(12) International application published on the basis of the Patent Cooperation Treaty
`
`(19) International Bureau of World
`
`Intellectual Property Organization
`
`
`(43) International laid-open date:
`
`November 1, 2001
`
`
`
`
`
`
`
`PCT
`
`
`
`
`
`(10) International laid-open number:
`
`
`
`WO 01/80858 A1
`
`
`
`
`(51) International patent classification7:
`A61K 31/4709
`
`(75) Inventors/Applicant (only USA):
`
`Masanori ARAKI (JP/JP); c/o Formulation
`
`Technology Research Center of Daiichi
`
`9/08, 47/02, C07D 401/04, A61P
`
`Pharmaceutical Co., Ltd. (588
`
`31/04
`
`
`
`Kanayakawara, Kanaya-Cho, Haibara-Gun,
`
`Shizuoka 428-0021, Japan),
`
`(21) International application No.:
`
`Hiroaki NAKAGAMI (JP/JP), and
`
`PCT/JP01/03457
`
`
`
`Azusa MATSUKAWA (JP/JP); c/o Tokyo
`
`Research & Development Center of Daiichi
`
`(22) International file date: April 23, 2001
`
`Pharmaceutical Co., Ltd. (16-13, Kitakasai
`
`
`
`1-Chome, Edogawa-Ku, Tokyo 134-0081,
`
`(25) Language in international application:
`
`Japan)
`
`Japanese
`
`
`
`(26) Language in international publication:
`
`Japanese
`
`
`
`
`
`(74) Patent attorney:
`
`Shohei OGURI, et al.; c/o Eikoh Patent Firm,
`P.C. (Ark Mori Building 28th Floor, 12-32,
`Akasaka 1-Chome, Minato-Ku, Tokyo
`
`(30) Priority data:
`
`107-6028, Japan)
`
`Japanese Patent Application No.
`
`
`
`2000-127622 (April 24, 2000), JP
`
`(81) Designated Countries (domestic): AE,
`
`Japanese Patent Application No.
`
`AG, AL, AM, AT, AU, AZ, BA, BB, BG,
`
`2000-149812 (May 17, 2000), JP
`
`BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`
`
`
`CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD,
`
`(71) Applicant (all designated countries
`
`GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
`
`except for USA):
`
`KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT,
`
`Daiichi Pharmaceutical Co., Ltd. (JP/JP)
`
`LU, LV, MA, MD, MG, MK, MN, MW,
`
`(14-10, Nihonbashi 3-Chome, Chuo-Ku,
`
`MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE,
`
`Tokyo 103-0027, Japan).
`
`SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA,
`
`
`
`(72) Inventors and
`
`
`
`UG, US, UZ, VN, YU, ZA, and ZW.
`
`
`
`(84) Designated Countries (broad region):
`
`MYLAN Ex. 1009, Page 1
`
`

`
`ARIPO Patent (GH, GM, KE, LS, MW, MZ,
`
`abbreviations, see “Guidance Note for
`
`SD, SL, SZ, TZ, UG, and ZW), Eurasia
`
`Codes and Abbreviations” described in the
`
`Patent (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`
`front of each PCT gazette published
`
`and TM), European Patent (AT, BE, CH,
`
`periodically.
`
`CY, DE, DK, ES, FI, FR, GB, GR, IE, IT,
`
`
`
`LU, MC, NL, PT, SE, and TR), and OAPI
`
`(54) Title: STABLE LIQUID
`
`Patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`
`PREPARATION
`
`GW, ML, MR, NE, SN, TD, and TG)
`
`
`
`
`
`(57) Abstract: Provided is a liquid
`
`Attached published document:
`
`preparation of sitafloxacin excellent in a
`
`INTERNATIONAL SEARCH REPORT
`
`light stability, comprising an aqueous
`
`
`
`solution containing sitafloxacin and sodium
`
`For two-letters codes and other
`
`chloride.
`
`
`
`MYLAN Ex. 1009, Page 2
`
`

`
`STABILIZED LIQUID PREPARATION
`
`
`
`TECHNICAL FIELD
`
`
`
`The present invention relates to a liquid preparation comprising an antimicrobial
`
`aqueous solution having an improved light stability and a process for producing the same.
`
`
`
`
`
`BACKGROUND ART
`
`Sitafloxacin (in this specification, the name according to International
`
`Nonproprietary Names (INN) is used) is a compound having the following chemical structure
`
`(Japanese Patent No. 2714597).
`
`
`
`This compound exhibits a very high antimicrobial activity and a high safety and has
`
`been studied with an expectation for application as an excellent quinolone synthetic
`
`antimicrobial drug.
`
`
`
`Sitafloxacin is a promising antimicrobial drug having potent antimicrobial activities,
`
`especially in the treatment of a serious infectious disease. Therefore, it is desirable that
`
`sitafloxacin be available in a parenteral formulation as well; and thus, inventors of the present
`
`invention investigated a liquid preparation comprising an aqueous sitafloxacin solution. As
`
`a result, it was found that sitafloxacin in aqueous solution lacks stability to a light. That is, it
`
`was found that sitafloxacin in aqueous solution undergoes decomposition when it is irradiated
`
`with a light, resulting in reduction in a sitafloxacin content, as well as lowering in pH and a
`
`light transmittance. Formation of sitafloxacin-related substances was also confirmed. That
`
`is, it was found that the light stability of an aqueous sitafloxacin solution needs to be
`
`improved in order to supply a liquid preparation comprising an aqueous sitafloxacin solution.
`
`
`
`
`
`DISCLOSURE OF INVENTION
`
`Under the situation as mentioned above, inventors of the present invention carried
`
`out an extensive investigation; and as a result, it was found that sitafloxacin in an aqueous
`
`solution can be prevented from decomposing upon irradiation in the presence of sodium
`
`chloride. That is, it was found that under the circumstance of the presence of sodium
`
`chloride in the aqueous solution, reduction in a sitafloxacin content, lowering in pH and a
`
`MYLAN Ex. 1009, Page 3
`
`

`
`light transmittance of the aqueous sitafloxacin solution, and formation of the related
`
`substances can be suppressed. The present invention could be completed on the basis of
`
`these findings.
`
`
`
`That is, the present invention relates to a (antimicrobial) liquid preparation
`
`comprising an aqueous solution containing sitafloxacin and sodium chloride.
`
`
`
`Also, the present invention relates to a liquid preparation comprising an aqueous
`
`solution containing a compound represented by the following formula and sodium chloride.
`
`
`
`
`
`Further, the present invention relates to a liquid preparation comprising an aqueous
`
`solution containing
`
`()-7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-l-[(1R,2S)-2-fluoro-1-cycl
`
`opropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and sodium chloride. The present
`
`invention also relates to the following embodiments:
`
`
`
`The above-mentioned liquid preparation, wherein sodium chloride is present in an
`
`amount of 0.01 to 10% by weight.
`
`
`
`The above-mentioned liquid preparation, wherein sodium chloride is present in an
`
`amount of 0.01 to 5% by weight.
`
`
`
`The above-mentioned liquid preparation, wherein sodium chloride is present in an
`
`amount of 0.05 to 3% by weight.
`
`
`
`The above-mentioned liquid preparation, wherein sodium chloride is present in an
`
`amount of 0.50 to 1% by weight.
`
`The above-mentioned liquid preparation, wherein pH of the aqueous solution is 3.5
`
`The above-mentioned liquid preparation, wherein pH of the aqueous solution is 3.8
`
`
`
`to 4.5.
`
`
`
`to 4.2.
`
`
`
`MYLAN Ex. 1009, Page 4
`
`

`
`The present invention further relates to the following processes for preparing of the
`
`above-mentioned liquid preparation:
`
`
`
`
`
`
`
`
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an acidic aqueous solution having dissolved therein sitafloxacin or a
`
`hydrate thereof and sodium chloride, and
`
`(2) adjusting pH of the said acidic aqueous solution.
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an acidic aqueous solution having dissolved therein a compound
`
`represented by the following formula or a hydrate thereof and sodium chloride, and
`
`(2) adjusting pH of the said acidic aqueous solution.
`
`
`
`
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an acidic aqueous solution having dissolved therein
`
`()-7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluo
`
`ro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid or a hydrate thereof
`
`and sodium chloride, and
`
`(2) adjusting pH of the said acidic aqueous solution.
`
`The above-mentioned process for preparing a liquid preparation, wherein the acidic
`
`aqueous solution is an aqueous hydrochloric acid solution.
`
`
`
`
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an aqueous solution having dissolved therein a sitafloxacin salt or a
`
`hydrate thereof and sodium chloride, and
`
`(2) adjusting pH of the said aqueous solution.
`
`The above-mentioned process for preparing a liquid preparation, wherein the
`
`sitafloxacin salt is a hydrochloride thereof, a nitrate thereof, a benzenesulfonate thereof, a
`
`methanesulfonate thereof or a toluenesulfonate thereof.
`
`
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an aqueous solution having dissolved therein a salt of a compound
`
`MYLAN Ex. 1009, Page 5
`
`

`
`represented by the following formula or a hydrate thereof and sodium chloride, and
`
`(2) adjusting pH of the said aqueous solution.
`
`
`
`
`
`The above-mentioned process for preparing a liquid preparation, wherein the salt of a
`
`compound represented by the following formula is a hydrochloride thereof, a nitrate thereof, a
`
`benzenesulfonate thereof, a methanesulfonate thereof or a toluenesulfonate thereof.
`
`
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an aqueous solution having dissolved therein
`
`()-7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluo
`
`ro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid salt or a hydrate
`
`thereof and sodium chloride, and
`
`(2) adjusting pH of the said acidic aqueous solution.
`
`
`
`
`
`The above-mentioned process for preparing a liquid preparation, wherein the salt of
`
`()-7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyc
`
`lopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is a hydrochloride thereof, a nitrate
`
`thereof, a benzenesulfonate thereof, a methanesulfonate thereof or a toluenesulfonate thereof.
`
`
`
`The above-mentioned process for preparing a liquid preparation, wherein (the step of
`
`adjusting pH) is carried out by addition of sodium hydroxide or an aqueous solution thereof.
`
`
`
`The above-mentioned process for preparing a liquid preparation, wherein sodium
`
`chloride is present in an amount of 0.01 to 5% by weight.
`
`
`
`The above-mentioned process for preparing a liquid preparation, wherein sodium
`
`chloride is present in an amount of 0.05 to 3% by weight.
`
`
`
`MYLAN Ex. 1009, Page 6
`
`

`
`The above-mentioned process for preparing a liquid preparation, wherein sodium
`
`chloride is present in an amount of 0.50 to 1% by weight.
`
`
`
`The above-mentioned process for preparing a liquid preparation, wherein pH of the
`
`aqueous solution is 3.5 to 4.5.
`
`
`
`The above-mentioned process for preparing a liquid preparation, wherein pH of the
`
`aqueous solution is 3.8 to 4.2; and so forth.
`
`
`
`
`
`Hereinafter, the present invention will be described in detail.
`
`The stabilized liquid sitafloxacin preparation according to the present invention can
`
`be prepared according to, for example, the following procedure.
`
`
`
`That is, sitafloxacin (or its hydrate) is added to water for injection, and then, sodium
`
`chloride is added thereto. Hydrochloric acid is added to the solution, followed by stirring or
`
`a like operation to dissolve sitafloxacin (or its hydrate) and sodium chloride. Thereafter, pH
`
`of the resulting acidic aqueous solution is adjusted by addition of sodium hydroxide or an
`
`aqueous solution thereof, and then the water for injection is added to make a predetermined
`
`amount of the liquid preparation.
`
`
`
`Sitafloxacin is registered as “sitafloxacin hydrate” according to JAN (Japanese
`
`Accepted Names), which is a 3/2 hydrate, free of an acid or a base adduct. The sitafloxacin
`
`as a raw material for preparing the liquid preparation of the present invention includes not
`
`only this free, hydrated compound but also a pharmaceutically acceptable acid adduct salt and
`
`a hydrate thereof. The pharmaceutically acceptable acid adduct salt includes inorganic acid
`
`salts, such as a hydrochloride salt and a nitrate salt, and organic acid salts, such as a
`
`methanesulfonate salt, a benzenesulfonate salt and a toluenesulfonate salt. When using the
`
`salt, the liquid preparation of the present invention can be prepared by dissolving the salt and
`
`then sodium chloride in water. The pH (acidity or basicity) of the aqueous solution can be
`
`adjusted if necessary. With this alternative way, the liquid preparation of the present
`
`invention can be prepared as well.
`
`
`
`The aqueous solution thus prepared may be provided after it is sterilized and
`
`dispensed into containers. (Sterilization may follow dispensing.)
`
`
`
`The sitafloxacin concentration of the aqueous solution is not particularly limited and
`
`can be selected according to the purpose and the method of use thereof within a range of
`
`solubility of sitafloxacin in water (or in water at a particular pH). A suitable concentration
`
`ranges, for example, from 0.1 to 20 mg/mL.
`
`MYLAN Ex. 1009, Page 7
`
`

`
`
`
`The sodium chloride content is usually selected from a range of 0.01 to 10% by
`
`weight. The liquid preparation comprising the aqueous sitafloxacin solution of the present
`
`invention is characterized by containing sodium chloride in the aqueous solution, with which
`
`the active ingredient, sitafloxacin, is stabilized against a light. This light stabilizing effect of
`
`sodium chloride is observed even in the concentration thereof as low as 0.01%. It has been
`
`confirmed that this light stabilizing effect is enhanced with an increase in the sodium chloride
`
`concentration. The light stabilizing effect is further enhanced with a sodium chloride
`
`concentration of 0.05% or higher; and it was found that the effect is sustained with a further
`
`increased concentration of sodium chloride. A particularly high stabilizing effect is obtained
`
`with a sodium chloride concentration of 0.1% or higher.
`
`
`
`Addition of hydrochloric acid is for facilitating dissolution of a free sitafloxacin, the
`
`active ingredient, because it has poor solubility in water around a neutral pH. Hydrochloric
`
`acid is usually added in excess within a range that is pharmaceutically acceptable and does
`
`not cause the active ingredient to decompose. Diluted hydrochloric acid, e.g., an aqueous
`
`hydrochloric acid solution with the concentration thereof being about 0.1 mol/L may be used.
`
`The acid to be added is not limited to hydrochloric acid; and any other pharmaceutically
`
`acceptable acid that facilitates dissolution of sitafloxacin may be used.
`
`
`
`Sodium hydroxide or an aqueous solution thereof is added to adjust pH (acidity or
`
`basicity) of the acidic solution in which the active ingredient compound is dissolved. In this
`
`case, too, a diluted aqueous solution thereof, a concentration thereof with about 0.1 mol/L,
`
`may be used. The addition thereof is to adjust the pH, and the base to be added is not limited
`
`to sodium hydroxide; and thus, it is a matter of course that any base other than sodium
`
`hydroxide may be used as well. Needless to mention, not only the aqueous solution but also
`
`sodium hydroxide in a solid state or a powder form may be used; however, it is more
`
`convenient for operation to use it in the state of a diluted aqueous solution.
`
`
`
`In combination of the acid and the base, it is the most general to use hydrochloric
`
`acid and sodium hydroxide in this combination. The solution is adjusted to pH of 3.5 to 4.5,
`
`preferably 3.7 to 4.2, or still preferably about 4.
`
`
`
`Further, the effect of the light stabilized preparation of the present invention obtained
`
`by adding sodium chloride is observed even at a higher pH. That is, it has been confirmed
`
`that the formation of related substances due to irradiation or lowering in pH are more
`
`suppressed even in a sodium chloride-containing aqueous solution adjusted to about pH 8
`
`than the aqueous solutions without sodium chloride. Therefore, pH of the liquid preparation
`
`containing sodium chloride in the present invention is not particularly limited to the
`
`above-mentioned ranges; and therefore, the upper limit thereof maybe approximately 8.
`
`MYLAN Ex. 1009, Page 8
`
`

`
`
`
`Water to be added in the final stage is to finally adjust the concentration of the liquid
`
`preparation in accordance with prescribed concentrations of the active ingredient and sodium
`
`chloride; and this method is commonly used in the art. Water as a solvent to be used for the
`
`preparation of the liquid preparation is not particularly limited as far as it is pharmaceutically
`
`acceptable, so that the water for injection or the equivalent thereof may be used.
`
`
`
`The sodium chloride-containing sitafloxacin aqueous solution thus prepared may be
`
`charged into a container for a single dose or for multiple doses. Illustrative example of the
`
`container includes an ampules, a vial, a plastic bag, and a syringe.
`
`
`
`Sterilization of the sitafloxacin-containing liquid preparations thus prepared may be
`
`effected in a usual manner, for example, by filtration or heating. Sterilization of the aqueous
`
`solution may be preceded or followed by charging into containers.
`
`
`
`If desired, the liquid preparation of the present invention can further contain a
`
`dissolving aid, a buffering component, a stabilizer, and the like.
`
`
`
`The liquid preparation of the present invention can be used not only as systemic
`
`administration such as injection and drop but also as topical administration such as a liquid
`
`for external use and a spray.
`
`
`
`
`
`BEST MODE FOR CARRYING OUT INVENTION
`
`Hereunder, the present invention will be specifically illustrated in greater detail with
`
`reference to the following examples, but this does not intend that the present invention be
`
`limited thereto.
`
`
`
`The sitafloxacin used herein was prepared by the applicant. Hydrochloric acid,
`
`sodium hydroxide, sodium chloride, and D-sorbitol were of JIS’s guaranteed reagent grade.
`
`Water used was the water for injection.
`
`
`
`1) Samples Tested for Light Stability:
`
`
`
`To 160 mL of the water for injection were added 213.2 mg of sitafloxacin (200 mg as
`
`active ingredient) and a varied amount of sodium chloride (0 mg, 20 mg, 100 mg, 200 mg, 1 g,
`
`2 g, 4 g, 6 g or 10 g) or 10 g of D-sorbitol. Further, 5 mL of 0.1 mol/L aqueous hydrochloric
`
`acid was slowly added to dissolve sitafloxacin and sodium chloride (stirring for 30 minutes).
`
`The nine kinds of solution each was adjusted to pH 4.0 by addition of 0.1 mol/L aqueous
`
`sodium hydroxide, and then, the water for injection was added to make 200 mL as the total
`
`MYLAN Ex. 1009, Page 9
`
`

`
`volume. Ten milliliter portions of the resulting aqueous solution were put into colorless
`
`ampules.
`
`
`
`2) Test Methods:
`
`
`
`a) Test Items and Methods for Evaluation of Light Stability:
`
`(i) pH: The test sample was measured by using a pH meter (F-16, manufactured by Horiba,
`
`Ltd.).
`
`(ii) Osmic pressure: The test sample was measured by using an osmometer (3C2,
`
`manufactured by Advanced Instruments, Inc.).
`
`(iii) (Light) Transmittance: A transmittance of the test sample at 430 nm was measured with a
`
`spectrophotometer (DU-640, manufactured by Beckman Corp.).
`
`(iv) Content: The test sample was prepared by accurately measuring 2 mL of a sample, adding
`
`an accurately measured 4 mL of an internal standard solution, adding a mobile phase to make
`
`20 mL, and then mixing a 5 mL aliquot of the resulting solution with a mobile phase to make
`
`20 mL as the total volume.
`
`
`
`Quantitative analysis of sitafloxacin was made in the following way. A standard
`
`sitafloxacin solution was prepared by dissolving about 0.1 g of accurately weighed
`
`sitafloxacin for quantitative analysis (whose water content had been previously measured) in
`
`the mobile phase to make a solution with an accurate amount of 100 mL. An accurately
`
`measured 5 ml aliquot of the solution was added with an accurately measured 5 mL of the
`
`internal standard solution shown below, which is followed by addition of the mobile phase to
`
`make 100 mL as the total volume; and after thoroughly stirring the resulting mixture, it was
`
`filtrated through a membrane filter to obtain a standard solution. The test solution and the
`
`standard solution each measuring 10 L were subjected to a liquid chromatography under the
`
`following conditions to obtain ratios of the peak areas of sitafloxacin of the test solution or the
`
`standard solution to the peak area of the internal standard, QT and QS; and the sitafloxacin
`
`content was determined according to the following equation:
`
`Sitafloxacin (C19H18ClF2N3O3) content (% to nominal amount) = amount (mg) of
`
`sitafloxacin for quantitative analysis (on dry basis)  (QT/QS)  (1/4)  (1/25)  100
`wherein,
`
`4: amount (mg) of sitafloxacin in 2 mL preparation
`
`1/25: dilution coefficient
`
`internal standard solution: methanol solution of ethyl p-oxybenzoate (1  4000)
`
`
`
`
`
`Operation Conditions:
`
`Detector: UV absorption spectrophotometer (measuring wavelength: 254 nm)
`
`Column: STR ODS-II (4.6 mm  150 mm, manufactured by Shimadzu Corp.)
`
`Column temperature: constant at around 40C
`
`MYLAN Ex. 1009, Page 10
`
`

`
`Mobile phase: phosphate buffer (pH 2.4)/acetonitrile mixture (4:1)
`
`Flow rate: controlled so that the retention time of sitafloxacin may be about 13 minutes.
`
`(v) Related Substances: A standard solution was prepared by weighing 0.100 g of sitafloxacin
`
`for quantitative analysis (whose water content had been previously measured), adding a
`
`mobile phase to accurately make 100 mL as the total volume, and adding the mobile phase to
`
`an accurately measured aliquot (1 mL) of this solution to make accurately 100 mL as the total
`
`volume.
`
`
`
`A 10 L aliquot of the test sample and the standard solution each was subjected to a
`
`liquid chromatography under the following conditions; and the peak areas of the respective
`
`solutions were calculated by an automatic integration method.
`
`
`
`
`
`Operating Conditions:
`
`Detector: UV spectrophotometer (measuring wavelength: 295 nm)
`
`Column: STR ODS-II (4.6 mm  250 mm, manufactured by Shimadzu Corp.)
`
`Column temperature: constant at around 40C
`
`Mobile phase: phosphate buffer (pH 2.4)/acetonitrile mixture (4:1)
`
`Flow rate: controlled so that the retention time of sitafloxacin may be about 20 minutes.
`
`
`
`3) Method for Evaluation of Light Stability of Aqueous Sitafloxacin Solution:
`
`Each of the aqueous solutions of sitafloxacin (1 mg/mL) was irradiated with a light
`
`of a white fluorescent tube (2500 Lx for 5 days with 300,000 Lxhr), and each of the items
`
`shown above was evaluated.
`
`
`
`4) Results and Discussions:
`
`
`
`a) Light Stability of Sitafloxacin in Aqueous Solution
`
`The effects of varied addition amount of sodium chloride on the light stability of the
`
`aqueous sitafloxacin solution (1 mg/mL) are shown in Table 1 below. For comparison, the
`
`results of aqueous solution thereof added with 5% D-sorbitol are also shown.
`
`[Table 1]
`
`
`
`Salt
`
`pH
`
`concentration
`
`(%)
`
`0
`
`0.01
`
`0.05
`
`0.10
`
`4.2
`
`4.4
`
`4.3
`
`4.3
`
`Initial
`
`300000 Lxhr
`
`Transmittance
`
`(%)
`
`77.6
`
`77.1
`
`76.8
`
`76.7
`
`Related
`
`pH
`
`substances
`
`(Total, %)
`
`0.31
`
`0.30
`
`0.29
`
`0.26
`
`3.4
`
`3.7
`
`3.8
`
`3.8
`
`Transmittance
`
`(%)
`
`47.1
`
`52.8
`
`61.0
`
`64.4
`
`Related
`
`Content
`
`substances
`
`(vs.
`
`(Total, %)
`
`Initial, %)
`
`5.90
`
`5.21
`
`3.84
`
`3.02
`
`84.2
`
`87.9
`
`91.7
`
`93.5
`
`MYLAN Ex. 1009, Page 11
`
`

`
`0.50
`
`1.0
`
`2.0
`
`3.0
`
`5.0
`
`D-sorb
`
`4.2
`
`4.3
`
`4.3
`
`4.3
`
`4.3
`
`4.3
`
`75.6
`
`74.7
`
`73.1
`
`72.8
`
`70.7
`
`77.2
`
`0.28
`
`0.30
`
`0.31
`
`0.30
`
`0.30
`
`0.30
`
`3.9
`
`3.9
`
`3.8
`
`3.9
`
`3.9
`
`3.5
`
`63.6
`
`62.6
`
`60.7
`
`61.0
`
`57.6
`
`56.8
`
`2.48
`
`2.02
`
`2.30
`
`2.01
`
`2.28
`
`5.90
`
`94.2
`
`94.7
`
`94.0
`
`95.5
`
`94.8
`
`86.6
`
`D-sorb: D-sorbitol Transmittance: T%, 430 nm
`
`
`
`As is understood from Table 1, the aqueous sitafloxacin solutions without sodium
`
`chloride or containing D-sorbitol in place of sodium chloride cause to lower the pH, decrease
`
`in transmittance and sitafloxacin content, and increase in related substances when irradiated.
`
`
`
`However, it is apparent that addition of sodium chloride suppresses these changing
`
`tendencies of the properties, thereby confirming improvement in sitafloxacin stability against
`
`light irradiation.
`
`
`
`Also, it was found that sodium chloride can improve the light stability even with the
`
`concentration thereof being as low as 0.01%, and that the stabilizing effect increases with the
`
`concentration thereof. The increase in the stabilizing effect with concentration is noticeable
`
`up to 0.5% concentration. The stabilizing effect was continuously observed with the sodium
`
`chloride concentrations higher than this concentration.
`
`
`
`In addition, a liquid preparation containing sodium chloride was prepared by using
`
`levofloxacin; and then, the sodium chloride-containing liquid preparation thereof was
`
`compared with the preparation without sodium chloride with respect to influences due to
`
`irradiation on levofloxacin. The levofloxacin used was prepared by the applicant.
`
`
`
`5) Preparation of Levofloxacin Test Samples for Light Stability:
`
`Levofloxacin and hydrochloric acid were added to about 800 mL of the water for
`
`injection and then dissolved completely. The sodium chloride-containing preparation was
`
`prepared in the same manner as before by mixing levofloxacin, sodium chloride and
`
`hydrochloric acid, followed by dissolving it. To each aqueous hydrochloric acid solution
`
`was added sodium hydroxide to adjust the pH thereof to 4. Thereafter, the water for
`
`injection was added thereto so as to adjust each concentration of levofloxacin (prescribed
`
`value: 2 mg/mL) and sodium chloride (prescribed value: 0.9%) to the prescribed values,
`
`thereby to make 1 liter as the total volume. The resulting aqueous solutions were charged
`
`into ampules and sealed, followed by steam-sterilization.
`
`
`
`6) Method for Evaluation of the Light Stability of Aqueous Levofloxacin Solution:
`
`MYLAN Ex. 1009, Page 12
`
`

`
`Each of the aqueous solutions (2 mg/mL) of levofloxacin was irradiated with the
`
`light of a white fluorescent tube (2500 Lx, 10 days: 600,000 Lxhr), and the same analysis
`
`methods and so on described above were repeated.
`
`
`
`7) Results and Discussions:
`
`It was found that the extents of lowering in pH and of reduction in formation of
`
`related substances when irradiated are lower in the case of the sodium chloride-containing
`
`preparation as compared with the case otherwise. The results are shown in Table 2 below.
`
`That is, it is apparent that the effect of sodium chloride on light stabilization of an active
`
`ingredient in the liquid preparation containing sodium chloride is eminent even if the active
`
`ingredient is levofloxacin, and that the stability of the active ingredient against irradiation can
`
`Change in pH
`
`Related substances (Total, %)
`
`Initial
`
`After irradiation
`
`Initial
`
`After irradiation
`
`4.27
`
`4.39
`
`3.94
`
`3.81
`
`0.15
`
`0.16
`
`2.45
`
`3.94
`
`INDUSTRIAL APPLICABILITY
`
`be maintained.
`
`[Table 2]
`
`
`
`NaCl
`
`present
`
`absent
`
`
`
`
`
`It was confirmed that a light stability of a liquid preparation comprising an aqueous
`
`sitafloxacin solution is improved in the presence of sodium chloride. The light stability
`
`increases with an increase of sodium chloride concentration up to about 0.1%. With the
`
`sodium chloride content in or above this level, the liquid preparation sustains the light
`
`stability; and therefore, it is useful as a liquid preparation.
`
`
`
`CLAIMS
`
`
`
`1.
`
`A liquid preparation comprising an aqueous solution containing sitafloxacin and
`
`sodium chloride.
`
`
`
`2.
`
`A liquid preparation comprising an aqueous solution containing a compound
`
`represented by the following formula and sodium chloride.
`
`
`
`MYLAN Ex. 1009, Page 13
`
`

`
`3.
`
`A
`
`liquid
`
`preparation
`
`comprising
`
`an
`
`aqueous
`
`solution
`
`containing
`
`()-7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-l-[(1R,2S)-2-fluoro-1-cycl
`
`opropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and sodium chloride.
`
`
`
`4.
`
`The liquid preparation according to any one of claims 1 to 3, wherein sodium
`
`chloride is present in an amount of 0.01 to 10% by weight.
`
`
`
`5.
`
`The liquid preparation according to any one of claims 1 to 3, wherein sodium
`
`chloride is present in an amount of 0.01 to 5% by weight.
`
`
`
`6.
`
`The liquid preparation according to any one of claims 1 to 3, wherein sodium
`
`chloride is present in an amount of 0.05 to 3% by weight.
`
`
`
`7.
`
`The liquid preparation according to any one of claims 1 to 3, wherein sodium
`
`chloride is present in an amount of 0.50 to 1% by weight.
`
`
`
`8.
`
`The liquid preparation according to any one of claims 1 to 7, wherein pH of the
`
`aqueous solution is 3.5 to 4.5.
`
`
`
`9.
`
`The liquid preparation according to any one of claims 1 to 7, wherein pH of the
`
`aqueous solution is 3.8 to 4.2.
`
`
`
`10. A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an acidic aqueous solution having dissolved therein sitafloxacin or a hydrate
`
`thereof and sodium chloride, and
`
`(2) adjusting pH of the said acidic aqueous solution.
`
`
`
`11.
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an acidic aqueous solution having dissolved therein a compound
`
`represented by the following formula or a hydrate thereof and sodium chloride, and
`
`(2) adjusting pH of the said acidic aqueous solution.
`
`
`
`
`
`12.
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an acidic aqueous solution having dissolved therein
`
`MYLAN Ex. 1009, Page 14
`
`

`
`()-7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1
`
`-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid or a hydrate thereof and
`
`sodium chloride. and
`
`(2) adjusting pH of the said acidic aqueous solution.
`
`
`
`13.
`
`The process for preparing a liquid preparation according to any one of claims 10 to
`
`12, wherein the acidic aqueous solution is an aqueous hydrochloric acid solution.
`
`
`
`14.
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an aqueous solution having dissolved therein a sitafloxacin salt or a hydrate
`
`thereof and sodium chloride, and
`
`(2) adjusting pH of the said aqueous solution.
`
`
`
`15.
`
`The process for preparing a liquid preparation according to claim 14, wherein the
`
`sitafloxacin salt is a hydrochloride thereof, a nitrate thereof, a benzenesulfonate thereof, a
`
`methanesulfonate thereof or a toluenesulfonate thereof.
`
`
`
`16.
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an aqueous solution having dissolved therein a compound represented by
`
`the following formula or a hydrate thereof and sodium chloride, and
`
`(2) adjusting pH of the said aqueous solution.
`
`
`
`17.
`
`The process for preparing a liquid preparation according to claim 16, wherein the salt
`
`of a compound represented by the following formula is a hydrochloride thereof, a nitrate
`
`thereof, a benzenesulfonate thereof, a methanesulfonate thereof or a toluenesulfonate thereof.
`
`
`
`18.
`
`A process for preparing a liquid preparation comprising the steps of:
`
`(1) preparing an aqueous solution having dissolved therein
`
`()-7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1
`
`-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid salt or a hydrate thereof and
`
`MYLAN Ex. 1009, Page 15
`
`

`
`sodium chloride, and
`
`(2) adjusting pH of the said acidic aqueous solution.
`
`
`
`19.
`
`of
`
`The process for preparing a liquid preparation according to claim 18, wherein the salt
`
`()-7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyc
`
`lopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is a hydrochloride thereof, a nitrate
`
`thereof, a benzenesulfonate thereof, a methanesulfonate thereof or a toluenesulfonate thereof.
`
`
`
`20.
`
`The process for preparing a liquid preparation according to any one of claims 10 to
`
`19, wherein the step of adjusting pH is carried out by addition of sodium hydroxide or an
`
`aqueous solution thereof.
`
`
`
`21.
`
`The process for preparing a liquid preparation according to any one of claims 10 to
`
`20, wherein sodium chloride is present in an amount of 0.01 to 10% by weight.
`
`
`
`22.
`
`The process for preparing a liquid preparation according to any one of claims 10 to
`
`20, wherein sodium chloride is present in an amount of 0.01 to 5% by weight.
`
`
`
`23.
`
`The process for preparing a liquid preparation according to any one of claims 10 to
`
`20, wherein sodium chloride is present in an amount of 0.05 to 3% by weight.
`
`
`
`24.
`
`The process for preparing a liquid preparation according to any one of claims 10 to
`
`20, wherein sodium chloride is prese