(12) Ulllted States Patent
`Higashiyama
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,784,789 B2
`Jul. 22, 2014
`
`US008784789B2
`
`g1_11<11II1i1et ?_11~
`2 :
`~~~~~~~~
`,
`,
`imme stein eta.
`.
`5,701,182 A * 12/1997 Horiet al.
`................... .. 358/296
`5,795,913 A *
`8/1998 Lehmussaariet al.
`...... .. 514/459
`5,856,345 A
`1/1999 Doiet al.
`5,839,030 A
`3/1999 D01 eta1,
`6,307,052 B1* 10/2001 Kita et al.
`Efilgfi
`514/310
`6/2002 Asgharian .......
`6:403:609 131*
`20017/5117355333‘ 31* 13/5881 2121' """"""" " 424/464
`2002/0026054 A1
`2/2002 Kim et a1,
`'
`2003/0139436 A1*
`7/2003 Araki etal.
`................. .. 514/278
`2004/0147605 A1*
`7/2004 Onuki et al.
`................ .. 514/561
`
`
`
`..... .. 546/194
`
`EP
`EP
`EP
`JP
`JP
`JP
`JP
`JP
`WO
`WQ
`W0
`
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`
`*
`
`0 949 260
`1136084
`1 277 471
`404018015
`11-228404
`11/228404
`2001-261553
`2001261553 A *
`98/29409
`01/02002
`WO 01/02002
`
`10/1999
`9/2001
`1/2003
`1/1992
`8/1999
`8/1999
`9/2001
`9/2001
`7/1998
`1/2001
`1/2001
`
`01/80858
`W001/80858
`
`11/2001
`* 11/2001
`
`....... .. A6lK31/4709
`
`OTHER PUBLICATIONS
`
`Remingt0n’s Pharmaceutical Sciences. 1980; pp. 1410-1419.*
`;f3‘5§’{iam‘de Opfl‘a1m‘° S°1““°“’ USP‘ Pa°k"geI“Se“‘ Remed’ Feb‘
`Derwent Publications, WPI 1999-543925, JP 11228404, Aug. 24,
`1999.
`Derwent Publications, WPI 2003-880762/200383, JP 2001261553,
`SeP~ 2_5a 2001~
`Chemical Abstracts, Vol. 76(1), p. 24 (1972).
`* cited by examiner
`
`Primary Examiner — Daniel Sullivan
`Assistant Examiner — Barbara Frazier
`(74) Anomeyflgeml Orpirm , Wendemth’ Lind& Pollack’
`LLP
`
`(54) AQUEOUS LIQUID PREPARATIONS AND
`_
`AQUEOUS LIQUID
`_
`_
`Inventor: Masayo H1gash1yama,Kobe (JP)
`
`(75)
`
`(73) Assignee: Senju Pharmaceutical Co., Ltd., Osaka
`(JP)
`subject to any disclaimer, iheierm oiihis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 403 days.
`
`<*> Notice:
`
`(21) Appl. No.:
`
`10/500,354
`
`(22) PCT Filed:
`
`Jul. 30, 2003
`
`(86) PCT No.:
`
`PCT/JP03/09713
`
`§ 371 (°)(1)’
`(2): (4) Dale
`
`J““- 302 2004
`
`(87) PCT Pub. No.: WO2004/011001
`
`PCT Pub. Date: Feb. 5, 2004
`
`(65)
`
`Prior Publication Data
`
`US 2005/0107429 A1
`
`May 19, 2005
`
`Foreign Application Priority Data
`(30)
`Jul. 31, 2002
`(JP) ................................. 2002—223804
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. C1.
`A6IK 31/4545
`A61K 47/02
`A61K 9/00
`(52) U'S' Cl‘
`CPC ......... .. A61K 9/0048 (2013.01); A61K 31/4545
`(201301); /161K 9/0043 (201301); 1461K 47/02
`(2013-01)
`USPC ....................... .. 424/78.04; 514/318; 514/327
`(58) Field of Classification Search
`None
`
`See application file for complete search history.
`
`(57)
`
`ABSTRACT
`
`(56)
`
`References Cited
`Us PATENT DOCUMENTS
`
`4,053,628 A * 10/1977 Stevenson etal.
`4,929,618 A
`5/1990 Koda et al.
`5,290,774 A
`3/1994 Morita et al.
`
`.......... .. 514/456
`
`An aqueous liquid preparation containing (+)-(S)-4-[4-[(4-
`chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or
`a pharrnacologically acceptable acid addition salt thereof,
`which 1s stabilized with a water-soluble metal chloride, 1s
`Pr0V1ded-
`
`11 Claims, N0 Drawings
`
`MYLAN EX. 1001, Page 1
`
`MYLAN Ex. 1001, Page 1
`
`

`
`US 8,784,789 B2
`
`1
`AQUEOUS LIQUID PREPARATIONS AND
`LIGHT-STABILIZED AQUEOUS LIQUID
`PREPARATIONS
`
`This application is a U.S. national stage of International
`Application No. PCT/JP2003/009713 filed Jul. 30, 2003.
`
`TECHNICAL FIELD
`
`The present invention relates to an aqueous liquid prepa-
`ration comprising (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)
`methoxy]piperidino]butyric acid or a pharmacologically
`acceptable acid addition salt thereof, and a water-soluble
`metal chloride. The present invention also relates to a method
`of
`light-stabilizing
`(+)-(S)-4-[4-[(4-chlorophenyl)(2-py-
`ridyl)methoxy]piperidino]butyric acid and a pharmacologi-
`cally acceptable acid addition salt thereof, which comprises
`adding a water-soluble metal chloride.
`
`BACKGROUND ART
`
`(+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]pip-
`eridino]butyric acid and a pharmacologically acceptable acid
`addition salt thereof have a11 antihistarnimc action and an
`
`antiallergic action. They are also characterized in that sec-
`ondary effects such as stimulation or suppression of the cen-
`tral nerve often seen in the case of conventional antihista-
`
`minic agents can be minimized, and can be used as effective
`pharmaceutical agents for the treatment of human and ani-
`mals (JP-B-5-33953, JP-A-2000-198784).
`Particularly, a tablet comprising (+)-(S)-4-[4-[(4-chlo-
`rophenyl)(2-pyridyl)methoxy]piperidino]butyric
`acid
`monobenzenesulfonate (general name: bepotastine besilate)
`has been already marketed as a therapeutic agent for allergic
`rhinitis and itching associated with hives and dermatoses.
`On the other hand, (+)-(S)-4-[4-[(4-chlorophenyl)(2-py-
`ridyl)methoxy]piperidino]butyric acid and a pharmacologi-
`cally acceptable acid addition salt thereofare unstable to light
`in an aqueous solution, and colored or precipitated with the
`lapse of time, which has made the use thereof as an aqueous
`liquid preparation difficult. In the case of an aqueous liquid
`preparation such as an eye drop and a nasal drop, a method
`comprising blocking light by preserving in a light-shielding
`container and the like can be used, but complete light-shield-
`ing is practically difiicult. Thus, stabilization of an aqueous
`liquid preparation itself as a preparation is desirable. As a
`method oflight-stabilizing an eye drop, a U.S. Pat. No. 2,929,
`274 discloses a method comprising adding boric acid and/or
`borax and glycerin, but according to this method, stabiliza-
`tion of (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]
`piperidino]butyric acid and a pharmacologically acceptable
`acid addition salt thereof to light was not observed. As a
`general stabilization method, a method comprising placing in
`the coexistence of an antioxidant such as BHT etc., and the
`like are known (JP-A-7-304670).
`
`DISCLOSURE OF THE INVENTION
`
`The present invention aims at providing an aqueous liquid
`preparation comprising stabilized (+)-(S)-4-[4-[(4-chlo-
`rophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or a
`pharmacologically acceptable acid addition salt thereof.
`Another object of the present invention is to provide a
`method oflight-stabilizing (+)-(S)-4-[4-[(4-chlorophenyl)(2-
`pyridyl)methoxy]piperidino]butyric acid and a pharmaco-
`logically acceptable acid addition salt thereof in an aqueous
`solution.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`Under the above-mentioned situation, the present inventor
`has conducted various studies and, as a result, found that
`(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperi-
`dino]butyric acid and a pharmacologically acceptable acid
`addition salt thereof can be light-stabilized in water by adding
`a water-soluble metal chloride, and further studied to com-
`plete the present invention.
`Accordingly, the present invention relates to
`(1) an aqueous liquid preparation comprising (+)-(S)-4-[4-
`[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]bu-
`tyric acid or a pharmacologically acceptable acid addi-
`tion salt thereof, and a water-soluble metal chloride,
`(2) the aqueous liquid preparation of the above-mentioned
`(1), wherein the metal chloride has a concentration
`selected from the range of a lower limit concentration of
`0.15 w/v % and an upper limit concentration of 1.5 w/v
`%s
`(3) the aqueous liquid preparation of the above-mentioned
`(l) or (2), wherein the metal chloride is at least one kind
`selected from sodium chloride, potassium chloride and
`calcium chloride,
`(4) the aqueous liquid preparation of any of the above-
`mentioned (1) to (3), wherein the (+)-(S)-4-[4-[(4-chlo-
`rophenyl)(2-pyridyl)methoxy]piperidino]butyric
`acid
`or the pharmacologically acceptable acid addition salt
`thereof has a concentration selected from the range of a
`lower limit concentration of 0.1 w/v % and an upper
`limit concentration of 2.0 w/v %,
`(5) the aqueous liquid preparation of any of the above-
`mentioned (1) to (4), which is an acid addition salt of
`(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]pi-
`peridino]butyric acid,
`(6) the aqueous liquid preparation of the above-mentioned
`(5), wherein the acid addition salt is monobenzene-
`sulfonate,
`(7) the aqueous liquid preparation of any of the above-
`mentioned (1) to (6), wherein the aqueous liquid prepa-
`ration has a pH in the range of 4-8.5,
`(8) the aqueous liquid preparation of any of the above-
`mentioned (1) to (7), which is an eye drop,
`(9) the aqueous liquid preparation of any of the above-
`mentioned (1) to (7), which is a nasal drop,
`(10) an aqueous eye drop comprising (+)-(S)-4-[4-[(4-
`chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric
`acid monobenzenesulfonate and sodium chloride at not
`less than 0.2 w/v % and not more than 0.8 w/v %, and
`(l l) a method of light-stabilizing (+)-(S)-4-[4-[(4-chlo-
`rophenyl)(2-pyridyl)methoxy]piperidino]butyric
`acid
`in an aqueous solution, which comprises adding a water-
`soluble metal chloride to an aqueous solution compris-
`ing (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]
`piperidino]butyric
`acid
`or
`a
`pharmacologically
`acceptable acid addition salt thereof.
`In the present invention, as a pharmacologically acceptable
`acid addition salt of (+)-(S)-4-[4-[(4-chlorophenyl)(2-py-
`ridyl)methoxy]piperidino]butyric acid, for example, salts
`with hydrohalic acid such as hydrochloride, hydrobromide
`and the like; salts with inorganic acid such as sulfate, nitrate,
`phosphate and the like; salts with organic acid such as acetate,
`propionate, hydroxyacetate, 2-hydroxypropionate, pyruvate,
`malonate, succinate, maleate, fumarate, dihydroxyfumarate,
`oxalate, benzoate, cinnamate, salicylate, methanesulfonate,
`ethanesulfonate,
`benzenesulfonate,
`p-toluenesulfonate,
`cyclohexylsulfarnate, 4-aminosalicylate and the like; and the
`like can be mentioned. The above-mentioned compound to be
`used in the present invention is generally preferably an acid
`addition salt, and of these acid addition salts, benzene-
`
`MYLAN EX. 1001, Page 2
`
`MYLAN Ex. 1001, Page 2
`
`

`
`US 8,784,789 B2
`
`3
`sulfonate and benzoate are more preferable, and monobenze-
`nesulfonate is particularly preferable.
`(+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]pip-
`eridino]butyric acid and a pharmacologically acceptable acid
`addition salt thereof can be produced by, for example, the
`methods described in JP-B-5-33953 and JP-A-2000-198784.
`
`In the aqueous liquid preparation of the present invention,
`the content of
`(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)
`methoxy]piperidino]butyric acid or a pharmacologically
`acceptable salt thereof as monobenzenesulfonate is generally
`shown by a lower limit of about 0.1 w/v %, preferably about
`0.3 w/v %, more preferably about 0.5 w/v %, and an upper
`limit of about 2.0 w/v %, preferably about 1.5 w/v %, which
`are increased or decreased appropriately depending on the
`object of use and the degree of symptoms.
`In the present invention, as a preferable water-soluble
`metal chloride, alkali metal chlorides such as sodium chlo-
`ride, potassium chloride and the like, and alkaline earth metal
`chlorides such as calcium chloride and the like can be men-
`
`tioned, which may be used alone, or in combination of two or
`more kinds thereof. Particularly preferred is sodium chloride.
`In the aqueous liquid preparation of the present invention,
`the content of the water-soluble metal chloride is generally
`shown by a lower limit of about 0. 1 5 w/v % and an upper limit
`of about 1.5 w/v %, preferably a lower limit of about 0.2 w/v
`% and an upper limit of about 1.2 w/v %. Particularly, as
`sodium chloride, it is not less than about 0.15 w/v %, about
`0.2 w/v %, about 0.3 w/v %, and not more than about 1.0 w/v
`%, about 0.8 w/v %, about 0.6 w/v %. As potassium chloride,
`it is not less than about 0.15 w/v %, about 0.2 w/v %, about 0.3
`w/v %, and not more than about 1.0 w/v %, about 0.9 w/v %,
`about 0.8 w/v %. As calcium chloride and as dihydrate, it is
`not less than about 0.2 w/v %, about 0.3 w/v %, and not more
`than about 1.5 w/v %, about 1.2 w/v %.
`Moreover, the concentration of these water-soluble metal
`chlorides is preferably determined as appropriate within the
`above-mentioned concentration range, such that the osmotic
`pressure is generally about 230 mOsm-about 350 mOsm, in
`consideration of the amount of other isotonic agents to be
`added, such as boric acid and the like, that do not influence
`stabilization.
`
`Various additives that are generally used such as buffer,
`preservative, chelating agent, flavor and the like may be
`appropriately added to the aqueous liquid preparation of the
`present invention.
`As the buffer, for example, phosphate buffer, borate buffer,
`citrate buffer, tartrate buffer, acetate buffer, amino acid and
`the like can be mentioned. As the preservative, for example,
`quaternary ammonium salts such as benzalkonium chloride,
`chlorhexidine gluconate and the like, parahydroxybenzoic
`acid esters such as methyl parahydroxybenzoate, propyl
`parahydroxybenzoate and the like, sorbic acid and a salt
`thereof and the like can be mentioned. As the chelating agent,
`disodium edetate, citric acid and the like can be mentioned.
`As the flavor, 1-menthol, borneol, carnphor, oil of eucalyptus
`and the like can be mentioned.
`
`The pH of the aqueous liquid preparation of the present
`invention is adjusted to not less than about 4, 5, 6, and not
`more than about 8.5, 8.
`In the aqueous liquid preparation of the present invention,
`other same or different kinds of eflicacious ingredients may
`be added appropriately as long as the object of the present
`invention is not impaired.
`As the aqueous liquid preparation of the present invention,
`an eye drop, a nasal drop, an ear drop and the like can be
`
`4
`
`mentioned. When the aqueous liquid preparation of the
`present invention is used as a nasal drop, it may be prepared
`into a propellant.
`The aqueous liquid preparation ofthe present invention can
`be produced by a production method known per se, such as a
`method described in the liquid preparation or eye drop of the
`General Rules for Preparations in the Japanese Pharmaco-
`poeia 14th Edition.
`The aqueous liquid preparation ofthe present invention can
`be used for warm-blooded animals (e.g., human, rat, mouse,
`rabbit, bovine, pig, dog, cat and the like).
`When the aqueous liquid preparation of the present inven-
`tion is used as, for example, an eye drop, it can be used for
`allergic conjunctivitis, spring catarrh, pollinosis and the like.
`The dose thereof when, for example, an eye drop of the
`present invention comprising 1.0 w/v % of (+)-(S)-4-[4-[(4-
`chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric
`acid
`monobenzenesulfonate (hereinafter to be referred to as bepo-
`tastine besilate) is instilled into the eye of an adult, is 1-2
`drops per instillation, which is given 3-6 times a day by
`instillation into the eye. The frequency can be increased or
`decreased appropriately depending on the degree of symp-
`tom.
`
`BEST MODE FOR EMBODYING THE
`INVENTION
`
`10
`
`15
`
`20
`
`25
`
`The present invention is explained in more detail by refer-
`ring to Experimental Examples and Examples, which are not
`to be construed as limitative.
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Experimental Example 1
`
`Effect of Water-Soluble Metal Chloride on
`
`Light-Stability of Bepotastine Besilate
`
`Test Method
`
`The aqueous liquid preparations (Formulations 1-6) shown
`in the following [Table 1], which contained bepotastine besi-
`late, were prepared according to conventional methods and
`filled in glass arnpoules by 5 mL each. Using a xenon long-life
`fade meter (FAL-25AX-Ec manufactured by SUGA TEST
`INSTRUMENTS Co., Ltd.), a light corresponding to not less
`than 200 W~h/m2 in a total near-ultraviolet radiation energy
`was irradiated (irradiation time: 23-34 hr), and appearance of
`each formulated liquid preparation was observed. The
`amount of light exposure was measured by a quinine chemi-
`cal actinometry system described in the Drug Approval and
`Licensing Procedures in Japan 2001.
`TABLE 1
`
`1
`
`1.5 g
`
`—
`
`bepotastine
`besilate
`sodium
`chloride
`potassium —
`chloride
`calcium
`chloride
`2H2O
`sodium
`hydroxide
`total
`amount
`pH
`
`suitable
`amount
`100 mL
`
`7.0
`
`Formulation
`
`2
`
`1.5 g
`
`0.1 g
`
`—
`
`3
`
`1.5 g
`
`0.2 g
`
`—
`
`4
`
`5
`
`6
`
`1.5 g
`
`1.5 g
`
`1.5 g
`
`0.3 g —
`
`—
`
`—
`
`0.79 g —
`
`1.18 g
`
`suitable
`suitable
`suitable
`suitable
`suitable
`amount
`amount
`amount
`amount
`amount
`100 mL 100 mL 100 mL 100 mL 100 mL
`
`7.0
`
`6.7
`
`6.9
`
`6.7
`
`6.8
`
`MYLAN EX. 1001, Page 3
`
`MYLAN Ex. 1001, Page 3
`
`

`
`US 8,784,789 B2
`
`Test Results
`
`5
`
`The appearance after light irradiation was black green in
`Formulation 1, and a precipitate was observed. It was slightly
`dark green-pale yellow in Formulation 2, and a precipitate
`was slightly observed. The appearance of Formulations 3-6
`did not change from that immediately after preparation and
`were pale yellow and clear. The results indicate that addition
`of a water-soluble metal chloride in not less than 0.2 w/v %
`
`improves stability of bepotastine besilate under light irradia-
`tion conditions.
`
`Experimental Example 2
`
`Effect of Boric Acid and Glycerin on Light-Stability
`of Bepotastine Besilate
`
`Test Method
`
`The aqueous liquid preparations (Formulations 7-9) shown
`in the following [Table 2], which contained bepotastine besi-
`late, were prepared according to conventional methods and
`processed in the same manner as in Experimental Example 1,
`and appearance of each formulated liquid preparation was
`observed.
`
`TABLE 2
`
`Formulation
`
`8
`
`—
`
`1.5 g
`0.1 g
`
`7
`
`—
`
`0.6 g
`
`—
`0.005 g
`suitable
`amount
`100 mL
`6.8
`
`9
`
`—
`
`—
`
`1.5 g
`
`0.5 g
`
`2.0 g
`0.005 g
`suitable
`amount
`100 mL
`6.8
`
`1.5 g
`
`1.0 g
`
`—
`
`0.5 g
`0.005 g
`suitable
`amount
`100 mL
`6.8
`
`bepotastine besilate
`sodium dihydrogen
`phosphate dihydrate
`boric acid
`sodium chloride
`glycerin
`benzalkonium chloride
`sodium hydroxide
`total amount
`pH
`
`Test Results
`
`The appearance after light irradiation did not change from
`that immediately after preparation and was pale yellow and
`clear for Formulation 7 comprising sodium chloride, but
`black green for Formulations 8 and 9 comprising boric acid
`and glycerin and a precipitate was observed. The results indi-
`cate that addition of boric acid and glycerin fails to improve
`stability of bepotastine besilate under light irradiation condi-
`tions.
`
`Experimental Example 3
`
`Effect of pH and Bepotastine Besilate Concentration
`on Light-Stability of Bepotastine Besilate
`
`Test Method
`
`The aqueous liquid preparations (Formulations 10-12)
`shown in the following [Table 3], which contained bepotast-
`ine besilate, were prepared according to conventional meth-
`ods and processed in the same manner as in Experimental
`Example 1, and appearance of each formulated liquid prepa-
`ration was observed.
`
`TABLE 3
`
`Formulation
`
`10
`
`1.5 g
`0.1 g
`
`0.6 g
`0.005 g
`
`11
`
`1.5 g
`0.1 g
`
`0.6 g
`0.005 g
`
`suitable
`amount
`100 mL
`4.0
`
`suitable
`amount
`100 mL
`8.5
`
`12
`
`0.1 g
`0.1 g
`
`0.82 g
`0.005 g
`
`suitable
`amount
`100 mL
`6.8
`
`Bepotastine besilate
`sodium dihydrogen
`phosphate dihydrate
`sodium chloride
`benzalkonium
`chloride
`sodium hydroxide
`total amount
`pH
`
`Test Results
`
`The appearance after light irradiation did not change from
`that immediately after preparation and was pale yellow and
`clear for Formulation 10 (pH 4) and Formulation 11 (pH 8.5)
`comprising sodium chloride. In addition, the appearance did
`not change from that immediately after preparation and was
`colorless and clear for Formulation 12 having a bepotastine
`besilate concentration of 0.1 w/v %. These results and the
`
`results of Formulation 7 (pH 6.8) in Experimental Example 2
`indicate that addition of sodium chloride, which is a water-
`soluble metal chloride, improves light stability ofbepotastine
`besilate at pH 4-8.5. In addition, they indicate that the light-
`stability of bepotastine besilate is improved in the concentra-
`tion range of 0.1 w/v %-1.5 w/v %.
`
`Experimental Example 4
`
`Effect of Bepotastine Besilate Concentration and pH
`on Light-Stability of Bepotastine Besilate in
`Aqueous Preparation Comprising Glycerin
`
`Test Method
`
`The aqueous liquid preparations (Formulations 13-17)
`shown in the following [Table 4], which contained bepotast-
`ine besilate, were prepared according to conventional meth-
`ods and processed in the same manner as in Experimental
`Example 1, and appearance of each formulated liquid prepa-
`ration was observed.
`
`TABLE 4
`
`Formulation
`
`13
`
`14
`
`15
`
`16
`
`17
`
`0.5 g
`
`0.1g
`
`bepotastine
`besilate
`sodium
`dihydrogen
`phosphate
`dihydrate
`glycerin
`benzalkonium
`chloride
`sodium hydroxide suitable
`amount
`total amount
`100 mL
`pH
`6.8
`
`2.2 g
`0.005 g
`
`1.0 g
`
`0.1g
`
`1.5 g
`
`0.1g
`
`1.5 g
`
`0.1g
`
`1.5 g
`
`0.1g
`
`2.0 g
`0.005 g
`
`suitable
`amount
`100 mL
`6.8
`
`1.7 g
`0.005 g
`
`suitable
`amount
`100 mL
`4.0
`
`1.7 g
`0.005 g
`
`1.7 g
`0.005 g
`
`suitable
`suitable
`amount
`amount
`100 mL 100 mL
`6.8
`8.5
`
`Test Results
`
`The appearance after light irradiation was pale black green
`for Formulation 13 and black green for Formulation 14, and a
`precipitate was observed in both Formulations. The results
`indicate that addition of glycerin results in coloration ofbepo-
`tastine besilate into black green even at a low concentration.
`
`MYLAN EX. 1001, Page 4
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`MYLAN Ex. 1001, Page 4
`
`

`
`US 8,784,789 B2
`
`7
`Formulation 15 (pH 4) turr1ed blue and a precipitate was
`observed. Formulation 16 (pH 6.8) turned black green and a
`precipitate was observed. Formulation 17 (pH 8.5) turned
`yellow brown but no precipitation was observed. The results
`indicate that bepotastine besilate is extremely unstable at a pH
`near neutral. The results also indicate that glycerin does not
`improve light-stability of bepotastine besilate in the range of
`pH 4-8.5. When 3.3 W/v % ofglucose or mannitol was added
`instead of glycerin of Formulation 16, black green was devel-
`oped and a precipitate was observed. These results indicate
`that a water-soluble metal chloride improves light-stability of
`bepotastine besilate, and isotonic agents such as glycerin,
`saccharides and the like do not improve light-stability of
`bepotastine besilate.
`
`Example 1
`
`Eye Drop
`
`bepotastine besilate
`Sodium dihydrogenphosphate dihydrate
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile purified Water total amount
`
`0.3 g
`0.1 g
`0.79 g
`0.005 g
`suitable amount
`100 mL
`pH 6.8
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Example 2
`
`Eye Drop
`
`bepotastine besilate
`Sodium dihydrogenphosphate dihydrate
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile purified Water total amount
`pH
`
`0.5 g
`0.1 g
`0.76 g
`0.005 g
`suitable amount
`100 mL
`6.8
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Example 3
`
`Eye Drop
`
`bepotastine besilate
`Sodium dihydrogenphosphate dihydrate
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile purified Water total amount
`pH
`
`1.0 g
`0.1 g
`0.68 g
`0.005 g
`suitable amount
`100 mL
`6.8
`
`8
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Example 4
`
`Eye Drop
`
`10
`
`15
`
`20
`
`25
`
`30
`
`bepotastine besilate
`Sodium acetate trihydrate
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile purified Water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0.005 g
`suitable amount
`100 mL
`4.0
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Example 5
`
`Eye Drop
`
`bepotastine besilate
`epsilon-aminocaproic acid
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile purified Water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0.005 g
`suitable amount
`100 mL
`4.0
`
`35
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Example 6
`
`Eye Drop
`
`bepotastine besilate
`citric acid
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile purified Water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0.005 g
`suitable amount
`100 mL
`6.8
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Example 7
`
`Eye Drop
`
`bepotastine besilate
`taurine
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile purified Water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0.005 g
`suitable amount
`100 mL
`8.5
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`MYLAN EX. 1001, Page 5
`
`MYLAN Ex. 1001, Page 5
`
`

`
`US 8,784,789 B2
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Example 8
`
`Eye Drop
`
`.
`.
`1 t
`b
`t
`t
`b
`sc:Ii,iOuf2iiS d1i1liyd::lg:i:phosphate dihydrate
`sodium chloride
`methyl parahydroxybenzoate
`propylparahydroxybenzoate
`sodium hydroxide
`sterile purified water total amount
`pH
`
`1.5
`0.1 :
`0.6 g
`0.026 g
`0.014 g
`suitable amount
`100 mL
`6.8
`
`5
`
`10
`
`15
`
`Exainpie i2
`
`Nasal Drop
`
`bepotastine besilate
`.
`.
`.
`Sodium dlhydirogenphosphate dlhydrate
`Sodlum chionde
`.
`b°“.Za”‘°““”“ fihlonde
`t
`Sfdlllim hyfgrojldet
`t t 1
`S13“ 6 pun C W3 er 0 a amoun
`p
`
`1.0 g
`0'1 g
`0'68 g
`0905 g
`Suitoag16 EmOunt
`6 8 m
`'
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`20
`
`Using the above-mentioned ingredients, a nasal drop is
`prepared by a Conventional method‘
`INDUSTRIAL APPLICABILITY
`
`Example 9
`
`Eye Drop
`
`In the present invention, the light-stability of (+)-(S)-4-[4-
`[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric
`acid or a pharmacologically acceptable acid addition salt
`25 thereof, particularly bepotastine besilate, which is monoben-
`zenesulfonate, can be improved by adding a water-soluble
`metal chloride to an aqueous liquid preparation comprising
`.
`.
`.
`(*.')'(S)'4'[.4'[(4f°h1°r°Pheny1)(2'Py“f1y1)meth°XyiPipe” .
`dino]butyric acid or a pharmacologically acceptable acid
`30 addition salt thereof, and a stable aqueous liquid preparation
`can be produced. Since an aqueous liquid preparation stable
`1. h
`~
`~
`~
`~
`~
`to ig t can be obtained by the light-stabilizing method ofthe
`present
`the aqueous liquid preparation of the
`invention,
`present invention is advantageously used for the treatment of
`Using ine an0Ve'nienii0ned ingredients: an eye die}? is 35 allergic conjunctivitis, spring catarrh, pollinosis, allergic
`prepared by a conventional method.
`rhinitis and the iikei
`While some of the embodiments of this invention have
`
`bepotastine besilate
`sodium dihydrogenphosphate dihydrate
`Sodium chloride
`potassium sorbate
`S°di”m hydr°Xide
`sterile purified water total amount
`PH
`
`1.5 g
`0.1 g
`o_5 g
`0.27 g
`Suitable ““°”m
`100 mL
`6_8
`
`Example 10
`
`Eye Drop
`
`bepotastine besilate
`sodium dihydrogenphosphate dihydrate
`sodium chloride
`chlorhexidme gluconate
`Sodium hydroxide
`sterile purified water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0005 g
`Suitable amount
`100 mL
`6.8
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a c0iiVemi0iia1 method.
`
`Example 11
`
`E D
`ye mp
`
`.
`.
`b
`epotastine besilate
`sodium dihydrogenphosphate dihydrate
`sodium chloride
`benzaiimninin °hi°n‘ie
`sodium hydroxide
`.
`.
`sterile purified water total amount
`PH
`
`1.5 g
`0.1 g
`0.6 g
`0-005 g
`suitable amount
`100 mL
`6_g
`
`been described in detail in the foregoing, it will be possible for
`those of ordinary skill in the art to variously modify and
`40 change the embodiments specifically shown herein, within
`the scope not substantially deviating from the novel teaching
`and benefit of the invention. Accordingly,
`this invention
`encompasses all such modifications and changes within the
`spirit and scope of the invention as defined by the following
`45 Claims.
`~
`~
`~
`~
`~
`~
`This application is based on a patent application No.
`223804/2002 filed in Japan, the contents of which are hereby
`incorporated by reference.
`
`50
`
`The invention claimed is:
`
`1- An aflneens ii‘l.nid.PiePai.aii0n eensisiing 012 in an aqne'
`ous solution, an active ingredient consisting of (+)-(S)-4-[4-
`[(4 -chlorophenyl)(2 -pyridyl)methoxy]piperidino]butyric
`acid or a pharmacologically acceptable acid addition salt
`g
`g
`55 thereof; a water-soluble metal chloride in a li ht-stabilizin
`effective amount; water; and o tionall
`at least one material
`Y
`P
`selected from the group consisting of a buffer, a preservative,
`a chelating agent, and a flavor; wherein the metal chloride has
`a concentration selected from the range of a lower limit con-
`60 centration of 0.2 w/v % and an upper limit concentration of
`0
`1'2 W/V A”
`2. The aqueous liquid preparation of claim 1, wherein the
`metal chloride is at least one kind selected from sodium
`-
`-
`-
`-
`-
`chloride, potassium chloride and calcium chloride.
`.
`.
`.
`.
`.
`.
`3. The aqueous liquid preparation of claim 1, which is an
`acid addition salt of (+)-(S)-4-[4-[(4-chlorophenyl)(2-py-
`ridyl)methoxy]piperidino]butyric acid.
`
`65
`
`MYLAN EX. 1001, Page 6
`
`MYLAN Ex. 1001, Page 6
`
`

`
`11
`
`12
`
`US 8,784,789 B2
`
`4. The aqueous liquid preparation of claim 3, wherein the
`acid addition salt is monobenzenesulfonate.
`5. The aqueous liquid preparation of claim 1, wherein the
`aqueous liquid preparation has a pH in the range of 4-8.5.
`6. The aqueous liquid preparation of claim 1, which is an
`eye drop.
`7. The aqueous liquid preparation of claim 1, which is a
`nasal drop.
`8. The aqueous liquid preparation of claim 1, wherein the
`metal chloride is at least one kind selected from alkali metal
`chlorides and alkaline earth metal chlorides.
`9. An aqueous eye drop consisting of: (a) an active ingre-
`dient consisting of (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)
`methoxy]piperidino]butyric acid or a pharmacologically
`acceptable acid addition salt thereof; (b) a water-soluble
`metal chloride; (c) sodium dihydrogen phosphate buffer; (d)
`a preservative; (e) water; and optionally (f) disodium edetate;
`wherein the metal chloride has a concentration selected from
`
`the range of a lower limit concentration of 0.2 w/v % and an
`upper limit concentration of 1.2 w/v %.
`10. An aqueous liquid preparation consisting of, in an
`aqueous solution, an active ingredient consisting of (+)-(S)-
`
`5
`
`10
`
`15
`
`20
`
`4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]bu-
`tyric acid or a pharmacologically acceptable acid addition salt
`thereof, a water-soluble metal chloride in a light-stabilizing
`effective amount, wherein the metal chloride has a concen-
`tration selected from the range of a lower limit concentration
`of 0.2 w/v % and an upper limit concentration of 1.2 w/v %,
`benzalkomum chloride, sodium dihydrogenphosphate dihy-
`drate, sodium hydroxide and water.
`11. The aqueous eye drop of claim 9, wherein:
`(i) the (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]
`piperidino]butyric
`acid or
`the pharmacologically
`acceptable acid addition salt thereof is (+)-(S)-4-[4-[(4-
`chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric
`acid monobenzenesufonate;
`(ii) the water-soluble metal chloride is sodium chloride;
`and
`
`(iii) the sodium chloride has a concentration selected from
`the range of a lower limit concentration of0.2 w/v % and
`an upper limit concentration of 0.8 w/v %.
`*
`*
`*
`*
`*
`
`MYLAN EX. 1001, Page 7
`
`MYLAN Ex. 1001, Page 7
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`APPLICATION NO.
`
`2 8,784,789 B2
`: 10/500354
`
`DATED
`INVENTOR(S)
`
`: July 22, 2014
`: Higashiyarna
`
`Pagg 1 Of]
`
`It is certified that error appears in the above—identified patent and that said Letters Patent is hereby corrected as shown below:
`
`On the Title Page:
`
`The first or sole Notice should read --
`
`Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. l54(b)
`
`by 533 days.
`
`Signed and Sealed this
`
`Fifteenth Day of September, 2015
`
`‘%u;uo&.X/..<:’.L_.
`
`Michelle K. Lee
`
`Director ofthe United States Patent and Trademark Oflice
`
`MYLAN EX. 1001, Page 8
`
`MYLAN Ex. 1001, Page 8