US009l07888B2
`
`(12) United States Patent
`Nishihata et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 9,107,888 B2
`Aug. 18, 2015
`
`(54) AQUEOUS LIQUID BROMFENAC
`COMPOSITION HAVING PRESERVATIVE
`EFFICACY
`
`(56)
`
`References Cited
`U S PATENT DOCUMENTS
`‘
`‘
`
`(75)
`
`_
`_
`_
`_
`_
`Inventors: Shu1ch1 Nishihata, Hyogo (JP); Wakiko
`Asayama, Hyogo (JP); Suzuka Iemoto,
`11y0g0(Jp)
`
`.
`(73) Assignee: SENJU PHARMACEUTICAL CO.,
`LTD., Osaka (JP)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U"S'C' 1540:’) by 0 days"
`
`(21)
`
`f\PP1~iJ04
`
`13/973,253
`
`(22) PCT Filed:
`
`Jan. 18, 2012
`
`(86) PCT No.:
`§ 371 <90):
`(2),(4)1ateI
`
`PCT/JP2012/050903
`
`Jul-3,2013
`
`(87) PCT Pub. No.: WO2012/099142
`
`PCT Pub. Date: Jul. 26, 2012
`
`(65)
`
`(30)
`
`PH" P“b“°a“°“ Data
`in
`_
`_
`_
`_
`_
`Foreign Application Priority Data
`
`(2006.01)
`(2006.01)
`(2006.01)
`(200601)
`(2006.01)
`
`(JP) ............................... .. 2011-007898
`
`(JP) . ... .
`. .... 2011-199480
`_
`(JP) ............................... .. 2011 289640
`
`Jan. 18, 2011
`Sep. 13,2011
`Dec. 28, 2011
`(51)
`Int. Cl.
`A61K 31/196
`A61K 31/14
`A61K 47/18
`A61K 9/08
`A6]K 9/00
`(52) US, Cl,
`CPC ............... .. A61K31/196 (2013.01); A61K 9/08
`(2013.01); A61K31/14 (2013.01); A61K47/18
`(2013.01); A61K 47/186 (2013.01); A6IK
`9/0043 (201301);/161K 9/0046 (201301);
`/461K 9/0048 (201301)
`(58) Field Of Classification Search
`CPC
`A61K 9/0048; A61K 31/14; A61K 47/18;
`A61K 9/0046; A61K 9/0043; A61K 47/186;
`A61K 9/08; A61K 31/196; A61K 31/195
`See application file for complete search history.
`
`3/1990 Ogawa et al.
`4,910,225 A
`5/1995 1:11 e1 31,
`5,414,011 A
`8/1999 Sawa
`5,942,508 A
`@2001 Saum
`6274592 B1
`11/2010 Sawa
`7,829,544 B2
`l.
`t
`10/2005 S
`2005/0239895 A1
`1/2007 5:3: :1 :1
`2007/0021507 A1
`12/2007 Sawa et al.
`2007/0287749 A1
`2010/0324031 A1* 12/2010 Kabra ...................... .. 514/226.5
`
`CN
`JP
`JP
`JP
`
`JP
`JP
`
`jg
`1?
`JP
`WO
`
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`101313899
`12/2008
`2-286627
`11/1990
`2683676
`8/1997
`10-109930
`4/1998
`
`10-279431
`10-279503
`
`10/1993
`10/1998
`
`20042/322332
`§882?8i‘13Z‘§8
`2009-161454
`96/14829
`
`2004/064828
`2006/049250
`
`2/3882
`7/2009
`5/1996
`
`8/2004
`5/2006
`
`OTHER PUBLICATIONS
`
`Liu et al (AAPS PharmSciTech, Vol. 10, No._ A, nee. 2009).*
`
`di
`
`It
`dM.19,2012'
`h" Ath "t"
`S
`“g “
`113?; $11,113,113? {$1351/1135612/65696317
`International Search Report issued Mar. 19, 2012 in International
`(PCT) Application No. PCT/JP2012/050903.
`Tri1<r(i)ha;ii1i
`let
`“Antisgiitic A:£nAt‘s8 alriglsgheir Influences on
`yes”,
`p t amo ogy,vo.
`,pp.
`-
`,
`.
`J. Shimazakia “Antiseptic Agents in Ophthalmic Solutions and
`21A9d9v1erse Reactions to Them”, Ophthalmology, vol. 33, pp. 533-538,
`
`-
`
`* cited by exanfiner
`
`Primary Examiner — Savitha Rao
`Assistant Examiner — Angela Brown-Pettigrew
`(74) Att0rney,Agenz, orFirm — Wenderoth, Lind& Ponack,
`L.L.P.
`
`ABSTRACT
`(57)
`An aqueous liquid bromfenac composition containing (a)
`bromfenac or a salt thereof and (b) benzalkonium chloride,
`characterized by that the composition has preservative effi-
`cacy and that the concentration of (b) benzalkonium chloride
`is higher than 0.0005% and lower than 0.005%.
`
`9 Claims, N0 Drawings
`
`Petitioner |nnoPharma EX 1103
`
`|PR2015—00902
`
`|PR2015—00903
`
`Page 1
`
`

`
`US 9,107,888 B2
`
`1
`AQUEOUS LIQUID BROMFENAC
`COMPOSITION HAVING PRESERVATIVE
`EFFICACY
`
`TECHNICAL FIELD
`
`The present invention relates to an aqueous liquid bro-
`mfenac composition in which a base containing a low con-
`centration of benzalkonium chloride is used and which has
`
`preservative efiicacy and stability. The present invention also
`relates to a method for preparing an aqueous liquid bro-
`mfenac composition having preservative efiicacy by combin-
`ing bromfenac and an aqueous base composition which con-
`tains benzalkonium chloride but does not have sufficient
`
`preservative efiicacy. The present invention also relates to a
`method for enhancing the preservative efiicacy of an aqueous
`solution.
`
`BACKGROUND ART
`
`Generally, a preservative is indispensable in (multidose)
`aqueous liquid compositions. A representative of such a pre-
`servative is Benzalkonium chloride. However, frequent appli-
`cation of an ophthalmic solution containing benzalkonium
`chloride or application thereof to those who have corneal
`injury or abnormal tear dynamics such as dry eye syndrome
`causes side effects and corneal damage (Non Patent Litera-
`ture 1 and 2). Therefore, it is desirable that the concentration
`of benzalkonium chloride added to ophthalmic solutions etc.
`is low. Considering both preservative efiicacy and safety, a
`desirable concentration ofbenzalkonium chloride added to an
`
`ophthalmic solution is said to be 0.002% to 0.005% (Non
`Patent Literature 1). Aqueous liquid bromfenac compositions
`containing 0.001% or 0.005% benzalkonium chloride are
`known (Patent Literature 1 to 7). However, the preservative
`efiicacy of the compositions is unknown.
`Bromfenac
`(2-arnino-3-(4-bromobenzoyl)phenylacetic
`acid) is a non-steroidal anti-inflammatory drug of which the
`preservative efficacy is unknown.
`Benzalkonium chloride is a cationic surfactant which is
`
`widely used as a preservative for topical aqueous liquids as
`mentioned above. A preferred concentration ofbenzalkonium
`chloride, in particular in ophthalmic solutions, is 0.002% to
`0.005%, but the preservative efficacy of benzalkonium chlo-
`ride can decline under the influence of other sub stances in an
`
`aqueous base. For example, a large amount of a non-ionic
`surfactant added to an aqueous liquid impairs the preservative
`efiicacy of benzalkonium chloride (Patent Literature 8). It is
`also known that benzalkonium chloride forms complexes
`with other substances in an aqueous liquid, resulting in
`impaired preservative efficacy. In particular, it is reported that
`a combination of a non-steroidal anti-inflammatory drug
`(NSAID) and a quaternary ammonium salt such as benzalko-
`nium chloride forms a complex, resulting in decline in the
`preservative efficacy (Patent Literature 9 and 10).
`No aqueous liquid bromfe11ac composition which has suf-
`ficient preservative efiicacy and stability as a result of com-
`bining bromfenac and a base which contains benzalkonium
`chloride but does not have suflicient preservative efficacy has
`so far been reported.
`
`CITATION LIST
`
`Patent Literature
`
`[PTL 1] JP 10-279481 A (U.S. Pat. No. 5,942,508)
`[PTL 2] JP 10-279503 A (U.S. Pat. No. 6,274,592)
`
`2
`
`[PTL 3] JP 2004-064828 W (US 2005-239895 A)
`[PTL 4] JP 2005-046700 W (US. Pat. No. 7,829,544)
`[PTL 5] JP 2006-049250 W (US 2007-021507 A)
`[PTL 6] JP Pat. No. 2683676 (U.S. Pat. No. 4,910,225)
`[PTL 7] CN 101313899 A
`[PTL 8] JP 10-109930A
`[PTL 9] JP 02-286627 A (U.S. Pat. No. 5,414,011)
`[PTL 10] JP Pat. No. 2954356 (WO 96/14829)
`
`Non Patent Literature
`
`[NPL 1] Ophthalmology Vol. 31 43-48, 1989 (published by
`Kanehara & Co., Ltd.)
`[NPL 2] Ophthalmology Vol. 33 533-538, 1991 (published by
`Kanehara & Co., Ltd.)
`
`SUMMARY OF INVENTION
`
`Technical Problem
`
`In view of the above problems, an object of the present
`invention is to provide an aqueous liquid bromfenac compo-
`sition having preservative efficacy and stability by combining
`bromfenac and an aqueous base which contains benzalko-
`nium chloride but does not have sufficient preservative effi-
`cacy. Another object of the present invention is to provide a
`method for preparing an aqueous liquid bromfenac composi-
`tion having preservative efficacy by combining bromfenac
`and an aqueous base which contains benzalkonium chloride
`but does not have sufficient preservative efficacy. Still another
`object of the present invention is to provide a method for
`enhancing the preservative efiicacy of an aqueous solution for
`use in ophthalmic solutions, etc.
`
`Solution to Problem
`
`In view of the above problems, the present inventors made
`extensive research, and found that an aqueous liquid bro-
`mfenac composition having preservative efiicacy can be pre-
`pared by combining bromfenac sodium and an aqueous base
`composition which contains up to 0.005% benzalkonium
`chloride but does not have sufficient preservative efficacy, as
`the base of the aqueous liquid composition containing bro-
`mfenac sodium. The present inventors also found a method
`for preparing an aqueous liquid bromfenac composition hav-
`ing preservative efficacy by combining bromfenac sodium
`and the above-mentioned aqueous base composition which
`contains benzalkonium chloride but does not have sufficient
`
`preservative efficacy.
`As described above, it is known that a combination of a
`non- steroidal anti-inflammatory drug (NSAID) and a quater-
`nary ammonium salt forms a complex, resulting in decline in
`the preservative efiicacy. Since bromfenac is a non-steroidal
`anti-inflammatory drug and benzalkonium chloride is a qua-
`ternary ammonium salt, it is expected that combining these
`two results in dcclinc in the preservative efiicacy. However,
`unexpectedly, a combination of bromfenac and benzalko-
`nium chloride both of which were at a concentration insufii-
`
`cient for exerting preservative efiicacy by itself significantly
`enhanced the preservative efiicacy specifically against
`Pseudomonas aeruginosa, that is, provided improved preser-
`vative efiicacy to the aqueous liquid composition. The
`obtained aqueous liquid bromfenac composition had also
`excellent stability.
`The present inventors also found that an aqueous liquid
`bromfenac composition having preservative efficacy can be
`prepared by combining (a) bromfenac or a salt thereof and (b)
`
`10
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`Page 2
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`Page 2
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`

`
`US 9,107,888 B2
`
`3
`benzalkonium chloride, even when the added amount of ben-
`zalkonium chloride is reduced to the minimum. In this way,
`the side effect of the aqueous liquid bromfenac composition
`containing benzalkonium chloride can be reduced.
`The present inventors also found that bacterial prolifera-
`tion in an aqueous solution can be suppressed by adding
`bromfenac or a salt thereof to the solution. Thus, the addition
`of bromfenac or a salt thereof to an aqueous solution can
`enhance the preservative efiicacy of the solution, and there-
`fore, a small amount of a preservative is sufiicient to suppress
`the proliferation ofbacteria or the like in the aqueous solution
`and hence a highly safe aqueous liquid composition etc. can
`be obtained.
`
`Based on the above findings, the inventors conducted fur-
`ther research and completed the present invention. That is, the
`present invention relates to the following (1) to (17).
`(1) An aqueous liquid bromfenac composition containing (a)
`bromfenac or a salt thereof and (b) benzalkonium chloride,
`characterized by that the composition has preservative effi-
`cacy and that the concentration of (b) benzalkonium chloride
`is higher than 0.0005% and lower than 0.005%.
`(2) The aqueous liquid composition of the above (1 ), wherein
`the concentration of (a) bromfenac or a salt thereof is 0.01%
`to 10%.
`
`(3) The aqueous liquid composition of the above (1) or (2),
`wherein the concentration of (b) benzalkonium chloride is
`0.00075% to 0.003%.
`
`(4) The aqueous liquid composition of any one of the above
`(1) to (3), further containing (c) at least one kind selected from
`the group consisting of a non-ionic surfactant and a water-
`soluble polymer.
`(5) The aqueous liquid composition of the above (4), wherein
`the total concentration of (c) at least one kind selected from
`the group consisting of a non-ionic surfactant and a water-
`soluble polymer is 0.0001% to 5%.
`(6) The aqueous liquid composition of the above (4) or (5),
`wherein the at least one kind selected from the group consist-
`ing of a non-ionic surfactant and a water-soluble polymer is a
`non-ionic surfactant.
`
`(7) The aqueous liquid composition of any one of the above
`(4) to (6), wherein the non-ionic surfactant is polysorbate 80.
`(8) The aqueous liquid composition of any one of the above
`(4) to (7), wherein the concentration of the non-ionic surfac-
`tant is 0.025% or higher and lower than 0.25%.
`(9) The aqueous liquid composition of any one of the above
`(4) to (8), wherein the concentration of the non-ionic surfac-
`tant is 0.025% to 0.15%.
`
`(10) The aqueous liquid composition of any one of the above
`(4) to (8), wherein the concentration of the non-ionic surfac-
`tant is 0.05% or higher and lower than 0.25%.
`(11) The aqueous liquid composition of the above (4) or (5),
`wherein the at least one kind selected from the group consist-
`ing of a non-ionic surfactant and a water-soluble polymer is a
`water-soluble polymer.
`(12) The aqueous liquid composition of any one of the above
`(4), (5), and (11), wherein the water-soluble polymer is at
`least one kind selected from the group consisting ofhydroxy-
`ethyl cellulose and povidone.
`(13) The aqueous liquid composition of any one of the above
`(4), (5), (11), and (12), wherein the concentration of the
`water-soluble polymer is 0.01% to 1.4%.
`(14) The aqueous liquid composition of any one of the above
`(1) to (13), which is an ophthalmic solution, a nasal solution,
`or an otic solution.
`
`(15) A method for providing preservative efiicacy to an aque-
`ous liquid composition containing bromfenac or a salt
`thereof, the method comprising combining bromfenac or a
`
`4
`
`salt thereof and an aqueous base which contains benzalko-
`nium chloride but does not have sufficient preservative effi-
`cacy.
`(16) A method for enhancing the preservative efficacy of an
`aqueous solution, the method comprising adding bromfenac
`or a salt thereof to the solution.
`
`(17) The method ofthe above (16), wherein the enhancement
`of the preservative efiicacy is evidenced by reduction in
`viable cell count of Staphylococcus aureus (S. aureus).
`The present invention also relates to the following (A1) to
`(A10).
`(A1) An aqueous liquid bromfenac composition containing
`(a) bromfenac or a salt thereof and (b) benzalkonium chlo-
`ride, characterized by that the concentration of (b) benzalko-
`nium chloride is higher than 0.0005% and lower than 0.005%.
`(A2) The aqueous liquid composition of the above (A1),
`wherein the concentration of (b) benzalkonium chloride is
`higher than 0.0005% and lower than 0.002%.
`(A3) The aqueous liquid composition of the above (A1) or
`(A2), which has preservative efiicacy.
`(A4) The aqueous liquid composition of any one of the above
`(A1) to (A3), wherein the concentration of (a) bromfenac or a
`salt thereofis 0.01% to 10%.
`
`10
`
`15
`
`20
`
`25
`
`(A5) The aqueous liquid composition of any one of the above
`(A1) to (A4), wherein the concentration of (b) benzalkonium
`chloride is 0.00075% to 0.0015%.
`
`30
`
`35
`
`40
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`45
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`50
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`60
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`(A6) The aqueous liquid composition of any one of the above
`(A1) to (A5), further containing (c) at least one kind selected
`from the group consisting of a non-ionic surfactant and a
`water-soluble polymer.
`(A7) The aqueous liquid composition of the above (A6),
`wherein the non-ionic surfactant is polysorbate 80.
`(A8) The aqueous liquid composition of the above (A6) or
`(A7), wherein the concentration ofthe non-ionic surfactant is
`0.001% to 5%.
`
`(A9) The aqueous liquid composition of any one of the above
`(A1) to (A8), which is an ophthalmic solution, a nasal solu-
`tion, or an otic solution.
`(A10) A method for providing preservative efficacy to an
`aqueous liquid composition containing bromfenac or a salt
`thereof, the method comprising combining bromfenac or a
`salt thereof and an aqueous base which contains benzalko-
`nium chloride but does not have sufficient preservative effi-
`cacy.
`
`Advantageous Effects of Invention
`
`According to the present invention, an aqueous liquid bro-
`mfenac composition having preservative efficacy and stabil-
`ity can be obtained even when the added amount of benza-
`lkonium chloride is reduced to the minimum. According to
`the present invention, an aqueous liquid bromfenac compo-
`sition having preservative efficacy can be provided by com-
`bining bromfenac and an aqueous base which contains a low
`concentration of benzalkonium chloride or contains benza-
`
`lkonium chloride but does not have sufiicient preservative
`efiicacy. The aqueous liquid bromfenac composition has the
`preservative efiicacy which complies with <51> ANTIMI-
`CROBIAL EFFECTIVENESS TESTING (preservatives-ef-
`fectiveness tests) of “Microbiological tests” specified in the
`United States Pharmacopeia (USP) 32. Therefore, the present
`invention can provide a bromfenac aqueous liquid composi-
`tion which causes fewer side effects and is safe and stable.
`
`In addition, according to the present invention, the preser-
`vative efiicacy of an aqueous solution can be enhanced by
`adding bromfenac or a salt thereof to the solution. Therefore,
`according to the present invention, a small amount of a pre-
`
`Page 3
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`Page 3
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`

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`US 9,107,888 B2
`
`5
`servative is sufiicient to suppress the proliferation of bacteria
`or the like in the aqueous solution and thus a highly safe
`aqueous liquid composition can be provided.
`
`DESCRIPTION OF EMBODIMENTS
`
`Definitions
`
`As used herein, "Preservatives-Effectiveness Tests” refers
`to the method specified in the Japanese Pharmacopoeia Fif-
`teenth Edition unless otherwise stated.
`
`In the method, with the use of bacteria, such as Staphylo-
`coccus aureus, Escherichia coli, and Pseudomonas aerugi—
`nosa, and fungi, such as Candida albicans and Aspergillus
`brasiliensis (niger), as test microorganisms, the following
`procedures (i) to (iv) are performed.
`(i) Each of the above-mentioned five strains for testing is
`inoculated onto the surface of a slant agar medium and pre-
`cultured. As the agar medium for preculture, a soybean casein
`digest agar medium is used for the bacteria, and a Sabouraud
`glucose agar medium is used for the fungi. The bacteria are
`precultured at 30 to 35° C. for 18 to 24 hours, Candida
`albicans is precultured at 20 to 25° C. for 40 to 48 hours, and
`Aspergillus brasiliensis (niger) is precultured at 20 to 25° C.
`for a week or until sufiicient sporulation is achieved.
`(ii) The aqueous liquid composition to be tested as a sample
`is dispensed to 5 sterile stoppered test tubes so that each tube
`contains 10 mL of the sample. To these, test microorganisms
`of (i) are inoculated at 105 to 106 cells/mL, and the thus
`prepared mixed samples are stored at 20 to 25° C. in light-
`shielded conditions. The test microorganism are not mixed
`with each other but separately inoculated into the samples.
`(iii) From each ofthe mixed samples, 1 mL is sampled after
`1 week, 2 weeks, and 4 weeks of storage, and diluted with 9
`mL of physiological saline. The same dilution is further per-
`formed twice or 3 times, and 1 mL of each diluent is trans-
`ferred into separate sterile petri dishes.
`(iv) Subsequently, a soybean casein digest agar medium
`supplemented with 0.1% lecithin and 0.7% polysorbate 80 is
`poured into the petri dishes containing the bacteria, and a
`Sabouraud glucose agar medium supplemented with 0.1%
`lecithin and 0.7% polysorbate 80 is poured into the petri
`dishes containing the fungi. After culturing under the condi-
`tions shown below, the number of the formed colonies is
`counted, and the theoretical cell count in 1 mL of each mixed
`sample is calculated.
`Culture conditions for bacteria: at 30 to 35° C. for about 3 to
`
`5 days
`Culture conditions for fungi: at 20 to 25° C. for about 5 days
`After the above (i) to (iv) are completed, the sample is
`judged as “having preservative efiicacy” in cases where the
`sample satisfies all the following criteria: all the bacterial
`viable cell counts (Staphylococcus aureus, Escherichia coli,
`and Pseudomonas aeruginosa) in the mixed solutions after 14
`days of storage are all reduced to 0.1% of the inoculated cell
`counts or less, and the bacterial viable cell counts after 28
`days of storage are still at the same level as those after 14 days
`of storage or less; and all the fungal viable cell counts in the
`mixed solutions after 14 days of storage and after 28 days of
`storage are all at the same level as the inoculated cell counts
`or less. In the cases where any one of the above bactcria and
`fungi does not satisfy the above criteria, the sample is judged
`as “not having sufiicient preservative efficacy”.
`In the <51> ANTIMICROBIAL EFFECTIVENESS
`
`TESTING (preservatives-effectiveness tests) of “Microbio-
`logical tests” specified in the United States Pharmacopeia
`(USP) 32, after the above (i) to (iv) are completed, the sample
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
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`40
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`50
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`60
`
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`6
`is judged as “having preservative efiicacy” in cases where the
`sample satisfies all the following criteria: (1) all the bacterial
`viable cell counts (Staphylococcus aureus, Escherichia coli,
`and Pseudomonas aeruginosa) in the mixed solutions after 7
`days of storage are reduced to 10% of the inoculated cell
`counts or less, all the viable cell counts after 14 days of
`storage are reduced to 0.1% of the inoculated cell counts or
`less, and all the viable cell counts after 28 days of storage
`remain the same level as those after 14 days of storage or less,
`and (2) all the fungal viable cell counts in the mixed solutions
`after 7, 14, and 28 days of storage are at the same level as the
`inoculated cell counts or less. In the cases where any one of
`the above bacteria and fungi does not satisfy the above crite-
`ria, the sample is judged as “not having sufiicient preservative
`efficacy”.
`The term “stable” or “having stability” means that the
`preservative efficacy is retained for, for example, at least 1
`year of storage and no changes are observed in the properties.
`As used herein, an aqueous liquid composition “having
`preservative efficacy” is the one that is judged as “having
`preservative efiicacy” in the above-mentioned preservatives-
`effectiveness tests specified in the Japanese Pharmacopoeia
`or the United States Pharmacopeia (USP). An aqueous liquid
`composition “not having sufficient preservative efiicacy” is
`the one that is judged as “not having sufiicient preservative
`efiicacy” in the above-mentioned preservatives-effectiveness
`tests. The term “preservative efiicacy” is synonymous with
`“antiseptic efficacy”, and the term “preservative” is synony-
`mous with “antiseptic”.
`As used herein, an “aqueous base” refers to an aqueous
`solution prepared by adding 1 or more additives to water as a
`vehicle, and “an aqueous liquid” refers to a liquid prepared by
`adding 1 or more pharmacologically active ingredient to the
`aqueous base, unless otherwise stated.
`As used herein, a “low concentration” refers to a concen-
`tration higher than 0.0005% and lower than 0.005%, unless
`otherwise stated.
`
`As used herein, % means w/v % (g/ 100 mL), unless other-
`wise stated.
`Herein, as described above, a benzalkonium chloride-con-
`taining aqueous base whose efiicacy as a preservative has
`declined under the influence of another substance and has
`
`beenjudged as “not having sufficient preservative efficacy” in
`the above-mentioned preservatives-effectiveness tests speci-
`fied in the Japanese Pharmacopoeia or the United States Phar-
`macopeia (USP) is described as an “aqueous base which
`contains benzalkonium chloride but does not have sufficient
`
`preservative efficacy”.
`As used herein, a “method for providing preservative effi-
`cacy” means a method comprising combining a composition
`and/or a base both of which were at a concentration insufii-
`
`cient for exerting preservative efficacy by itself to give a
`composition having preservative efficacy.
`The present invention provides an aqueous liquid bro-
`mfenac composition containing bromfenac and a low concen-
`tration of benzalkonium chloride. The aqueous liquid bro-
`mfenac composition ofthe present invention has preservative
`efiicacy.
`The aqueous liquid bromfenac composition of the present
`invention having preservative efficacy is an aqueous liquid
`composition containing (a) bromfenac or a salt thereof and
`(b) benzalkonium chloride, and the concentration of (b) ben-
`zalkonium chloride is higher than 0.0005% and lower than
`0.005%.
`
`The salt of bromfenac added to the aqueous liquid compo-
`sition of the present invention is not particularly limited as
`long as the salt is pharmaceutically acceptable. Examples of
`
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`US 9,107,888 B2
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`7
`the salt include, alkali metal salts, such as sodium salt and
`potassium salt; alkaline earth metal salts, such as calcium salt
`and magnesium salt, and these can be used as appropriate
`unless the objects of the present invention are hindered.
`Depending on the conditions of synthesis, recrystallization,
`etc., the above compounds may be obtained in the form of a
`hydrate, which can be used in the present invention without
`any inconvenience. Among the salts of bromfenac, preferred
`is sodium salt.
`The concentration of bromfenac or a salt thereof in the
`
`aqueous liquid composition ofthe present invention is usually
`about 0.001% to 10%, preferably about 0.01% to 10%, more
`preferably about 0.01% to 1%, still more preferably about
`0.02% to 0.15%, and particularly preferably about 0.02% to
`0.1%.
`
`In another preferred embodiment of the present invention,
`the concentration of bromfenac or a salt thereof is preferably
`about 0.05% to 0.15%.
`
`Bromfenac and a pharrnacologically acceptable salt
`thereof can be appropriately produced by the method accord-
`ing to JP 52-23052 A (corresponding to U.S. Pat. No. 4,045,
`576) or an equivalent method (for example, FDA Drug Master
`File #16414, or the like). Depending on the conditions of
`synthesis, recrystallization, etc., bromfenac and a pharmaco-
`logically acceptable salt thereof are usually obtained as
`hydrates thereof. Examples of the hydrate include 1/2 hydrate,
`monohydrate, and 3/2 hydrate, and preferred is 3/2 hydrate.
`As used herein, the term benzalkonium chloride has the
`same meaning as a chloride of benzalkonium.
`The generally used benzalkonium chloride, which is rep-
`resented by the rational formula: [C6H5CH2N(CH3)2R]Cl, is
`a mixture of compounds having CSH 17 to C ISH37 as the alkyl
`group R in the rational formula as described in the pharma-
`copoeias of Japan, the U.S., and Europe. Shown below are the
`descriptions ofbenzalkonium chloride in the pharmacopoeias
`of Japan, the U.S., and Europe.
`Japanese Pharmacopoeia:
`represented by the formula
`[C6H5CH2N(CH3)2R]Cl, in which R is CSHI7 to CISH37,
`mainly comprising C12H25 and C 14H29.
`The U.S. Pharmacopeia (USP): a mixture of alkylben-
`zyldimethylamrnonium chlorides represented by the formula
`[C6H5CH2N(CH3)2R]Cl, in which R is a mixture of all or
`some of alkyl groups equal to or longer than CSHI7, mainly
`comprising C12H25, CMH29, and CMH33.
`European Pharmacopoeia: a mixture of alkylbenzyldim-
`ethylamrnonium chlorides with alkyl chain lengths of C8 to
`C18.
`As used herein, “benzalkonium chloride” usually refers to
`the mixture of benzalkonium chlorides as described above.
`
`When benzalkonium chloride is designated by the number
`of carbon atoms, the number denotes the length of the carbon
`chain of the alkyl group represented by “R” in the above-
`mentioned pharmacopoeias.
`The benzalkonium chloride added to the aqueous liquid
`composition of the present invention may be one of those
`represented by the rational formula: [C6H5CH2N(CH3)2R]Cl
`in which the alkyl group R is CSHI7 to CISH37, or a mixture
`thereof. Preferred is a mixture represented by the rational
`formula in which R mainly comprising C12H25 and C 14H29,
`and more preferred is a mixture represented by the rational
`formula in which R is a mixture in which the amount of
`
`C12H25 is about 80 to 85% and the amount of C12H25 and
`C1 4H29 together is about 98% or more.
`The lower limit ofthe concentration ofbenzalkomum chlo-
`
`ride in the aqueous liquid composition of the present inven-
`tion is usually higher than about 0.0005%, preferably about
`0.0006%, more preferably about 0.0007%, still more prefer-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`ably about 0.00075%, particularly preferably about 0.0008%,
`and most preferably about 0.001 %. The upper limit thereof is
`usually lower than about 0.005%, preferably about 0.004%,
`more preferably about 0.003%, still more preferably about
`0.002%, particularly preferably about 0.0015%, and most
`preferably about 0.001%. Even when the concentration of
`benzalkomum chloride is within the above range, such ben-
`zalkomum chloride can be combined with bromfenac or a salt
`
`thereof to give an aqueous liquid composition having preser-
`vative efiicacy.
`The concentration range of benzalkomum chloride
`blended in the aqueous liquid composition of the present
`invention is usually higher than about 0.0005% and lower
`than about 0.005%, preferably about 0.00075% to 0.003%,
`and still more preferably about 0.001% to 0.002%.
`The aqueous liquid composition of the present invention
`has preservative efiicacy because the composition contains
`(a) bromfenac or a salt thereof and (b) benzalkonium chlo-
`ride, the concentration of (b) being higher than 0.0005%.
`Therefore, the composition need not contain any preserva-
`tives other than benzalkonium chloride. The composition
`may, however, further contain an additional preservative if
`desired.
`
`As the additional preservative, one or more kinds of, for
`example, chlorhexidine salt, benzethonium chloride, p-hy-
`droxybenzonates, benzyl
`alcohol, p-chlorometaxylenol,
`chlorocresol, phenethyl alcohol, sorbic acid or a salt thereof,
`thimerosal, chlorobutanol, boric acid, sodium edetate, and the
`like. The amount of the additional preservative is not particu-
`larly limited as long as the effect of the present invention is
`exerted, and can be determined as appropriate.
`The aqueous liquid composition of the present invention
`can further contain a compound having a surface-activating
`action. Examples of the compound having a surface-activat-
`ing action include a non-ionic surfactant, a water-soluble
`polymer, and the like. Such an aqueous liquid composition
`further containing at least one kind selected from the group
`consisting of a non-ionic surfactant and a water-soluble poly-
`mer is a preferred embodiment of the present invention. Inter
`alia, more preferred is the one containing a non-iomc surfac-
`tant.
`The total concentration of the non-ionic surfactant and the
`
`water-soluble polymer in the aqueous liquid composition of
`the present invention is usually about 0.0001% to 5%, pref-
`erably about 0.01% to 3%, more preferably about 0.01% to
`1.4%, still more preferably about 0.025% to lower than
`0.25%, particularly preferably about 0.025% to 0.15%, and
`most preferably about 0.05% to 0.15%.
`In another preferred embodiment of the present invention,
`the total concentration of the non-ionic surfactant and the
`
`water-soluble polymer is further preferably about 0.05% to
`0.3%.
`
`Examples of the non-ionic surfactant in the aqueous liquid
`composition of the present invention include polyoxyethyl-
`ene sorbitan fatty acid esters, polyoxyethylene hydrogenated
`castor oils, alkyl aryl polyether alcohol-type polymers, poly-
`oxyethylene fatty acid esters, polyoxyethylene polyoxypro-
`pylene glycols, and sucrose fatty acid esters. Preferred are
`polyoxyethylene sorbitan fatty acid esters, such as polyoxy-
`ethylene sorbitan monooleate, polyoxyethylene sorbitan
`monolaurate, polyoxyethylene
`sorbitan monopalmitate,
`polyoxyethylene sorbitan monostearate, and polyoxyethyl-
`ene sorbitan tristearate; polyoxyethylene hydrogenated cas-
`tor oils, such as polyoxyethylene hydrogenated castor oil 10,
`polyoxyethylene hydrogenated castor oil 40, polyoxyethyl-
`ene hydrogenated castor oil 50, and polyoxyethylene hydro-
`genated castor oil 60; alkyl aryl polyether alcohol-type poly-
`
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`US 9,107,888 B2
`
`9
`mers, such as tyloxapol; and polyoxyethylene fatty acid
`esters, such as polyoxyl stearate. Inter alia, further preferred
`are polysorbate 80, polyoxyethylene hydrogenated castor oil
`60, tyloxapol, polyoxyl 40 stearate, etc., and particularly
`preferred is polysorbate 80. These non-ionic surfactants may
`be used alone or as a mixture of two or more thereof. The
`lower limit of the concentration of the non-iomc surfactant in
`
`the aqueous liquid composition is usually about 0.001%,
`preferably about 0.005%, more preferably about 0.01%, still
`more preferably about 0.05%, and particularly preferably
`about 0.1%. The upper limit of the concentration of the non-
`ionic surfactant is usually about 5%, preferably about 2%,
`more preferably about 1%, still more preferably about 0.5%,
`furthermore preferably about 0.4%, particularly preferably
`about 0.3%, particularly preferably about lower than 0.25%,
`particularly preferably about 0.2%, and most preferably
`about 0.15% or lower.
`
`The concentration of the non-ionic surfactant in the aque-
`ous liquid composition of the present invention is preferably
`about 0.001% to 5%, more preferably about 0.01% to 1%, still
`more preferably about 0.01% to lower than 0.25%, further
`preferably about 0.025% to lower than 0.25%, particularly
`preferably about 0.025% to 0.15%, and most preferably about
`0.1% to 0.15%.
`
`In another preferred embodiment of the present invention,
`the concentration