throbber
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`I, Alan F. Siegrist, of CROSSLINGUAL, LLC, hereby declare that:
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`I am fluent in Japanese and English.
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`Translator of Japanese to English.
`
`3. The English translation attached to this declaration is an accurate and correct
`translation of the following document, attached hereto:
`DRAFT Sawa Declaration_12.15.2015 Japanese
`I declare that the foregoing is true and correct to the best of my knowledge.
`
`Executed on December 16, 2015
`
`
`
`Certification #63788
`
`Alan F. Siegrist, CT
`CROSSLINGUAL, LLC
`ATA Member No. 31889
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`documents to which this certificate are attached, and not the truthfulness, accuracy, or validity of that document.
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`
`
`1 A notary public or other officer completing this certificate verifies only the identity of the individual who signed the
`StateofCa|ifornia,Countyof
`.
`I
`
`
`fob’;
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`_
`On K
`£,£n"i0-£1"
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`personally appeared
`Sié ?Fl '2.
`who proved to me onthe basis ofsatisfactory
`
`evidence to be the person whose nam 5 subscribed to the within instrument and acknowledged to me
`that he executed the same in his authorized capacity, and that by his signature on the instrument the
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`JMIQIJELIIIEIILEI
`c0|INI.a2Io5829
`
`PAGE 1 OF 613
`
`SENJU EXHIBIT 2098
`
`INNOPHARMA v SENJU
`IPR2015—00903
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS
`INC., and MYLAN INC.
`
`Petitioner,
`
`V.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARIVIA HOLDINGS CORP.
`
`Patent Owner.
`
`Cases IPR2015-00902 & IPR2015-00903
`
`Patents 8,669,290 & 8,129,431
`
`DECLARATION OF SHIROU SAWA
`
`PAGE 2 OF 613
`
`

`
`I, Shirou Sawa, under penalty of perjury, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`2.
`
`I am of legal age and otherwise competent to make this declaration.
`
`I am the first named inventor on U.S. Patent Nos. 8,129,431
`
`(“the ’431 patent”) and 8,669,290 (“the ’290 patent”). I have been asked to submit
`
`a declaration attesting to how the data provided below, including data disclosed in
`
`the specification of the ’43l patent and ’290 patent, were generated.
`
`II.
`
`EDUCATION AND WORK EXPERIENCE
`
`3.
`
`I graduated from the University of Tokushima, Tokushima, Japan in
`
`1988, with a bachelor’s degree from the Department of Chemical Engineering, in
`
`the Faculty of Engineering.
`
`I received a master’s degree in engineering, with
`
`chemical engineering specialization, from the University of Tokushima,
`
`Tokushima, Japan in 1990.
`
`4.
`
`I am currently employed by Senju Pharmaceutical, Co., Ltd. (“Senju”)
`
`and have been with Senju since 1990. I have worked at Senju as a researcher in
`
`the ophthalmic formulations area from 1990 to the present.
`
`III. DATA, INCLUDING DATA IN THE ’431 AND ’290 PATENTS
`
`5.
`
`I was involved in formulating and testing bromfenac sodium (sodium
`
`2-amino-3-(4-bromobenzoyl)-phenylacetate) formulations, including the
`
`formulations of the Experimental Examples reported in the ’43l and ’290 patents.
`
`2
`
`PAGE 3 OF 613
`
`

`
`As such, I have first-hand knowledge of how the formulations reported below were
`
`made and tested.
`
`6.
`
`The laboratory notebooks in Appendices A, B and C describe the
`
`tested formulations and the experimental test results obtained with them.
`
`A.
`
`Stability data, including data from Table 1 of the ’431 and ’290
`patents
`
`7.
`
`I prepared and tested the stability of the bromfenac sodium
`
`formulations disclosed in Table l of the ’43l and ’290 patents. The table below
`
`contains bromfenac sodium formulations from Table 1 of the patents, as well as
`
`additional formulations with varying amounts of tyloxapol. (Appendix A.) As the
`
`table indicates, formulations A—20, A-21 and A-27 correspond to Comparison
`
`Examples 1, A-O2 and A-O3, respectively, from Table 1 of the ’43l and ’290
`
`patents.
`
`8.
`
`As reflected in the laboratory notebook of Appendix A, the stability of
`
`these bromfenac sodium formulations was tested after adjusting the pH of the
`
`formulations to 7. Using these formulations, accelerated stability tests were
`
`conducted for various lengths of time and elevated temperatures, including for four
`
`weeks at 60 °C. The percent of bromfenac sodium remaining was measured using
`
`a High Performance Liquid Chromatography (“HPLC”) method under the
`
`following conditions:
`
`0 Ultraviolet absorbance spectroscopy at 266 nm;
`
`3
`
`PAGE 4 OF 613
`
`

`
`0 Column: Capcelpak column;
`
`0 Column temperature: 25 °C;
`
`0 Mobile phase: 1.98 g of ammonium dihydrogen phosphate was dissolved
`
`in 750 mL of water, the pH was adjusted to 7.3 by adding phosphoric
`
`acid, and 250 mL of acetonitrile was added;
`
`0 Flow rate: Adjusted so that the elution time of bromfenac sodium
`
`becomes 18 minutes; and
`
`0
`
`Injection Volume of sample: 10 uL
`
`9.
`
`The percent of bromfenac sodium remaining in each formulation after
`
`four weeks at 60 °C is tabulated below. The percent of bromfenac sodium
`
`remaining was adjusted to take into account the amount of water evaporation from
`
`the formulation.
`
`PAGE 5 OF 613
`
`

`
`
`
`
`
`
`P
`
`1
`
`1.5 g
`
`0.005 g
`-
`0.15 g
`q.s.
`q.s.
`100 mL
`
`7
`73.81%
`
`0.1 g
`.
`
`0.1 g
`1.6 ;
`
`0.005 g
`
`
`89.64%
`85.96%
`82.01%
`
`Formulation code
`
`A-20
`
`A-03
`
`N/A
`
`Designated code in Comparison
`Table 1 of the ’431
`and ’290 patents
`Example 1
`Bromfenac sodium
`
`0.1 g
`1.5 g
`
`I
`
`hydrate]
`Boric acid
`Benzalkonium
`chloride
`Polysorbate 80
`Tyloxaml
`__ Sodium hydroxide
`Distilled water
`Total amount
`
`0.005 g
`0.17 g
`-
`q.s.
`q.s.
`100 mL
`
`pH
`60 °C — 4 weeks
`
`7
`I_ 51.27%
`
`B.
`
`Stability data, including data disclosed in Table 2 of the ’431
`and ’290 patents
`
`10.
`
`I prepared and tested the stability of the following bromfenac sodium
`
`formulations, including those disclosed in Table 2 of the ’431 and ’290 patents. As
`
`indicated in the following table, formulations A—01, A—02 and A-03 correspond to
`
`formulations A—04, A-05 and A—06, respectively, from Table 2 of the ’431
`
`and ’290 patents. Stability tests on these formulations were carried out for various
`
`lengths of time and elevated temperatures, including four weeks and 60 °C,
`
`adjusted to a pH of about 8.15, as indicated. The percent of bromfenac sodium
`
`remaining in each formulation after four weeks at 60 °C was measured using the
`
`1 In the appended laboratory notebooks, I used the shorthand “bromfenac sodium”
`to refer to “bromfenac sodium hydrate.”
`
`PAGE 6 OF 613
`
`

`
`HPLC method described above, which was adjusted to take into account the
`
`amount of water evaporation. The data are tabulated below. (Appendix C.)
`
`Formulation code
`
`
`
`Designated code in Table 2 of
`the ’431 and ’29O patents
`
`Bromfenac sodium hydrate
`0.1 g
`0.1 g
`0.1 g
`Boric acid
`1.1 g
`1.1g
`1.1 g
`Borax
`1.1 g
`1.1 g
`1.l_g_
`_Benzalkonium chloride
`0.005_g
`0.005 g
`0.005 g
`Tyloxapol
`0.02 g
`0.05 _g
`0.03 g_
`Polyvinylpyrrolidone
`2.0 g
`2.0 g
`2.0 g
`Disodium edetate
`0.02 g
`0.02 g
`0.02 g
`
`
`
`Sodium hydroxide
`Distilled water
`Total amount
`
`pH
`60 °C - 4 weeks
`
`q.s
`q.s.
`100 mL
`
`q.s
`q.s.
`100
`
`q.s.
`q.s.
`100
`
`8.15
`L_92.57%
`
`8.15
`90.93%
`
`8.15
`91.97%
`
`I
`
`C.
`
`Stability data for bromfenac sodium formulations containing
`polysorbate 80 and bromfenac sodium formulations containing
`tyloxapol
`
`11.
`
`I prepared and tested the following bromfenac sodium formulations,
`
`containing the components and amounts as indicated below. Stability tests on
`
`these formulations, adjusted to a pH of about 8.2 to 8.3, were carried out for
`
`various lengths of time and elevated temperatures, including for four weeks and
`
`60 °C, as indicated. The percent of bromfenac sodium remaining in each
`
`formulation after four weeks at 60 °C was measured using the HPLC method
`
`PAGE 7 OF 613
`
`

`
`described above, which was adjusted to take into account the amount of water
`
`evaporation. The data are tabulated below. (Appendix C.)
`
`
`
`A-03 (PE)
`
`0.1 g
`1.1g_
`1.1g
`0.005 g
`-
`0.03 g
`2.0g
`0.02 g
`-
`q.s.
`q.s.
`100
`8.27
`95.07%
`
`
`
`0.1 _g_
`1.1g
`1.1g_
`0 005 g
`-
`0 02 g
`2.0 g
`0.02 g
`—
`q.s
`q.s.
`100 mL
`8.20
`93.61%
`
`Formulation code
`
`Bromfenac sodium hydrate
`lBoricacid
`lBorax
`|Benzalkonium chloride
`Polysorbate 80
`T loxa ol
`Polyvinylpyrrolidone
`Disodium edetate
`Sodium sulfite
`Sodium hydroxide
`Distilled water
`Total amount
`H
`60 °C — 4 weeks
`
`.
`1.1g
`1.1g
`0.005 g
`0.15 g
`-
`2.0 g
`0.02 g
`0.2 g
`q.s
`q.s.
`100 m
`8.20
`_I_ 91.45%
`
`__
`
`__!
`
`D.
`
`Preservative efficacy of bromfenac sodium formulations
`
`12.
`
`I was involved with testing the preservative efficacy of bromfenac
`
`sodium formulations as part of projects P2002B116 and P2002Bl31 at Senju. I
`
`formulated a bromfenac sodium formulation containing polysorbate 80 (identical
`
`to Bronuck) and bromfenac sodium formulations containing tyloxapol as shown in
`
`the following table. (Appendices B & C.) Formulations A-01 and A-02 in this
`
`table are the bromfenac sodium formulations containing tyloxapol and correspond
`
`2 “PE” in these designations signifies that the stability test was conducted using
`polyethylene containers.
`
`PAGE 8 OF 613
`
`

`
`to formulations A-04 and A-05, respectively, from Tables 2, 3-1 and 3-2 of
`
`the ’43l and ’290 patents:
`
`Formulation Code
`
`Bronuck
`
`Designated code in Tables 2, 3-
`1 and 3-2 of the ’431 and ’290
`
`N/A
`
`
`
`A_04 &
`Table 3-1
`
`
`
`__
`
`patents
`Bromfenac sodium hydrate
`Boric acid
`
`Borax
`Benzalkonium chloride
`Polysorbate 80
`Tyloxapol
`Polyvinylpyrrolidone
`Disodium edetate
`Sodium sulfite
`
`Sodium_hLdroxide
`Distilled water
`Total Amount
`LpH
`
`
`
`_
`
`l
`
`q.s.
`100
`8.20
`
`2.0 g
`0.02 g_
`-
`
`qfi
`q.s.
`100 mL
`8.19
`
`0.1 g
`1.1 g
`
`1.1 g
`0.005 g
`0.15
`-
`2.0 g
`0.02 g
`0.2 g
`
`q.s.
`q.s.
`100 mL3
`8.3
`
`13.
`
`The preservative efficacy of the bromfenac sodium formulation
`
`containing polysorbate 80 (identical to Bronuck) was tested as part of project
`
`P2002Bl 16 at Senju. (Appendix B.) The preservative efficacy of the two
`
`bromfenac sodium formulations containing tyloxapol (formulations A-04 and A-05
`
`from Tables 2, 3-1 and 3-2 of the ’43l and ’290 patents) was tested as part of
`
`project P2002B13l at Senju. (Appendix C.) The preservative efficacy tests were
`
`3 In Appendix B, the concentration of each component is disclosed as amount of
`component per 1 mL of the fonnulation. The value is converted to the amount of
`each component per 100 mL of the formulation.
`
`8
`
`PAGE 9 OF 613
`
`

`
`conducted at Senju using the European Pharmacopoeia (“EP”) standards, and I
`
`reviewed the results obtained from this testing. (Appendices B & C.)
`
`14. According to the EP standards, the tested formulations were
`
`distributed in sterilized test tubes with stoppers. For inoculation of the organisms,
`
`suspensions containing 108 colony forming units (“CFU”)/mL were prepared for
`
`each bacterial species, and suspensions containing 107 CFU/mL were prepared for
`
`each fungal species. Each test formulation was inoculated in a separate test tube
`
`with a final concentration of 106 CFU/mL of bacteria and 105 CFU/mL of fungi.
`
`The test tubes were stored at 20 to 25 °C after inoculation. Samples were taken
`
`from each test tube after 6 hours, 24 hours, 1 week, 2 weeks, 3 weeks and 4 weeks.
`
`From each sample, 0.5 mL of the sample was diluted with 4.5 mL of sterilized
`
`isotonic sodium chloride solution. Ten-fold dilution was performed 1 to 3 times,
`
`and 1 mL of the diluted solution was placed onto a plate, and 15 to 20 mL of a
`
`culture medium was added to each plate. With respect to bacteria cultures,
`
`soybean-casein digest agar medium (SCD agar medium) containing inactivators
`
`(0.1% lecithin, 0.7% polysorbate 80) was used. With respect to fungi cultures,
`
`sabouraud’s glucose medium containing inactivators (0.1% lecithin, 0.7%
`
`polysorbate 80) was used. Cultures were kept under the following conditions, and
`
`the number of microorganisms was counted.
`
`PAGE 10 OF 613
`
`

`
` Culture Condition
`Microorganism
`Staphylococcus aureus ATCC
`
`6538
`
`Escherichia C0[i ATCC 8739
`30-35 °C
`
`Pseudomonas aeruginosa ATCC
`9027
`
`
`
`
`
`20_25 QC
`
`
`
`
`
`Candzda albzcans ATCC 1023 1
`Aspergillus niger ATCC 16404
`
`Bacteria
`
`Fungi
`
`15.
`
`The results obtained from these preservative efficacy tests are as
`
`follows (Appendices B & C):
`
`Cell count (CFU/mL)
`
`inoculati
`
`inoculati
`
`inoculati
`
`10
`
`PAGE 11 OF 613
`
`

`
` Cell count (CFU/mL)
`
`A-01 (A-
`Inoculu 6 hours 24 hours
`
`
`after
`after
`04 in
`m
`inoculati
`inoculati
`inoculati
`inoculati
`inoculati
`inoculati
`specificati Count
`
`
`
`on
`on)
`
`
`
`3.0 X 10]
`
`
`
`S. aureus
`
`E. coli
`
`.
`P'
`_aerugm0sa
`
`C. albicans
`A. niger
`
`11?‘
`
`-
`—
`
`—
`-
`
`0
`0
`
`0
`0
`
`|
`
`0
`
`0
`
`0
`0
`
`0
`
`0
`0
`
`
`Table 3-2 2
`A-02
`Inocul
`6 hours
`(A-04 in
`um
`
`specificati Count
`inoculati
`
`
`
`
`
`
`
`
`
`
`
`
`0
`
`
`
`
`S. aureus
`21%)?
`1.7 x 105 2.0 x10‘
`
`
`6&3‘
`E. coli
`0
`P‘
`.
`5'83‘
`0
`aerugmosa
`10
`
`Cell count (CFU/mL)
`
`24 hours
`7 days
`14 days
`21 days
`28 days
`after
`after
`after
`after
`after
`
`inoculati
`inoculati
`inoculati
`inoculati
`inoculati
`on
`on
`on
`on
`
`
`
`
`
`
`
`0
`0
`0
`
`0
`0
`0
`
`0
`0
`0
`
`0
`0
`0
`
`
`31%;‘
`C. albicans
`A. mger L 105
`
`1.8 X
`
`.
`
`—
`-
`
`—
`-
`
`0
`0
`
`0
`0
`
`0_|
`0
`
`0
`0
`
`16.
`
`The EP-A and EP-B standards used to compare the obtained results, at
`
`the time of testing, are the following:
`
`ll
`
`PAGE 12 OF 613
`
`

`
`European Pharmacopoeia Standards
`Viable cell counts of
`
`Viable cell counts of
`
`fungi (C. albicans & A.
`niger) 7 days after
`inoculation decreases to
`not more than 1/100’ and
`the cell count levels off or
`
`decreases thereafter.
`
`bacteria (S. aureus, E. coli
`& P. aeruginosa) 6 hours,
`24 hours and 28 days after
`.
`.
`1nocu1at1on decrease to
`not more than 1/ 100 not
`’
`more than 1/1000, and
`.
`undetectable respect1ve_lL
`Viable cell counts of
`
`A standard
`
`B standard
`
`bacteria (S. aureus, E. coli Viable cell counts of
`& P. aeruginosa) 24
`fungi (C. albicans & A.
`hours and 7 days after
`niger) 14 days after
`inoculation decrease to
`inoculation decreases to
`
`not more than 1/10 and
`
`not more than 1/10, and
`
`not more than 1/1000, and the cell count levels off or
`the cell count levels off or decreases thereafter.
`
`decreases thereafter.
`
`17.
`
`Based on the EP-A and EP-B standards, the bromfenac sodium
`
`formulation containing polysorbate 80 did not pass either EP standard. The
`
`bromfenac sodium formulation containing tyloxapol and designated A-01
`
`(corresponding to A-O4 from the ’43l and ’290 patents) passed both standards.
`
`The bromfenac sodium formulation containing tyloxapol and designated A-O2
`
`(corresponding to A-05 from the ’431 and ’290 patents) passed the EP-B standard
`
`but not the EP-A standard.
`
`E.
`
`The data in the specification and data disclosed in this declaration
`
`18.
`
`Based on my involvement with the formulations of Tables 1, 2 and 3
`
`of the ’431 and ’290 patents, I have personal knowledge about how the test data
`
`12
`
`PAGE 13 OF 613
`
`

`
`disclosed in the ’431 and ’290 patents were generated. Based on my involvement
`
`with the remaining formulations and test data (beyond those disclosed in Tables 1,
`
`2 and 3 of the ’431 and ’290 patents) provided in this declaration, including in
`
`Appendices A, B and C, I have personal knowledge about how such information
`
`was generated.
`
`19.
`
`I hereby declare under penalty of perjury under the laws of the United
`
`States of America that the foregoing is true and correct, and that all statements
`
`made of my own knowledge are true and that all statements made on information
`
`and belief are believed to be true.
`
`Date:
`
`I2/16/’15
`
`Shirou Sawa |signature|
`Shirou Sawa
`
`13
`
`PAGE 14 OF 613
`
`

`
`5lélE5f'%*r%‘Ff1"
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`INNOPHARMA LICENSING, lNC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS
`INC., zw‘
`MYLAN INC.
`
`EEFRA
`
`v.
`
`=I'-%§«¥¥1°3Eit%¥i,BAUscH & LOMB, INC., 2520‘
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
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`PAGE 15 OF 613
`
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`PAGE 25 OF 613
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`PAGE 26 OF 613
`
`

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`
`PAGE 27 OF 613
`
`

`
`APPENDIX A
`
`

`
`CERTIFICATION OF TRANSLATION
`
`The undersigned. Ryan Malcho. whose address is
`and states as follows:
`
`-
`
`/¢9/“"79,
`
`declares
`
`I am well acquainted with the English and Japanese languages; 1 have in the past translated
`
`numerous Japanese documents oflegal and/or technical content into English.
`
`I have been requested to translate into English the attached Japanese documents titled:
`
`0
`
`0
`
`0
`
`Exhibit A_P2000B177 data relied on.pdf
`
`Exhibit B_P2002B116 data relied on.pdf
`
`Exhibit C__P2002B13l data relied on.pdf
`
`To copies of these Japanese documents I therefore attach the English translations and my
`Certification of Translation.
`
`I hereby eeiti I'_\;' that the English translations of the attached documents titled
`
`0
`
`-
`
`0
`
`Exhibit A_P2000B177 data relied on.pdf
`
`Exhibit B_P2002B116 data relied on.pdf
`
`Exhibit C_P2002B131 data relied on.pdf
`
`are, to the best ofnty knowledge and ability, accurate translations.
`
`And I declare further that all statements made herein of in}; own knowledge are true, that all
`
`statements made on information and beliefare believed to be true, and that false statements and the like are
`
`llllllihlti-litlfly}-' fine and ln1BI'l\ttltIt1e|t[. or both. under Section 1001 ofTitle l8 ofthe United States Code.
`.'
`-I
`
` _
`
`:9t/
`
`Date
`
`r
`
`PAGE 29 OF 613
`
`

`
`FORM Protocol 4-2-1 (Version 3, 1 February 2000)
`
`Test Protocol
`
`Name of test: Study of the Formulation of Bronuck Ophthalmic Solution at pH 7
`Test code: P2000B 1 77
`
`Test system: None
`Development code: AHRl 0282B
`Test start date: 7 December 2000
`
`Scheduled start date of test operations: 7 December 2000
`Scheduled end date of test operations: 15 March 2000 [sic]
`Scheduled test end date: 30 March 2001
`
`Test facility: Kobe Creative Center, Senju Pharmaceutical Co., Ltd.
`l-5-4 Murotani, Nishi-ku, Kobe—shi
`
`(Division of work duties)
`
`Study director: Shirou Sawa
`Study personnel:
`Test substance: Bromfenac sodium
`
`Purpose: Bromfenac sodium is less soluble and unstable in the low pH range, so the pH (midpoint of the
`standard) of Bronuck Ophthalmic Solution is set to 8.3. The pH of tears is generally said to be around 7 to
`7.4, and since the pH of Bronuck Ophthalmic Solution is believed to be near the upper limit used in
`ophthalmic solutions, a formulation at a lower pH is desired. Bromfenac sodium has an acetic acid group
`in its molecules, so its solubility increases at a pH of 6.5 and higher. Since the dissolution of Bronuck
`Ophthalmic Solution mostly occurs in association with the acetic acid group, control of the acetic acid
`group for solubilization and stabilization is believed to be important. Although the addition of counterions
`to control the acetic acid group has been considered, bromfenac sodium forms insoluble complexes due to
`the addition of quaternary ammonium salt and becomes cloudy. Thus, the purpose of this test is to use
`water-soluble aminosugars to study the solubilization and stabilization of bromfenac sodium, even if
`complexes are formed.
`
`Test method:
`
`1) Solubilization study
`Add an excessive amount of bromfenac sodium to acetic acid (pH 3~6), phosphoric acid (pH 5~7), or
`boric acid (pH 7~9) buffer solution, add 0.1 to 1.0% of N—methylglucamine or glucosamine hydrochloride,
`and adjust the pH with hydrochloric acid. Filter this solution, and measure the concentration of bromfenac
`sodium in the filtrate by HPLC.
`
`PAGE 30 OF 613
`
`

`
`2) Stabilization study
`Add N-methylglucamine or glucosamine hydrochloride to the following bromfenac sodium
`ophthalmic solutions, and adjust the pH to 7. In experiment 1), the N—methylglucamine or glucosamine
`hydrochloride has a pH of 6.5 and an amount in which 0.1% bromfenac sodium is dissolved. Fill this
`solution into colorless polypropylene containers, and store at 70°C, 60°C, and 40°C at 75% RH and at
`25°C at 60% RH. Perform tests on the bromfenac sodium content, pH, external appearance, and foreign
`insoluble matter of

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