a lower mydriatic action. Furthermore, the present inventors have also foundthat,
`in an aqueous composition comprising atropine or a salt thereof and a water-soluble
`
`polymer whichis at a pH range of 6 or lower, the addition of a nonionic tonicity agent
`can make it possible to inhibit the debasementover time of the viscosity given by the
`
`water-soluble polymer and additionally maintain the stability of atropine or a salt
`thereof. The aqueous composition of the present invention is expected to inhibit or
`prevent the progression of myopia and lead to a lesser degree of mydriasis, and lesser
`loss of accommodationso as to be optimal in terms of quality of life.
`Thatis, the present invention relates to the following.
`(Term 1)
`
`An aqueous composition comprising 0.001 - 0.1 % (w/v) atropine ora salt thereof, a
`
`water-soluble polymer, and buffer U1), which is at a pH range of 6 or lower, wherein
`
`the buffer (1) is at least one selected from the group consisting of a phosphate buffer,
`
`an aminocarboxylate buffer, a carbonate buffer, an acetate buffer, a tartrate buffer, a
`
`[0008]
`
`[0009]
`
`borate buffer, and trometamol.
`
`[0010]
`
`(Term 2)
`
`The aqueous composition of Term 1, wherein the buffer (1) is at least one selected
`from the group consisting of a phosphate buffer, an aminocarboxylate buffer, a
`
`carbonate buffer, and an acetate buffer.
`
`[0011]
`
`(Term 3)
`
`The aqueous composition of Term | or 2, wherein the buffer (1) is a phosphate
`
`buffer.
`
`[0012]
`
`(Term 4)
`
`The aqueous composition of Term | or 2, wherein the aminocarboxylate bufferis at
`
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`least one selected from the group consisting of epsilon-aminocaproic acid, a glutamate
`
`buffer, and an aspartate buffer.
`(Term 5)
`
`[0013]
`
`The aqucous composition according to any one of Terms 1 to 4, wherein
`the phosphate buffer is derived from at least one selected from the group consisting
`of dibasic sodium phosphate hydrate, sodium dihydrogen phosphate, sodium di-
`hydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium
`dihydrogen phosphate, sodium monohydrogen phosphate heptahydrate, trisodium
`phosphate, and dipotassium phosphate,
`the carbonate buffer is derived from at least one selected from the group consisting of
`
`carbonic acid, sodium bicarbonate, sodium carbonate, ammonium carbonate,
`
`potassium carbonate, calcium carbonate, potassium bicarbonate, and magnesium
`
`carbonate,
`
`the acetate buffer is derived from at least one selected from the group consisting of
`acetic acid, ammonium acetate, potassium acetate, calcium acetate, and sodium
`
`acetate,
`
`the tartrate buffer is derived from at least one selected from the group consisting of
`sodium tartrate and potassium tartrate,
`the borate buffer is derived from at least one selected from the group consisting of
`
`boric acid, sodium borate, potassium borate, potassium tetraborate, potassium
`metaborate, ammonium borate, and borax,
`
`the glutamate buffer is derived from at least one selected from the group consisting
`of glutamic acid, sodium glutamate and potassium glutamate, and/or
`the aspartate buffer is derived from at least one selected from the group consisting of
`aspartic acid, sodium aspartate and magnesium aspartate.
`(Term 6)
`
`The aqueous composition according to any one of Terms | to 5, further comprising a
`citrate buffer as buffer (ID).
`
`[0014]
`
`[0015]
`
`(Term 7)
`
`The aqueous composition of Term 6 wherein the citrate buffer is derived from at
`
`least one selected from the group consisting of citric acid hydrate, sodium citrate,
`sodium citrate hydrate, potassium citrate, calcium citrate, sodium dihydrogencitrate,
`
`and disodium citrate.
`
`[0016]
`
`(Term 8)
`
`The aqueous composition according to any one of Terms 1 to 7, wherein the water-
`soluble polymeris at least one selected from the group consisting of a cellulose
`derivative, carboxyvinyl polymer and sodium alginate.
`(Term 9)
`
`[0017]
`
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`
`The aqueous composition of Term 8, wherein the cellulose derivative is at least one
`
`selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methyl-
`cellulose, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl
`
`ccllulose, hydroxycthyl methyl cellulose, carboxymethyl]cellulose, sodium car-
`boxymethy1]cellulose, hypromellose acetate succinate, hypromellose phthalate, car-
`boxymethylethyl cellulose, and cellulose acetate phthalate.
`(Term 10)
`
`[0018]
`
`The aqueous composition of Term 8 or 9, wherein the cellulose derivative is at least
`one selected from the group consisting of hydroxyethyl cellulose and hydroxypropyl
`methylcellulose.
`
`[0019]
`
`(Term 11)
`
`The aqueous composition according to any one of Terms 8 to 10, wherein the
`
`ccllulose derivative is hydroxycthyl] cellulose.
`(Term 12)
`
`[0020]
`
`An aqueous composition comprising 0.001 - 0.1 % (w/v) atropine ora salt thereof,
`hydroxyethyl cellulose, and buffer (1), which is at a pH range of 6 or lower, wherein
`the buffer (1) is a phosphate buffer.
`(Term 13)
`
`[0021]
`
`The aqueous composition of Term 12, further comprising a citrate buffer as buffer
`
`di).
`
`[0022]
`
`(Term 14)
`
`[0023]
`
`[0024]
`
`[0025]
`
`The aqueous composition according to any one of Terms | to 13, which comprises
`less than 50 ppm benzalkonium chloride.
`(Term 15)
`
`The aqueous composition according to any one of Terms | to 14, which does not
`substantially comprise benzalkonium chloride.
`(Term 16)
`
`The aqueous composition according to any one of Terms1 to 15, further comprising
`a nonionic tonicity agent.
`(Term 17)
`
`The aqueous composition of Term 16, wherein the nonionic tonicity agentis at least
`one selected from the group consisting of glycerin, mannitol, propylene glycol,
`
`polyethylene glycol, glucose, sorbitol, xylitol and trehalose.
`(Term 18)
`
`[0026]
`
`The aqueous composition of Term 16 or 17, wherein the nonionic tonicity agentis at
`least one compoundselected from the group consisting of glycerin and mannitol.
`(Term 19)
`
`[0027]
`
`The aqueous composition according to any one of Terms 16 to 18, wherein the
`
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`
`nonionic tonicity agent is glycerin.
`
`[0028]
`
`(Term 20)
`
`The aqueous composition according to any one of Terms 1 to 19, wherein the con-
`
`centration of the buffer is 0.001 - 10 % (w/v).
`
`[0029]
`
`(Term 21)
`
`The aqueous composition according to any one of Terms6 to 11 and 13 to 20,
`wherein the concentration of citrate buffer is 0.001 - 1.0 % (w/v).
`
`[0030]
`
`(Term 22)
`
`The aqueous composition of Term 21, wherein the concentration of citrate buffer is
`0.01 - 0.05 % (w/v).
`
`[0031]
`
`(Term 23)
`
`The aqueous composition according to any one of Terms 1 to 22, wherein the con-
`
`centration of the water-soluble polymeris 0.01 - 5 % (w/v).
`(Term 24)
`
`[0032]
`
`The aqueous composition according to any one of Terms 16 to 23, wherein the con-
`centration of the nonionic tonicity agent is 0.01 to 10 % (w/v).
`(Term 25)
`
`[0033]
`
`An aqueous composition comprising 0.001 - 0.1 % (w/v) atropine ora salt thereof, a
`water-soluble polymer, and a buffer, which is at a pH rangeof less than 5.
`
`[0034]
`
`(Term 26)
`
`The aqueous composition of Term 25, wherein the buffer is at least one selected from
`
`the group consisting of a phosphate buffer, a citrate buffer, an aminocarboxylate
`
`buffer, a carbonate buffer, an acetate buffer, a tartrate buffer, a borate buffer, and
`
`trometamol.
`
`[0035]
`
`(Term 27)
`
`[0036]
`
`The aqueous composition of Term 25 or 26, wherein the buffer is a citrate buffer.
`(Term 28)
`
`An aqueous composition comprising 0.001 - 0.1 % (w/v) atropineora salt thereof,
`and a phosphate buffer, which is at pH rangeof 6 or lower.
`(Term 29)
`
`The aqueous composition of Term 28, further comprising a water-soluble polymer.
`(Term 30)
`
`The aqueous composition of Term 29, wherein the water-soluble polymeris at least
`one selected from the group consisting of hydroxyethy] cellulose, carboxyvinyl
`polymer, hydroxypropyl methylcellulose, and sodium alginate.
`(Term 31)
`
`[0037]
`
`[0038]
`
`[0039]
`
`The aqueous composition according to Term 29 or 30, wherein the water-soluble
`polymeris hydroxyethyl]cellulose.
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`WO 2017/204262
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`
`[0040]
`
`(Term 32)
`
`The aqueous composition according to any one of Terms | to 24 and 28 to 31, which
`is ata pH rangeof 4 - 6.
`
`[0041]
`
`(Term 33)
`
`The aqueous composition according to any one of Terms | to 32, wherein the con-
`centration of phosphate buffer is 0.01 - 1.0 % (w/v).
`(Term 34)
`
`The aqueous composition according to any one of Terms 1 to 33, wherein the con-
`centration of the atropine or a salt thereof is 0.001 to 0.025% (w/v).
`(Term 35)
`
`[0042]
`
`[0043]
`
`The aqueous composition according to any one of Terms | to 34, wherein the con-
`centration of the atropine ora salt thereof is 0.001 to 0.01% (w/v).
`
`[0044]
`
`(Term 36)
`
`The aqueous composition according to any one of Terms 1 to 35, wherein the
`atropine or a salt thereof is atropine sulfate or a hydrate thereof.
`(Term37)
`
`[0045]
`
`The aqueous composition according to any one of Terms 1 to 36, which is enclosed
`
`in a unit-dose container.
`
`[0046]
`
`(Term 38)
`
`The aqueous composition according to any one of Terms | to 37, wherein the
`aqueous composition is an eyedrop.
`
`[0047]
`
`(Term 39)
`
`The aqueous composition according to any one of Terms | to 38, for inhibiting and/
`or preventing progression of myopia.
`(Term 40)
`
`Use of an aqueous composition according to any one of Terms 1| to 38 in the
`preparation of a medicamentto inhibit and/or preventing the progression of myopia.
`(Term 41)
`
`[0048]
`
`[0049]
`
`A methodfor inhibiting and/or preventing progression of myopia comprising admin-
`istering to a subject a composition according to any one of Terms1 to 38.
`
`[0050]
`
`(Term 42)
`
`The aqueous composition according to any one of Terms 1 to 38 for use in inhibiting
`
`and/or preventing progression of myopia.
`(Term 43)
`
`[0051]
`
`A methodfor inhibiting the viscosity reduction of an aqueous composition
`comprising 0.001 - 0.1 % (w/v)atropine ora salt thereof and a water-soluble polymer
`which is at a pH range of 6 or lower, by adding a nonionic tonicity agent thereto.
`(Term 44)
`
`[0052]
`
`

`

`WO 2017/204262
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`PCT/JP2017/019423
`
`A methodfor stabilizing atropine or a salt thereof in an aqueous composition
`comprising 0.001 - 0.1 % (w/v)atropine or a salt thereof and a water-soluble polymer
`
`which is at a pH range of 6 or lower, by adding a nonionic tonicity agent thereto.
`AdvantageousEffect of Invention
`
`[0053]
`
`As is apparent from the test results which will be described later, it has been shown
`that an aqueous composition comprising 0.001 - 0.1 % (w/v) atropineora salt thereof,
`a water-soluble polymer, and a buffer (1), which is at a pH range of 6 or lower, wherein
`
`the buffer (1) is at least one selected from the group consisting of a phosphate buffer,
`an aminocarboxylate buffer, a carbonate buffer, an acetate buffer, a tartrate buffer, a
`
`borate buffcr, and tromctamol, has a potent action for inhibiting the clongation of cyc
`axial length and improving the refractive error without exacerbating the mydriatic
`action of atropine. Additionally, it has been also shownthat the above aqueous com-
`position, but which comprises no benzalkoniumchloride or a limited amount of ben-
`zalkonium chloride, has a lower mydriatic action. Furthermore, it has been also shown
`that, in an aqueous composition comprising atropine or a salt thereof and a water-
`soluble polymer which is at a pH range of 6 or lower, the addition of a nonionic
`
`tonicity agent can make it possible to inhibit the debasement over time of the viscosity
`given by the water-soluble polymerand additionally maintain the stability of atropine
`
`or a salt thereof. The present aqueous composition is therefore expected to inhibit or
`prevent the progression of myopia and lead to a lesser degree of mydriasis, and lesser
`
`loss of accommodation so as to be optimal in terms of quality of life. A further
`advantage associated with the compositions of the present invention, such as com-
`positions that further comprise a tonicity agent, is that the compositions may retain
`their initial viscosity (or a substantial proportion thereof) over an extended period of
`time.
`
`[0054]
`
`Brief Description of Drawings
`[fig.1]Fig. 1 shows the results of the viscosity determination test in Test 5.
`[fig.2]Fig. 2 shows the results of the stability test in Test 5.
`[fig.3]Fig. 3 shows the results of Examples 23 to 25 in the viscosity determinationtest
`in Test 6.
`
`[fig.4]Fig. 4 shows the results of Examples 26 to 28 in the viscosity determination test
`in Test 6.
`
`[0055]
`
`[0056]
`
`Description of Embodiments
`The present aqueous composition comprises "atropine or a salt thereof," which serves
`as an active ingredient.
`
`In the present invention, the term "atropine or a salt thereof” also includes (i) a
`hydrate of atropine or a salt thereof, (ii) an organic solvate of atropine or a salt thereof,
`
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`and (iii) a combination of the hydrate and the organic solvate.
`
`[0057|
`
`The salt of atropine includes atropine sulfate or a hydrate thereof, and is preferably
`an atropine sulfate hydrate.
`
`[0058]
`
`Atropine sulfate hydrate is a compound represented by the following structural
`
`formula:
`
`» FRSCH ~ He
`
`a PSS
`
`[0059]
`
`In a case where the atropineor the salt thereof includes a crystal polymorph and a
`group of crystal polymorphs(crystal polymorph system), those crystal polymorph and
`group of crystal polymorphs (crystal polymorph system) are also encompassed by the
`scope of the present invention. Here, the group of crystal polymorphs (crystal
`
`[0060]
`
`polymorph system) means not only individual crystal forms obtained at respective
`stages where crystals transform into various forms depending on conditions and states
`
`during the manufacture, crystallization, storage, and the like of the crystals, but also a
`mixture of the crystal forms obtained at two or more ofthe stages.
`Atropine ora salt thereof can be manufactured in accordance with a method
`commonly employedin the field of organic synthetic chemistry or can alternatively be
`a commercially available product. For example, atropine sulfate hydrate can be a com-
`mercially available product from Tokyo Chemical Industry Co., Ltd. (product code:
`A0550).
`
`[0061]
`
`In the present invention, the concentration of atropine or a salt thereof is preferably
`0.001 to 0.1 % (w/v), more preferably 0.001 to 0.05 % (w/v), still more preferably
`
`0.001 to 0.025 % (w/v), and particularly preferably 0.001 to 0.01 % (w/v). More
`specifically, the concentration is preferably 0.0010 % (w/v), 0.0015 % (w/v), 0.0020 %
`
`(w/v), 0.0025 % (w/v), 0.0030 % (w/v), 0.0035 % (w/v), 0.0040 % (w/v), 0.0045 %
`
`(w/v), 0.0050 % (w/v), 0.0055 % (w/v), 0.0060 % (w/v), 0.0065 % (w/v), 0.0070 %
`
`(w/v), 0.0075 % (w/v), 0.0080 % (w/v), 0.0085 % (w/v), 0.0090 % (w/v), 0.0095 %
`
`(w/v), or 0.010 % (w/v).
`
`[0062]
`
`[0063]
`
`In the present invention, the term "aqueous composition" means a composition
`containing water that serves as a solvent.
`In the present invention, the "water-soluble polymer" can be any pharmaceutically
`
`acceptable polymer capable of dissolving in water. Non-limiting examples of such a
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`polymerinclude celluloses and their derivatives (e.g., methyl cellulose, hydroxypropyl
`
`methylcellulose, hydroxypropyl! cellulose, hydroxypropyl methylcellulose phthalate,
`hydroxypropyl methylcellulose acetate succinate, carboxymethylethyl cellulose, car-
`
`boxymethyl ccllulose, sodium carboxymethyl cellulose, hydroxycthyl! cellulose,
`cellulose acetate phthalate, ethyl cellulose, hydroxymethyl] cellulose, hydrox-
`yethylmethyl] cellulose, hypromellose acetate succinate and hypromellose phthalate);
`synthetic polymers(e.g., polyethylene glycol, polyvinyl alcohol, polyvinyl
`pyrrolidone, polyvinylacetal diethylamino acetate, aminoalkyl methacrylate copolymer
`E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic
`acid copolymer LD, methacrylic acid copolymer S, and carboxyvinyl polymer); and
`
`naturally-occurring polymers and saccharides (e.g., gum arabic, sodium alginate,
`alginic acid propylene glycol ester, agar, gelatin, tragacanth, and xanthan gum).
`
`Among them, preferably used in the present invention as the water-soluble polymerare
`cellulose and its derivative, carboxyvinyl polymer and sodium alginate. Among them,
`more preferably used in the present invention as the water-soluble polymer are hy-
`droxyethyl cellulose, carboxyvinyl polymer and hydroxypropy] methylcellulose.
`The present aqueous composition can comprise one or more types of water-soluble
`polymers.
`In the present invention, the concentration of the water-soluble polymerin the
`
`present aqueous composition is set to a value by adjusting the content of a water-
`soluble polymer as appropriate to reflect the influence of the water-soluble polymer on
`
`a medicinal substance (active ingredient), other additive(s), pH, osmotic pressure, and/
`or viscosily. However, the concentration of the water-soluble polymerin the present
`aqueous composition is preferably 0.01 to 5 % (w/v), and more preferably 0.1 to 2 %
`(w/v).
`
`In the present invention, in a case where the water-soluble polymeris cellulose and
`its derivative, the concentration of the cellulose and its derivative is preferably 0.01 to
`5 % (w/v), more preferably 0.1 to 2 % (w/v), still more preferably 0.1 to 1 % (w/v),
`particularly preferably 0.1 to 0.6 %.
`In the present invention, in a case where the water-soluble polymer is hydroxyethyl
`
`cellulose, the concentration of the hydroxyethy] cellulose is preferably 0.1 to 1.0 %
`(w/v), and more preferably 0.1 to 0.6 % (w/v).
`
`In the present invention, in a case where the water-soluble polymeris carboxyvinyl
`polymer, the concentration of the carboxyvinyl polymeris preferably 0.04 to 0.4 %
`(w/v), and more preferably 0.08 to 0.4 % (w/v).
`In the present invention, in a case where the water-soluble polymeris hydroxypropyl
`methylcellulose, the concentration of the hydroxypropyl methylcellulose is preferably
`0.1 to 1.0 % (w/v), and more preferably 0.1 to 0.6 % (w/v).
`
`[0064]
`
`[0065]
`
`[0066]
`
`[0067]
`
`[0068]
`
`[0069]
`
`

`

`WO 2017/204262
`
`PCT/JP2017/019423
`
`10
`
`[0070]
`
`In the present invention, in a case where the water-soluble polymer is sodium
`
`alginate, the concentration of the sodium alginate is preferably 0.1 to 2% (w/v), and
`more preferably 0.5 to 2% (w/v).
`
`[0071]
`
`In the present invention, the term "buffer" should not be limited as long as it is phar-
`maceultically acceptable ones, which includes, for example, a phosphate buffer, a
`citrate buffer, a borate buffer, a carbonate buffer, an acetate buffer, a tartrate buffer, an
`
`aminocarboxylate buffer, and trometamol. The aminocarboxylate buffer includes, for
`example, an aspartate buffer, a glutamate buffer, and epsilon-aminocaproic acid. These
`buffers may be used as a single ingredient or as a combination of any two or more in-
`gredients. Among these buffers, a phosphate buffer, a citrate buffer, a carbonate buffer,
`
`an acetate buffer, and an aminocarboxylate buffer are preferable; a phosphate buffer, a
`citrate buffer, an acetate buffer, and an aminocarboxylate buffer are more preferable; a
`
`phosphate buffer and/or a citrate buffer are still more prefcrable; and a phosphate
`buffer and a citrate buffer are particularly preferable.
`In the present invention, the concentration of the buffer in the present aqueous com-
`position is set to a value by adjusting the content of the buffer as appropriate to reflect
`the influence of the buffer on a medicinal substance (active ingredient), other
`additive(s), pH, osmotic pressure, and/or viscosity. However, the concentration of the
`buffer in the present aqueous composition is preferably 0.001 to 10 % (w/v), more
`
`preferably 0.01 to 5 % (w/v), still more preferably 0.01 to 3 % (w/v), still much more
`preferably 0.01 to 1 % (w/v), particularly preferably 0.01 to 0.5 % (w/v), more par-
`
`ticularly preferably 0.01 to 0.1 % (w/v), wherein the weight of the buffer is that of a
`buffering agent as its material.
`In the present invention, the phosphate buffer can be derived from any pharma-
`ceutically acceptable phosphate buffering agent. Non-limiting examples of such a
`phosphate buffering agent include: phosphoric acid; phosphates such as alkali metal
`phosphates and alkaline earth metal phosphates; and hydrates thereof. More
`specifically, the phosphate buffering agent includes dibasic sodium phosphate hydrate
`(referred to as "dibasic sodium phosphate” or "sodium phosphate"), sodium dihydrogen
`phosphate (referred to as "monosodium phosphate"), sodium dihydrogen phosphate
`
`monohydrate (referred to as "monosodium phosphate”), sodium dihydrogen phosphate
`dihydrate (referred to as "monosodium phosphate"), potassium dihydrogen phosphate
`
`(referred to as "monopotassium phosphate"), sodium monohydrogen phosphate hep-
`tahydrate, trisodium phosphate, dipotassium phosphate, and the like.
`In the present invention, the concentration of the phosphate buffer in the present
`aqueous composition is set to a value by adjusting the content of the phosphate buffer
`as appropriate to reflect the influence of the phosphate buffer on a medicinal substance
`(active ingredient), other additive(s), pH, osmotic pressure, and/or viscosity. However,
`
`[0072]
`
`[0073]
`
`[0074]
`
`

`

`WO 2017/204262
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`PCT/JP2017/019423
`
`11
`
`[0075]
`
`the concentration of the phosphate buffer in the present aqueous composition is
`
`preferably 0.01 to 1.0 % (w/v), more preferably 0.05 to 1.0 % (w/v), and still more
`preferably 0.05 to 0.5 % (w/v), wherein the weight of the phosphate buffer is that of a
`
`phosphate buffcring agentas its material.
`In the present invention, the "citrate buffer" can be derived from a citrate buffering
`agent which should not be limited as long asit is pharmaceutically acceptable ones,
`which includes, for example, citric acid; citrates such as alkali metal citrates and
`alkaline earth metal citrates; and hydrates thereof. More specifically, the citrate buffer
`includescitric acid hydrate, sodium citrate, sodium citrate hydrate, potassium citrate,
`calcium citrate, sodium dihydrogencitrate, and disodium citrate.
`
`[0076]
`
`In the present invention, the concentration ofthe citrate buffer in the present aqueous
`composition is set to a value by adjusting the content of citrate buffer as appropriate to
`
`reflect the influence of the citrate buffer on a medicinal substance (active ingredicnt),
`other additive(s), pH, osmotic pressure, and/or viscosity. However, the concentration
`of the citrate buffer in the present aqueous composition is preferably 0.001 to 1.0 %
`(w/v), more preferably 0.005 to 0.5 % (w/v), still more preferably 0.01 to 0.1 % (w/v),
`still much more preferably 0.01 to 0.05 % (w/v) and particularly preferably 0.02 to
`0.04 % (w/v), wherein the weight of the citrate buffer is that of a citrate buffering agent
`as its material.
`
`[0077]
`
`In the present invention, the "borate buffer" can be derived from a borate buffering
`agent which includes, for example, boric acid or a salt thereof, and borax. More
`
`specifically, the borate buffering agent includes boric acid, sodium borate, potassium
`borate, potassium tetraborale, potassium metaborate, ammonium borate, and borax.
`The "carbonate buffer" can be derived from a carbonate buffering agent which
`includes, for example, carbonic acid ora salt thereof. More specifically, the carbonate
`buffering agent includes carbonic acid, sodium bicarbonate, sodium carbonate,
`ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate,
`and magnesium carbonate. The "acetate buffer" can be derived from an acetate
`buffering agent which includes, for example, acetic acid or a salt thereof. More
`specifically, the acetate buffering agent includes acetic acid, ammonium acetate,
`
`potassium acetate, calcium acetate, and sodium acetate, The "tartrate buffer" can be
`derived from a tartrate buffering agent which includes, for example, tartaric acid or a
`
`salt thereof. More specifically, the tartrate buffering agent includes sodium tartrate and
`potassium tartrate. The "aspartate buffer" can be derived from an aspartate buffering
`agent which includes, for example, aspartic acid or a salt thereof. More specifically,
`the aspartate buffering agent includes sodium aspartate and magnesiumaspartate. The
`"glutamate buffer” can be derived from a glutamate buffering agent which includes, for
`example, glutamic acid or a salt thereof. More specifically, the glutamate buffering
`
`

`

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`12
`
`agent includes sodium glutamate and potassium glutamate.
`
`[0078]
`
`The aqueous composition of the present invention may comprise buffer (1) as sole
`buffers, or buffer (1) and buffer (ID as sole buffers. And, the aqueous composition of
`
`the present invention may also comprise further different buffers besides buffer (1) and
`buffer UD.
`
`[0079]
`
`In the present invention, the term "buffer (1)”is at least one selected from the group
`consisting of a phosphate buffer, an aminocarboxylate buffer, a carbonate buffer, an
`acetate buffer, a tartrate buffer, a borate buffer, and trometamol. The definition of each
`
`buffer and the preferred range of each concentration are as explained in the above
`section of "buffer".
`
`[0080]
`
`In the present invention, the term "buffer (1])" is a citrate buffer. The definition ofthe
`citrate buffer and the preferred range of the concentration are as explained in the above
`
`section of "buffer".
`
`[008 1]
`
`[0082]
`
`The viscosity of the present aqueous composition is adjusted to fall within preferably
`a range of 3 to 500 mPa ° s, and more preferably a range of 6 to 70 mPa ° s, when
`measured by an E-type viscometer (25°C; shear rate of 50 s-1).
`The present aqueous composition may further comprise a tonicity agent. The tonicity
`agent used