USOO8877168B1
`
`(12) Umted States Patent
`Higashiyama
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,877,168 B1
`*Nov. 4, 2014
`
`(54) AQUEOUS LIQUID PREPARATIONS AND
`LIGHT-STABILIZED AQUEOUS LIQUID
`PREPARATIONS
`
`(71) Applicant: Senju Pharmaceutical Co., Ltd., Osaka
`(JP)
`
`(72) Inventor: Masayo Higashiyama, Kobe (JP)
`
`.
`.
`.
`(73) Asslgnee: Senju Pharmaceuticals Co., Ltd.,
`Osaka (JP)
`
`_
`5,701,182 A 12/1997 Hori et a1.
`2
`gehmtuslsaan er al~
`,
`,
`01 e a.
`5,889,030 A
`3/l999 D01 et a1.
`6,307,052 B1
`10/2001 K't t l.
`6,331,540 Bl
`12/2001 Kills; a
`6,369,001 B1
`4/2002 Jimoh
`6,403,609 B1
`6/2002 Asgharian
`7,175,854 B2
`2/2007 Dletmh et 31'
`2001/0033837 A1 10/2001 Metzner et a1.
`2002/0026054 A1
`2/2002 Kita et a1.
`2003/0139436 A1
`700% Amki et al‘
`2004/0147605 A1
`7/2004 Onuki et a1.
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`
`FOREIGN PATENT DOCUMENTS
`
`U.S.C. 154(b) by 0 days. This patent is subject to a terminal dis-
`
`Claimer_
`
`_
`(21) Appl. No.. 14/314,678
`_
`(22) F11ed:
`
`Jun. 25, 2014
`
`Related US. Application Data
`
`EP
`JP
`JP
`JP
`WO
`WO
`WO
`WO
`
`1/2003
`01914396332 1 277 471
`
`1/1992
`404018015
`8/1999
`ll-228404
`9/2001
`2001-261553
`7/1998
`98/29409
`l/2001
`01/02002
`11/2001
`01/80858
`ll/2009
`2009/l42950
`OTHER PUBLICATIONS
`
`(63) Continuation of application No. 10/500,354, ?led as
`application NO PCT/JP03/09713 on Jul 30 2003
`'
`'
`’
`’
`HOW pat NO' 8’784’789'
`
`_
`_
`_
`_
`Internatlonal Search Report malled Oct. 14, 2003 1n Internatlonal
`Application No. PCT/JP03/09713.
`Derwent Publications, WPI 1999-543925, JP 11228404, Aug. 24,
`
`(30)
`
`_
`
`_
`
`_
`
`_
`
`_
`
`Forelgn APPllcatlon Pmrlty Data
`
`Jul. 31, 2002 (JP) ............................... .. 2002-223804
`
`(51) Int. C1.
`A61K 31/4545
`
`(2006.01)
`
`(52) U.S.Cl.
`CPC ............. .. A61K 47/02 (2013.01); A61K 9/0048
`(2013.01); A61K 31/4545 (2013.01); A61K
`
`(
`
`~
`
`)
`
`1999.
`
`Derwent Publications, WPI 2003-880762/200383, JP 2001261553,
`Sep. 26, 2001.
`Remington’s Pharmaceutical Sciences, pp. 1410-1419 (1980).
`Tropicamide Opthalmic Solution, USP. Package Insert. Revised, Feb.
`2000
`llthgmkIInfdeX’ Pt}? llo'lggisggg'clgiggcézsgglfl (2°06)
`rug n orma lon, pp.
`an
`ALBALON package insert (1996).
`Print out from: http://WWW.paylessonlinepharmacy.com/customer/
`product-l342-HerpleX-D-Idoxuridine-T0pical-Solution.html
`(2010)
`Chenncal Abstracts, V°1~ 76(1), P 24 (1972)
`
`.
`
`USPC
`(58) Field 0
`None
`See application ?le for complete search history.
`
`424/78 04
`Search' ’
`
`13625011230217)
`’
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,053,628 A 10/1977 Stevenson et a1.
`4,929,618 A
`5/1990 Kodaet a1.
`5,290,774 A
`3/1994 Morita et a1.
`5,294,623 A
`3/1994 Fukumiet a1.
`5,599,534 A
`2/1997 Himmelstein et al.
`
`Primary Examiner * David J Blanchard
`Assistant Examiner * Barbara Frazier
`(74) Attorney, Agent, or Firm * Wenderoth, Lind & Ponack,
`LLP'
`
`ABSTRACT
`(57)
`An aqueous liquid preparation containing (+)-(S)-4-[4-[(4
`chlorophenyl) (2-pyridyl)methoxy]piperidino]butyric acid
`or a pharmacologically acceptable acid addition salt thereof,
`Which is stabilized With a water-soluble metal chloride, is
`provided.
`
`30 Claims, No Drawings
`
`MYLAN Ex. 1002, Page 1
`
`

`
`US 8,877,168 B1
`
`1
`AQUEOUS LIQUID PREPARATIONS AND
`LIGHT-STABILIZED AQUEOUS LIQUID
`PREPARATIONS
`
`This application is a continuation application ofU.S. appli
`cation Ser. No. 10/500,354, ?led Jun. 30, 2004, issued as US.
`Pat. No. 8,784,789 on Jul. 22, 2014, which is the national
`phase ?ling of International Patent Application No. PCT/
`JP2003/009713, ?led Jul. 30, 2003.
`
`TECHNICAL FIELD
`
`The present invention relates to an aqueous liquid prepa
`ration comprising (+)-(8)-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 an antihistaminic 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 thereof are unstable to light
`in an aqueous solution, and colored or predipitated with the
`lapse of time, which has made the use thereof as an aqueous
`liquid preparation dif?cult. 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 dif?cult. Thus, stabilization of an aqueous
`liquid preparation itself as a preparation is desirable. As a
`method of light-stabilizing an eye drop, a US. 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).
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`DISCLOSURE OF THE INVENTION
`
`60
`
`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 of light-stabilizing (+)-(S)-4-[4-[(4-chlorophenyl)(2
`
`65
`
`2
`pyridyl)methoxy]piperidino]butyric acid and a pharmaco
`logically acceptable acid addition salt thereof in an aqueous
`solution.
`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]butyric
`acid or a pharmacologically acceptable acid addition 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 %,
`(3) the aqueous liquid preparation of the above-mentioned (1)
`or (2), wherein the metal chloride is at least one kind selected
`from sodium chloride, potassium chloride and calcium chlo
`ride,
`(4) the aqueous liquid preparation of any of the above-men
`tioned (1) to (3), wherein the (+)-(S)-4-[4-[(4-chlorophenyl)
`(2-pyridyl)methoxy]piperidino]butyric acid or the pharma
`cologically acceptable acid addition salt thereof has a
`concentration selected from the range of a lower limit con
`centration 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-men
`tioned (1) to (4), which is an acid addition salt of (+)-(S)-4
`[4-[(4-chlorophenyl)(2-pyridyl) methoxy]piperidino]butyric
`acid,
`(6) the aqueous liquid preparation of the above-mentioned
`(5), wherein the acid addition salt is monobenzenesulfonate,
`(7) the aqueous liquid preparation of any of the above-men
`tioned (1) to (6), wherein the aqueous liquid preparation has
`a pH in the range of 4-8.5,
`(8) the aqueous liquid preparation of any of the above-men
`tioned (1) to (7), which is an eye drop,
`(9) the aqueous liquid preparation of any of the above-men
`tioned (1) to (7), which is a nasal drop,
`(10) an aqueous eye drop comprising (+)-(S)-4-[4-[(4-chlo
`rophenyl)(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
`(1 1) a method of light-stabilizing (+)-(S)-4-[4-[(4-chlorophe
`nyl)(2-pyridyl)methoxy]piperidino]butyric acid in an aque
`ous solution, which comprises adding a water-soluble metal
`chloride to an aqueous solution comprising (+)-(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,
`cyclohexylsulfamate, 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. 1002, Page 2
`
`

`
`US 8,877,168 B1
`
`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 (+)-(8)-4-[4-[(4-chlorophenyl) (2-pyridyl)
`methoxy]piperidino]butyric acid or a pharrnacologically
`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 in?uence
`stabilization.
`Various additives that are generally used such as buffer,
`preservative, chelating agent, ?avor 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 ?avor, l-menthol, bomeol, camphor, 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 e?icacious 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 of the 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 of the 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
`
`The present invention is explained in more detail by refer
`ring to Experimental Examples and Examples, which are not
`to be construed as limitative.
`
`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
`?lled in glass ampoules 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.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`TABLE 1
`
`Formu—
`lation
`
`55
`
`bepotastine
`besilate
`sodium
`chloride
`
`l
`
`2
`
`3
`
`4
`
`5
`
`6
`
`1.5 g
`
`1.5 g
`
`1.5 g
`
`1.5 g
`
`1.5 g
`
`1.5 g
`
`i 0.1 g
`
`0.2 g
`
`0.3 g
`
`i
`
`i
`
`potassium i i i i 0.79 g
`
`i
`
`chloride
`
`calcium
`
`i i i i
`
`i
`
`1.18 g
`
`chloride
`2H2O
`sodium
`hydroxide
`total
`amount
`pH
`
`suitable
`suitable
`suitable suitable suitable suitable
`amount
`amount
`amount amount amount amount
`100 mL 100 mL 100 mL 100 mL 100 mL 100 mL
`
`7.0
`
`7.0
`
`6.7
`
`6.9
`
`6.7
`
`6.8
`
`60
`
`65
`
`MYLAN Ex. 1002, Page 3
`
`

`
`US 8,877,168 B1
`
`5
`
`Test Results
`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.
`
`TABLE 3-continued
`
`Formulation
`
`10
`
`1 1
`
`12
`
`phosphate dihydrate
`sodium chloride
`benzalkonium
`chloride
`sodium hydroxide
`
`total amount
`pH
`
`0.6 g
`0.005 g
`
`0.6 g
`0.005 g
`
`0.82 g
`0.005 g
`
`suitable
`amount
`100 mL
`4.0
`
`suitable
`amount
`100 mL
`8.5
`
`suitable
`amount
`100 mL
`6.8
`
`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
`
`bepotastine besilate
`sodium dihydrogen
`phosphate dihydrate
`boric acid
`sodium chloride
`glycerin
`benzalkonium chloride
`sodium hydroxide
`
`total amount
`pH
`
`7
`
`1.5 g
`0.1 g
`
`8
`
`1.5 g
`i
`
`9
`
`1.5 g
`i
`
`i
`0.6 g
`i
`0.005 g
`suitable
`amount
`100 mL
`6.8
`
`1.0 g
`i
`0.5 g
`0.005 g
`suitable
`amount
`100 mL
`6.8
`
`0.5 g
`i
`2.0 g
`0.005 g
`suitable
`amount
`100 mL
`6.8
`
`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.
`
`40
`
`45
`
`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
`
`bepotastine besilate
`sodium dihydrogen
`
`10
`
`1.5 g
`0.1
`
`1 1
`
`1.5 g
`0.1
`
`12
`
`0.1 g
`0.1 g
`
`50
`
`55
`
`60
`
`65
`
`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 of bepotastine
`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
`
`20
`
`25
`
`30
`
`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
`
`bepotastine
`besilate
`sodium
`dihydrogen
`phosphate
`dihydrate
`glycerin
`benzal—
`konium
`chloride
`sodium
`hydroxide
`total
`amount
`pH
`
`0.5 g
`
`1.0 g
`
`1.5 g
`
`1.5 g
`
`1.5 g
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`2.2 g
`0.005 g
`
`2.0 g
`0.005 g
`
`1.7 g
`0.005 g
`
`1.7 g
`0.005 g
`
`1.7 g
`0.005 g
`
`suitable
`suitable
`suitable
`suitable
`suitable
`amount
`amount
`amount
`amount
`amount
`100 mL 100 mL 100 mL 100 mL 100 mL
`
`6.8
`
`6.8
`
`4.0
`
`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 of bepo
`tastine besilate into black green even at a low concentration.
`Formulation 15 (pH 4) turned 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
`
`MYLAN Ex. 1002, Page 4
`
`

`
`US 8,877,168 B1
`
`7
`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- 5
`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.
`
`10
`
`Example 1: eye drop
`
`bepotastine besilate
`Sodium dihydrogenphosphate dihydrate
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile puri?ed water total amount
`pH
`
`0.3 g
`0.1 g
`0.79 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 2 eye drop
`
`bepotastine besilate
`Sodium dihydrogenphosphate dihydrate
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile puri?ed water total amount
`pH
`
`0.5 g
`0.1 g
`0.76 g
`0.005 g
`suitable amount
`100 mL
`6.8
`
`15
`
`20
`
`25
`
`30
`
`Using the above-mentioned ingredients, an eye drop is 35
`prepared by a conventional method.
`
`8
`-continued
`
`Example 5 eye drop
`
`sodium chloride
`
`benzalkonium chloride
`
`sodium hydroxide
`
`sterile puri?ed water total amount
`pH
`
`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 6 eye drop
`
`bepotastine besilate
`citric acid
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile puri?ed 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 puri?ed water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0.005 g
`suitable amount
`100 mL
`8.5
`
`Using the above-mentioned ingredients, an eye drop is
`40 prepared by a conventional method.
`
`Example 8 eye drop
`
`bepotastine besilate
`sodium dihydrogenphosphate dihydrate
`sodium chloride
`methyl parahydroxybenzoate
`propyl parahydroxybenzoate
`sodium hydroxide
`sterile puri?ed water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0.026 g
`0.014 g
`suitable amount
`100 mL
`6.8
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Example 9 eye drop
`
`bepotastine besilate
`sodium dihydrogenphosphate dihydrate
`sodium chloride
`potassium sorbate
`sodium hydroxide
`sterile puri?ed water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0.27 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 puri?ed water total amount
`pH
`
`1.0 g
`0.1 g
`0.68 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 4 eye drop
`
`bepotastine besilate
`Sodium acetate trihydrate
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile puri?ed water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0.005 g
`suitable amount
`100 mL
`4.0
`
`45
`
`50
`
`55
`
`Using the above-mentioned ingredients, an eye drop is 60
`prepared by a conventional method.
`
`Example 5 eye drop
`
`bepotastine besilate
`epsilon—aminocaproic acid
`
`1.5 g
`0.1 g
`
`65
`
`MYLAN Ex. 1002, Page 5
`
`

`
`US 8,877,168 B1
`
`9
`
`Example 10 eye drop
`
`bepotastine besilate
`sodium dihydrogenphosphate dihydrate
`sodium chloride
`chlorhexidine gluconate
`sodium hydroxide
`sterile puri?ed water total amount
`pH
`
`1.5 g
`0.1 g
`0.6 g
`0.005 g
`suitable amount
`100 mL
`6.8
`
`01
`
`Using the above-mentioned ingredients, an eye drop is
`prepared by a conventional method.
`
`Example 11 eye drop
`
`bepotastine besilate
`sodium dihydrogenphosphate dihydrate
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile puri?ed 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 12 nasal drop
`
`bepotastine besilate
`sodium dihydrogenphosphate dihydrate
`sodium chloride
`benzalkonium chloride
`sodium hydroxide
`sterile puri?ed water total amount
`pH
`
`1.0 g
`0.1 g
`0.68 g
`0.005 g
`suitable amount
`100 mL
`6.8
`
`Using the above-mentioned ingredients, a nasal drop is
`prepared by a conventional method.
`
`INDUSTRIAL APPLICABILITY
`
`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
`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-[(4-chlorophenyl) (2-pyridyl)methoxy]piperi
`dino]butyric acid or a pharmacologically acceptable acid
`addition salt thereof, and a stable aqueous liquid preparation
`can be produced. Since an aqueous liquid preparation stable
`to light can be obtained by the light-stabilizing method of the
`present invention, the aqueous liquid preparation of the
`present invention is advantageously used for the treatment of
`allergic conjunctivitis, spring catarrh, pollinosis, allergic
`rhinitis and the like.
`While some of the embodiments of this invention have
`been described in detail in the foregoing, it will be possible for
`those of ordinary skill in the art to variously modify and
`change the embodiments speci?cally shown herein, within
`the scope not substantially deviating from the novel teaching
`and bene?t of the invention. Accordingly, this invention
`encompasses all such modi?cations and changes within the
`spirit and scope of the invention as de?ned by the following
`claims.
`This application is based on a patent application No.
`223804/ 2002 ?led in Japan, the contents of which are hereby
`incorporated by reference.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`10
`
`The invention claimed is:
`1. An aqueous liquid preparation consisting of, in an aque
`ous solution:
`(a) an active ingredient consisting of (+)-(S)-4-[4-[(4-chlo
`rophenyl)(2-pyridyl)methoxy]piperidino]butyric acid
`or a pharmacologically acceptable acid addition salt
`thereof;
`(b) a water-soluble metal chloride in a light-stabilizing
`effective amount;
`(c) water; and
`(d) at least one material selected from the group consisting
`of a buffer, a preservative, a chelating agent, sodium
`hydroxide, and a ?avor;
`wherein the (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)
`methoxy]piperidino]butyric acid or the pharmacologi
`cally acceptable acid addition salt thereof has a concen
`tration selected from the range of a lower limit
`concentration of 0.1 w/v % and an upper limit concen
`tration of2.0 w/v %; and
`wherein the metal chloride has a concentration selected
`from the range of a lower limit concentration of 0. 1 5 w/v
`% and an upper limit concentration of 1.5 w/v %.
`2. The aqueous liquid preparation according to claim 1,
`wherein the metal chloride is selected from the group con
`sisting of sodium chloride, potassium chloride and calcium
`chloride.
`3. The aqueous liquid preparation according to claim 1,
`wherein the acid addition salt is monobenzenesulfonate.
`4. The aqueous liquid preparation according to claim 1,
`wherein the aqueous liquid preparation has a pH in the range
`of 4-8.5.
`5. The aqueous liquid preparation according to claim 1,
`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 %.
`6. The aqueous liquid preparation according to claim 1,
`wherein the metal chloride has a concentration selected from
`the range of a lower limit concentration of 0.3 w/v % and an
`upper limit concentration of 1.2 w/v %.
`7. The aqueous liquid preparation according to claim 1,
`wherein the metal chloride is sodium chloride and has a
`concentration selected from the range of a lower limit con
`centration of 0.3 w/v % and an upper limit concentration of
`1.0 w/v %.
`8. The aqueous liquid preparation according to claim 1,
`wherein the (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)meth
`oxy]piperidino]butyric acid or the pharmacologically accept
`able acid addition salt thereof has a concentration selected
`from the range of a lower limit concentration of 0.3 w/v % and
`an upper limit concentration of 2.0 w/v %.
`9. The aqueous liquid preparation according to claim 1,
`wherein the (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)meth
`oxy]piperidino]butyric acid or the pharmacologically accept
`able acid addition salt thereof has a concentration selected
`from the range of a lower limit concentration of 0.3 w/v % and
`an upper limit concentration of 1.5 w/v %.
`10. The aqueous liquid preparation according to claim 1,
`wherein the (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)meth
`oxy]piperidino]butyric acid or the pharmacologically accept
`able acid addition salt thereof has a concentration selected
`from the range of a lower limit concentration of 0.5 w/v % and
`an upper limit concentration of 1.5 w/v %.
`11. The aqueous liquid preparation according to claim 1,
`which is an eye drop.
`12. The aqueous liquid preparation according to claim 1,
`which is a nasal drop.
`
`MYLAN Ex. 1002, Page 6
`
`

`
`US 8,877,168 B1
`
`11
`13. The aqueous liquid preparation according to claim 1,
`wherein:
`(a) the acid addition salt of the (+)-(S)-4-[4-[(4-chlorophe
`nyl)(2-pyridyl)methoxy]piperidino]butyric
`acid
`is
`monobenzenesulfonate salt, and the acid addition salt
`has a concentration selected from the range of a lower
`limit concentration of 0.3 w/v % and an upper limit
`concentration of 1.5 w/v %;
`(b) the water-soluble metal chloride is selected from the
`group consisting of sodium chloride, potassium chlo
`ride, and calcium chloride, and the metal chloride has a
`concentration selected from the range of a lower limit
`concentration of 0.3 w/v % and an upper limit concen
`tration of 1.0 w/v %; and
`the aqueous liquid preparation has a pH min the range of
`5-8.
`14. The aqueous liquid preparation according to claim 13,
`wherein the metal chloride is sodium chloride.
`15. The aqueous liquid preparation according to claim 13,
`wherein the metal chloride is potassium chloride.
`16. An aqueous eye drop consisting of:
`(a) an active ingredient consisting of (+)-(S)-4-[4