(12) United States Patent
`Sawa et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,669,290 B2
`*Mar. 11, 2014
`
`US008669290B2
`
`(54) AQUEOUS LIQUID PREPARATION
`CONTAINING
`2-AMINO-3-(4-BROMOBENZOYL)
`PHENYLACETIC ACID
`
`(71) Applicant: Senju Pharmaceutical Co., Ltd., Osaka
`(JP)
`
`(72) Inventors: Shirou SaWa, Hyogo (JP); Shuhei
`Fujita, Hyogo (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. 154(b) by 0 days.
`This patent is subject to a terminal dis
`claimer.
`
`(21) App1.No.: 13/687,242
`
`(22) Filed:
`
`Nov. 28, 2012
`
`(65)
`
`Prior Publication Data
`US 2013/0090384 A1
`Apr. 11, 2013
`
`Related US. Application Data
`
`(62) Division of application No. 13/353,653, ?led on Jan.
`19, 2012, noW Pat. No. 8,497,304, Which is a division
`ofapplication No. 10/525,006, ?led as application No.
`PCT/JP2004/000350 on Jan. 16, 2004, noW Pat. No.
`8,129,431.
`
`(30)
`
`Foreign Application Priority Data
`
`8/1999 SaWa
`5,942,508 A
`5,998,465 A 12/1999 Hellberg et al.
`6,162,393 A * 12/2000 De Bruiju et a1. ............ .. 422/28
`6,274,592 B1
`8/2001 SaWa
`6,274,609 B1
`8/2001 Yasueda et al.
`6,319,513 B1
`11/2001 DobroZsi
`6,369,112 B1
`4/2002 Xia
`6,383,471 B1
`5/2002 Chen et a1.
`6,395,746 B1
`5/2002 Cagle et a1.
`2001/0056098 A1
`12/2001 SaWa
`2007/0082857 A1
`4/2007 SaWa
`
`FOREIGN PATENT DOCUMENTS
`
`AU
`CA
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`WO
`WO
`WO
`W0
`WO
`
`9/1995
`707 119
`9/1990
`2 013188
`6/1987
`62-126124
`4/1989
`1-104023
`3/1990
`02083323
`5/1990
`2-124819
`8/1993
`5-223052
`4/1997
`9-503791
`8/1999
`11-228404
`10/2002
`2002-308764
`5/1996
`96/14829
`10/2000
`00/59475
`3/2001
`01/15677
`W0 0115677 A2 * 3/2001
`02/13804
`2/2002
`
`OTHER PUBLICATIONS
`
`New Drugs in Japan, 2001, 2001 Edition, Published byYakuji Nippo
`Ltd., May 11, 2001, pp. 27-29, and its English translation of the
`material portions.
`
`(Continued)
`
`Jan. 21, 2003
`
`(JP) ............................... .. 2003-012427
`
`Primary Examiner * Layla Soroush
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A01N37/18
`A61K 31/165
`A01N37/44
`A61K 31/24
`A01N37/10
`A61K 31/19
`(52) US. Cl.
`USPC .......... .. 514/619; 514/535; 514/570; 514/618
`(58) Field of Classi?cation Search
`USPC ........................................ .. 514/619, 535, 570
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`8/1977 Welstead, Jr. et al.
`4,045,576 A
`7/1987 Poser
`4,683,242 A
`3/1990 Ogawaet a1. ............... .. 514/561
`4,910,225 A *
`5/1992 Cherng-Chyiet al.
`5,110,493 A
`5,475,034 A 12/1995 Yanniet a1.
`5,540,930 A
`7/1996 Guy
`5,558,876 A *
`9/1996 Desaiet a1. ................. .. 424/427
`5,597,560 A
`1/1997 Bergaminiet al.
`5,603,929 A
`2/1997 Desaiet a1.
`5,653,972 A
`8/1997 Desaiet a1.
`
`(74) Attorney, Agent, or Firm * Wenderoth, Lind & Ponack,
`L.L.P.
`
`(57)
`
`ABSTRACT
`
`An aqueous liquid preparation of the present invention con
`taining 2-amino-3-(4-bromobenZoyl)phenylacetic acid or its
`pharmacologically acceptable salt or a hydrate thereof, an
`alkyl aryl polyether alcohol type polymer such as tyloxapol,
`or a polyethylene glycol fatty acid ester such as polyethylene
`glycol monostearate is stable. Since even in the case Where a
`preservative is incorporated into said aqueous liquid prepa
`ration, the preservative exhibits a su?icient preservative
`effect for a long time, said aqueous liquid preparation in the
`form of an eye drop is useful for the treatment of blepharitis,
`conjunctivitis, scleritis, and postoperative in?ammation.
`Also, the aqueous liquid preparation of the present invention
`in the form of a nasal drop is useful for the treatment of
`allergic rhinitis and in?ammatory rhinitis (e.g. chronic rhini
`tis, hypertrophic rhinitis, nasal polyp, etc.).
`
`30 Claims, No Drawings
`
`Metrics EX1001, Page 1
`
`

`
`US 8,669,290 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`ISTA Pharmaceuticals, “New Drug Applications: Xibrom”,http://
`WWW.drugs.com/nda/Xibromi040525.htrnt, accessed online Sep.
`19, 2007.
`Nolan et al., “The Topical Anti-In?ammatory and Analgesic Proper
`ties of Bromfenic in Rodents”, Agents and Actions, vol. 25, No. 1-2,
`pp. 77-85, Aug. 1988.
`Corrected partial English translation of New Drugs in Japan, 2001,
`2001 Edition, Published by Yakuji Nippo Ltd., May 11, 2001, pp.
`27-29, previously submitted on Apr. 11, 2005.
`
`Complete English translation of New Drugs in Japan, 2001, 2001
`Edition, Published byYakuji Nippo Ltd., May 11, 2001, pp. 27-29.
`Notice of Opposition dated Feb. 19, 2009 issued by EPO in connec
`tion With the corresponding European patent application and Oppo
`sition.
`http://medical-dictionary.thefreedictionary.com/prolohylactic
`accessed Dec. 15, 2009.
`H. Scott et al., “Comparing the Surface Chemical Properties and the
`Effect of Salts on the Cloud Point of a Conventional Nonionic
`Surfactant, OctoXynol 9 (Triton X-100), and of its Oligomer,
`TyloXapol (Triton WR-1339)”, Journal of Colloid and Interface Sci
`ence, vol. 205, pp. 496-502, 1998.
`
`* cited by examiner
`
`Metrics EX1001, Page 2
`
`

`
`US 8,669,290 B2
`
`1
`AQUEOUS LIQUID PREPARATION
`CONTAINING
`2-AMINO-3-(4-BROMOBENZOYL)
`PHENYLACETIC ACID
`
`This is a divisional of Ser. No. 13/353,653 ?led Jan. 19,
`2012, Which is a divisional of Ser. No. 10/525,006, ?led Mar.
`28, 2005, noW issued as US. Pat. No. 8,129,431, Which is a
`US. national stage of International Application No. PCT/
`JP2004/000350 ?led Jan. 16, 2004.
`
`TECHNICAL FIELD
`
`The present invention relates to an aqueous liquid prepa
`ration containing 2-amino-3-(4-bromobenZoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a
`hydrate thereof. More particularly, the present invention
`relates to an aqueous liquid preparation containing 2-amino
`3-(4-bromobenZoyl)phenylacetic acid or a pharmacologi
`cally acceptable salt thereof or a hydrate thereof and an alkyl
`aryl polyether alcohol type polymer or a polyethylene glycol
`fatty acid ester.
`
`BACKGROUND ART
`
`BenZoylphenylacetic acid derivatives including bromfenac
`(generic name) of formula (I):
`
`COOH
`
`Br
`
`of Which chemical name is 2-amino-3-(4-bromobenZoyl)
`phenylacetic acid are knoWn as disclosed in JP-A-23052/
`1977 and its corresponding US. Pat. No. 4,045,576.
`2-Amino-3-(4-bromobenZoyl)phenylacetic acid, its pharma
`cologically acceptable salt and a hydrate thereof are knoWn as
`a non-steroidal anti-in?ammatory agent, and they are effec
`tive against in?ammatory diseases of anterior or posterior
`segment of the eye, such as blepharitis, conjunctivitis, scleri
`tis, and postoperative in?ammation in the ?eld of ophthal
`mology, and its sodium salt has been practically used in the
`form of eye drops (“New Drugs in Japan, 2001”, 2001 Edi
`tion, Published by Yakuji Nippo Ltd., May 11, 2001, p.
`27-29).
`The eye drop as mentioned above is designed to stabiliZe
`2-amino-3-(4-bromobenZoyl)phenylacetic acid by means of
`addition of a Water-soluble polymer (e.g. polyvinylpyrroli
`done, polyvinyl alcohol, etc.) and a sul?te (eg sodium
`sul?te, potassium sul?te, etc.) (Japanese patent No. 2,683,
`676 and its corresponding US. Pat. No. 4,910,225).
`In addition, as an eye drop other than the above-mentioned
`one, Japanese patent No. 2,954,356 (corresponding to US.
`Pat. Nos. 5,603,929 and 5,653,972) discloses a stable oph
`thalmic composition Which comprises incorporating an anti
`bacterial quaternary ammonium polymer and boric acid into
`an acidic ophthalmic agent. The acidic agent described
`therein includes, for example, 2-amino-3-(4-bromobenZoyl)
`phenylacetic acid.
`Further, in Japanese patent No. 2,954,356, there is the
`folloWing description-“BenZalkonium chloride is a Widely
`used preservative in ophthalmic solutions. HoWever, benZa
`lkonium chloride and other quaternary ammonium com
`
`2
`pounds are generally considered to be incompatible With
`ophthalmic compositions of drugs With acidic groups, such as
`nonsteroidal anti-in?ammatory drugs. These preservatives
`lose their ability to function as they form complexes With the
`charged drug compounds”.
`In these prior art references, there is no disclosure that alkyl
`aryl polyether alcohol type polymers or polyethylene glycol
`fatty acid esters are able to stabiliZe an aqueous liquid prepa
`ration of 2-amino-3-(4-bromobenZoyl)phenylacetic acid or
`its pharmacologically acceptable salt, and inhibit decrease in
`preservative effect of benZalkonium chloride and other qua
`ternary ammonium compounds.
`
`DISCLOSURE OF THE INVENTION
`
`It is an object of the present invention to provide an aque
`ous liquid preparation comprising 2-amino-3-(4-bromoben
`Zoyl)phenylacetic acid or a pharmacologically acceptable salt
`thereof or a hydrate thereof, Which is stable Within a pH range
`giving no irritation to eyes and in Which, When a preservative
`such as benZalkonium chloride is incorporated therein, pre
`servative effect of the preservative does not substantially
`deteriorate.
`Another object of the invention is to provide a method for
`stabiliZing an aqueous liquid preparation of 2-amino-3-(4
`bromobenZoyl)phenylacetic acid or a pharmacologically
`acceptable salt thereof or a hydrate thereof.
`Further object of the invention is to provide an aqueous
`liquid preparation comprising 2-amino-3-(4-bromobenZoyl)
`phenylacetic acid or a pharmacologically acceptable salt
`thereof or a hydrate thereof and a preservative, Wherein, When
`speci?cally a quaternary ammonium salt such as benzalko
`nium chloride is incorporated as a preservative, decrease in
`preservative effect of said preservative is inhibited.
`As a result of various studies, the inventors of the present
`invention have found that, by adding, for example, an alkyl
`aryl polyether alcohol type polymer such as tyloxapol, or a
`polyethylene glycol fatty acid ester such as polyethylene
`glycol monostearate to an aqueous liquid preparation of
`2-amino-3-(4-bromobenZoyl)phenylacetic acid or a pharma
`cologically acceptable salt thereof or a hydrate thereof, the
`aqueous solution becomes stable Within a pH range giving no
`irritation to eyes, and change of the 2-amino-3-(4-bromoben
`Zoyl)phenylacetic acid over time can be inhibited, and fur
`thermore, When the aqueous solution contains a preservative,
`deterioration in the preservative effect of said preservative
`can be inhibited for a long period of time. The inventors of the
`present invention have further studied extensively and com
`pleted the present invention.
`Namely, the present invention relates to:
`(1) An aqueous liquid preparation comprising 2-amino-3-(4
`bromobenZoyl)phenylacetic acid or a pharmacologically
`acceptable salt thereof or a hydrate thereof, and an alkyl aryl
`polyether alcohol type polymer or a polyethylene glycol fatty
`acid ester,
`(2) The aqueous liquid preparation according to the above (1),
`Wherein the alkyl aryl polyether alcohol type polymer has a
`polymeriZation degree of 3 to 10, the alkyl contains 1 to 18
`carbon atoms, the aryl is a phenyl residue, and the polyether
`alcohol is represented by the formula O(CH2CH2O),€H in
`Which X is an integer of 5 to 100,
`(3) The aqueous liquid preparation according to the above (1)
`or (2), Wherein the alkyl aryl polyether alcohol type polymer
`is tyloxapol,
`(4) The aqueous liquid preparation according to the above (1),
`Wherein the carbon number of the fatty acid in the polyethyl
`ene glycol fatty acid ester is 12 to 18,
`
`5
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Metrics EX1001, Page 3
`
`

`
`US 8,669,290 B2
`
`3
`(5) The aqueous liquid preparation according to the above (1)
`or (4), Wherein the polyethylene glycol fatty acid ester is
`polyethylene glycol monostearate,
`(6) The aqueous liquid preparation according to any one of
`the above (1) to (3), Wherein the concentration of the alkyl
`aryl polyether alcohol type polymer is selected from a range
`of minimum concentration of 0.01 W/v % to maximum con
`centration of 0.5 W/v %,
`(7) The aqueous liquid preparation according to any one of
`the above (1), (2) or (4), Wherein the concentration of the
`polyethylene glycol fatty acid ester is selected from a range of
`minimum concentration of 0.02 W/v % to maximum concen
`tration of 0.1 W/v %,
`(8) The aqueous liquid preparation according to any one of
`the above (1) to (7), Wherein the concentration of the
`2-amino-3-(4-bromobenZoyl)phenylacetic acid or a pharma
`cologically acceptable salt thereof or a hydrate thereof is 0.01
`to 0.5 W/v %,
`(9) The aqueous liquid preparation according to any one of
`the above (1) to (8), Wherein benZalkonium chloride is con
`tained as a preservative,
`(10) The aqueous liquid preparation according to anyone of
`the above (1) to (9), Wherein the pharmacologically accept
`able salt of 2-amino-3-(4-bromobenZoyl)phenylacetic acid is
`a sodium salt,
`(1 l) The aqueous liquid preparation according to any one of
`the above (1) to (10), Wherein the pH of the aqueous liquid
`preparation is Within a range of 7 to 9,
`(12) The aqueous liquid preparation according to the above
`(11), Wherein the pH of the aqueous liquid preparation is
`Within a range of 7.5 to 8.5,
`(13) The aqueous liquid preparation according to any one of
`the above (1) to (12), Wherein the aqueous liquid preparation
`is an eye drop,
`(14) The aqueous liquid preparation according to any one of
`the above (1) to (12), Wherein the aqueous liquid preparation
`is a nasal drop,
`(15) An eye drop comprising sodium 2-amino-3-(4-bro
`mobenZoyl)phenylacetate hydrate and 0.01 to 0.5 W/v % of
`tyloxapol,
`(16) An eye drop comprising sodium 2-amino-3-(4-bro
`mobenZoyl)phenylacetate hydrate and 0.02 to 0.1 W/v % of
`polyethylene glycol monostearate,
`(17) A method for stabiliZing 2-amino-3-(4-bromobenZoyl)
`phenylacetic acid or a pharmacologically acceptable salt
`thereof or a hydrate thereof in an aqueous liquid preparation,
`Which comprises incorporating tyloxapol or polyethylene
`glycol monostearate into an aqueous liquid preparation con
`taining 2-amino-3-(4-bromobenZoyl)phenylacetic acid or a
`pharmacologically acceptable salt thereof or a hydrate
`thereof, and
`(18) A method for inhibiting decrease in preservative effect of
`a preservative in an aqueous liquid preparation of 2-amino
`3-(4-bromobenZoyl)phenylacetic acid or a pharmacologi
`cally acceptable salt thereof or a hydrate thereof, Which com
`prises incorporating tyloxapol or polyethylene glycol
`monostearate into an aqueous liquid preparation containing
`2-amino-3-(4-bromobenZoyl)phenylacetic acid or a pharma
`cologically acceptable salt thereof or a hydrate thereof and a
`preservative.
`According to the present invention, a stable aqueous liquid
`preparation containing 2-amino-3-(4-bromobenZoyl)pheny
`lacetic acid or a pharmacologically acceptable salt thereof or
`a hydrate thereof can be prepared by incorporating an alkyl
`aryl polyether alcohol type polymer such as tyloxapol, or a
`polyethylene glycol fatty acid ester such as polyethylene
`glycol monostearate into an aqueous liquid preparation con
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`taining 2-amino-3-(4-bromobenZoyl)phenylacetic acid or a
`pharmacologically acceptable salt thereof or a hydrate
`thereof. Also, an aqueous liquid preparation of the present
`invention, Wherein a preservative is incorporated, has a suf
`?cient preservative effect.
`Therefore, the aqueous liquid preparation of the present
`invention is advantageously used as an eye drop for the treat
`ment of, for example, blepharitis, conjunctivitis, scleritis, and
`postoperative in?ammation. In addition, such aqueous liquid
`preparation can be used as a nasal drop for the treatment of,
`for example, allergic rhinitis and in?ammatory rhinitis (e.g.
`chronic rhinitis, hypertrophic rhinitis, nasal polyp, etc.).
`The pharmacologically acceptable salt of 2-amino-3-(4
`bromobenZoyl)phenylacetic acid includes, for example, an
`alkali metal salt such as sodium salt and potassium salt, and
`an alkaline earth metal salt such as calcium salt and magne
`sium salt, among Which sodium salt is especially preferable.
`2-Amino-3-(4-bromobenZoyl)phenylacetic acid and its
`pharmacologically acceptable salt can be prepared according
`to the method as described in JP-A-23052/l 977 (correspond
`ing to Us. Pat. No. 4,045,576) or by a similar method thereof.
`These compounds can be obtained as their hydrate depending
`on synthetic conditions and recrystallization conditions. The
`hydrate includes 1/2 hydrate, l hydrate, and 3/ 2 hydrate,
`among Which 3/2 hydrate is preferable.
`In the aqueous liquid preparation of the present invention,
`the content (concentration range) of 2-amino-3-(4-bro
`mobenZoyl)phenylacetic acid or a pharmacologically accept
`able salt thereof or a hydrate thereof is usually about 0.01 to
`0.5 W/v %, preferably about 0.05 to 0.2 W/v %, especially
`about 0.1 W/v %, and it is preferable to appropriately vary the
`content depending on the purpose of use and the degree of
`disease to be treated.
`The carbon number of the alkyl in the an alkyl aryl poly
`ether alcohol type polymer Which is a non-ionic surfactant
`used as a stabiliZer for 2-amino-3-(4-bromobenZoyl)pheny
`lacetic acid or a pharmacologically acceptable salt thereof or
`a hydrate thereof is approximately 1 to 18. Speci?cally, the
`alkyl group includes, for example, methyl, ethyl, propyl, iso
`propyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
`cyclobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, l-ethyl
`propyl, 4-methylpentyl, l,l-dimethylbutyl, 2,2-dimethylbu
`tyl, l,2-dimethylbutyl, 2-ethylbutyl, cyclopentyl, hexyl,
`cyclohexyl, heptyl, isoheptyl, octyl, isooctyl, nonyl,
`isononyl, decyl, isodecyl, undecyl, isoundecyl, dodecyl, isod
`odecyl, tridecyl, isotridecyl, tetradecyl, isotetradecyl, penta
`decyl, isopentadecyl, hexadecyl, isohexadecyl, heptadecyl,
`isoheptadecyl, octadecyl, isooctadecyl, and isomers thereof,
`among Which octyl and its isomer (e.g. isooctyl, sec-octyl,
`l-methylheptyl, l-ethylhexyl, 2-ethylhexyl, l-propylpentyl,
`l,5-dimethylhexyl, l,l,3,3-tetramethylbutyl, etc.) are prefer
`able, and l,l,3,3-tetramethylbutyl Which is an isomer of octyl
`groups is especially preferable.
`The aryl in the alkyl aryl polyether alcohol type polymer
`can be preferably a phenyl residue. The polyether alcohol can
`be represented by the formula O(CH2CH2O)xH in Which X is
`an integer of 5 to 100, preferably 5 to 30, more preferably 8 to
`10. The average polymerization degree is preferably about 3
`to 10.
`Among the above-mentioned alkyl aryl polyether alcohol
`type polymers, tyloxapol having the folloWing formula is
`especially preferable.
`
`Metrics EX1001, Page 4
`
`

`
`US 8,669,290 B2
`
`CH3
`
`CH3
`
`C(CH3)3
`R: (CHZCHZO) XH
`X Z 8-10
`
`In < 6
`
`6
`mobenZoyl)phenylacetic acid or its pharmacologically
`acceptable salt or a hydrate thereof.
`The preservative used in the present invention includes, for
`example, quaternary ammonium salts (e.g. benZalkonium
`chloride, benZethonium chloride, etc.), chlorhexidine glu
`conate, and the like, among Which benZalkonium chloride is
`especially preferable.
`Further, so long as the purpose of the present invention is
`achieved, conventional various additives such as isotonics,
`buffers, thickners, stabiliZers, chelating agents, pH control
`ling agents, perfumes and the like may be appropriately added
`to the aqueous liquid preparation of the present invention. The
`isotonics include sodium chloride, potassium chloride, glyc
`erine, mannitol, sorbitol, boric acid, glucose, propylene gly
`col and the like. The buffers include, for example, phosphate
`buffer, borate buffer, citrate buffer, tartarate buffer, acetate
`buffer, boric acid, borax, amino acids, and the like. The thick
`ners include polyvinylpyrrolidone, carboxymethylcellulose,
`carboxypropylcellulose, hydroxyethylcellulose, hydrox
`ypropylcellulose, hydroxypropylmethylcellulose, polyvinyl
`alcohol, sodium polyacrylate, and the like. The stabiliZers
`include sul?tes such as sodium sul?te and the like. The chelat
`ing agents include sodium edetate, sodium citrate, condensed
`sodium phosphate and the like. The pH controlling agents
`include hydrochloric acid, sodium hydroxide, phosphoric
`acid, acetic acid and the like. The perfumes include l-men
`thol, borneol, camphor, Eucalyptus oil, and the like.
`With respect to the concentrations of the above various
`additives in the aqueous liquid preparation of the present
`invention,
`the isotonic is incorporated into an osmotic pressure ratio of
`about 0.8 to 1.2, and the concentrations of the buffer and the
`thickner to be added are about 0.01 to 2 W/v % and 0.1 to 10
`W/v %, respectively.
`The pH of the aqueous liquid preparation of the present
`invention is adjusted to about 6 to 9, preferably about 7 to 9,
`especially about 7.5 to 8.5.
`So long as the purpose of the present invention is achieved,
`other same or different kind of active ingredients may be
`appropriately added.
`The aqueous liquid preparation of the present invention can
`be prepared by per se knoWn method or according to the
`method as described in the Japanese Pharmacopoeia, 14th
`Edition, General Rules for Preparations, Solutions or Oph
`thalmic solutions.
`The aqueous liquid preparation of the present invention can
`be applied to Warm-blooded animals such as human, rat,
`mouse, rabbit, coW, pig, dog, cat, and the like.
`The aqueous liquid preparation of the present invention can
`be prepared easily by dissolving the above-mentioned com
`ponents in, for example, distilled Water or sterile puri?ed
`Water. For example, the aqueous liquid preparation in the
`form of an eye drop can be used for the treatment of in?am
`matory diseases in anterior or posterior segment of the eye
`such as blepharitis, conjunctivitis, scleritis, postoperative
`in?ammation, and the like. The dose of the aqueous liquid
`preparation containing 0.1 W/v % of sodium 2-amino-3-(4
`bromobenZoyl)phenylacetate hydrate is, for example, admin
`istered to an adult 3 to 6 times daily in an amount of l to 2
`drops per one time. Depending on the degree of diseases,
`frequency of dosing is appropriately controlled.
`
`The fatty acid of the polyethylene glycol fatty acid ester
`Which is a non-ionic surfactant used as a stabilizer for
`2-amino-3-(4-bromobenZoyl)phenylacetic acid or a pharma
`cologically acceptable salt thereof or a hydrate thereof can be
`preferably a fatty acid having the carbon number of 12 to 18.
`Speci?c examples of such polyethylene glycol fatty acid
`esters are polyethylene glycol monostearate (e.g. polyoxyl 8
`stearate, polyoxyl 40 stearate, etc.), polyethylene glycol
`monolaurate, polyethylene glycol monooleate, polyethylene
`glycol diisostearate, polyethylene glycol dilaurate, polyeth
`ylene glycol dioleate, and the like. Among these compounds,
`polyethylene glycol monostearate is preferable, and polyoxyl
`40 stearate is especially preferable. The polyoxyl 40 stearate
`is a monostearic acid ester of an ethylene oxide condensed
`polymer, and can be represented by the formula C17H35COO
`(CH2CH2O)nH Which is a non-ionic surfactant and n is about
`40.
`Although the content (concentration range) of the alkyl
`aryl polyether alcohol type polymer in the aqueous liquid
`preparation of the present invention depends on the kind of
`compounds used, the minimum concentration is about 0.01
`W/v % and the maximum concentration is about 0.5 W/v %.
`With respect to the tyloxapol content (concentration range),
`for example, the minimum content is about 0.01 W/v %, 0.02
`W/v % or 0.03 W/v %, and the mamximum content is about
`0.05 W/v %, 0.1 W/v %, 0.3 W/v % or 0.5% W/v, and preferably
`the minimum content is about 0.02 W/v % and the maximum
`content is about 0.05 W/v %.
`Although the content (concentration range) of the polyeth
`ylene glycol fatty acid ester in the aqueous liquid preparation
`of the present invention depends on the kind of compounds
`used, it is Within a range of about 0.02 W/v % of minimum
`concentration to about 0.1 W/v % of maximum concentration.
`For example, the content (concentration range) of polyethyl
`ene glycol monostearate is Within a range of about 0.02 W/v %
`of minimum content to about 0.1 W/v % of maximum content,
`and preferably Within a range of about 0.02 W/v % of the
`minimum content to about 0.05 W/v % of the maximum
`content.
`The incorporation ratio of tyloxapol in the aqueous liquid
`preparation of the invention is Within a range of the minimum
`content of about 0.1 or 0.2 part by Weight to the maximum
`content of about 0.5, 1,3 or 5 parts by Weight, relative to 1 part
`by Weight of 2-amino-3-(4-bromobenZoyl)phenylacetic acid
`or its pharmacologically acceptable salt or a hydrate thereof.
`The incorporation ratio of polyethylene glycol monostear
`ate in the aqueous liquid preparation of the present invention
`is Within a range of the minimum content of about 0.2 part by
`Weight to the maximum content of about 0.5 or 1 part by
`Weight, relative to 1 part by Weight of 2-amino-3-(4-bro
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Metrics EX1001, Page 5
`
`

`
`7
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`8
`0.02 W/v % of tyloxapol is more stable than that in composi
`tion A-02 containing 0.15 W/v % of tyloxapol.
`
`US 8,669,290 B2
`
`The present invention is illustrated by Way of the following
`Experimental Examples and Working Examples, but it is not
`restricted by these Examples.
`
`Experimental Example 2
`
`Experimental Example 1
`
`Stability Test of Sodium
`2-amino-3-(4-bromobenZoyl)phenylacetate
`
`Stability Test of Sodium
`2-amino-3-(4-bromobenZoyl)phenylacetate
`
`10
`
`Four eye drops of sodium 2-amino-3-(4-bromobenZoyl)
`phenylacetate comprising the components as shoWn in Table
`1 Were prepared, ?lled respectively into a polypropylene con-
`tainer and subjected to stability test at 600 C.
`
`Five eye drops of sodium 2-amino-3-(4-bromobenZoyl)
`phenylacetate comprising the components as shoWn in Table
`2 Were prepared, ?lled respectively into a polypropylene con
`tainer and preserved at 60° C. for 4 Weeks, and then the
`content of 2-amino-3-(4-bromobenZoyl)phenylacetic acid
`and the pH in each eye drop Were measured.
`
`TABLE 2
`
`Components
`
`A-04
`
`A-05
`
`A-06
`
`A-07
`
`A-08
`
`0.1 g
`
`Sodium 2-amino-3-(4-
`bromobenzoyl)phenyl—
`acetate
`1.1 g
`Boric acid
`1.1 g
`Borax
`Benzalkonium chloride 0.005 g
`
`Polysorbate 80
`
`i
`
`i
`
`i
`
`i
`
`Tyloxapol
`
`0.02 g
`
`0.05 g
`
`0.03 g i
`
`0.1g
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`1.1 g
`1.1 g
`0.005 g
`
`1.1 g
`1.1 g
`0.005 g
`
`1.1 g
`1.1 g
`0.005 g
`
`i
`2.0 g
`
`0.02 g
`q.s.
`q.s.
`
`i
`2.0 g
`
`0.02 g
`2.0 g
`
`0.02 g
`q.s.
`q.s.
`
`0.02 g
`q.s.
`q.s.
`
`1.1 g
`1.1 g
`0.005 g
`
`i
`
`i
`
`0.05 g
`1.0 g
`
`0.02 g
`q.s.
`q.s.
`
`Polyoxyl 40 stearate i
`Polyvinyl-
`2.0 g
`pyrrolidone (K-30)
`Sodium edetate
`Sodium hydroxide
`Sterile puri?ed
`Water
`Total volume
`pH
`60° C.,
`4 Weeks
`
`0.02 g
`q.s.
`q.s.
`
`100 mL 100 mL
`8.17
`8.16
`Remaining 92.6
`90.9
`rate (%)
`pH
`
`8.15
`
`8.16
`
`100 mL 100 mL
`8.15
`8.19
`92.0
`93.4
`
`100 mL
`8.19
`93.1
`
`8.15
`
`8.13
`
`8.14
`
`TABLE 1
`
`Component
`
`Companson
`Example 1
`
`A-01
`
`A-02
`
`A-03
`
`0.1 g
`
`Sodium 2-amino-3-(4-
`bromob?nzoyl)
`1 5 g
`gllerlfcyglcciitm
`Benzalkonium chloride 0.005 g
`Polysorbate 80
`0.15 g
`PolyoXyl 40 Swarm *
`gtyl‘é’l‘apm ,? d
`t i
`er1epur1 e Wa er
`q.s.
`Total volum?
`100 mL
`pH
`7_@
`Remaining rate (%) at
`51.3
`60° C- aim 4 W?eks
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`1 5 g
`1 5 g
`1 5 g
`0.005 g
`0.005 g
`0.005 g
`i
`i
`i
`i
`0-15 g i
`0'02 g
`i
`0'15 g
`q.s
`q.s.
`q.s.
`100 mL 100 mL 100 mL
`7_@
`7_@
`7_@
`63.7
`73.8
`89.6
`
`The remaining rate (%) in the above Table 1 indicates
`values obtained by correcting moisture vaporiZation from the
`container. As is apparent from the Table 1, stability test Was
`carried out under the conditions of pH 7.0 at 600 C. for 4
`Weeks, and sodium 2-amino-3-(4-bromobenZoyl)phenylac
`etate in each eye drop Was stable in the order of tyloxapol
`containing preparation>polyoxyl 40 stearate-containing
`preparation>polysorbate 80-containing preparation.
`Further, With respect to eye drops containing tyloxapol
`(compositions A-02 and A-03), sodium 2-amino-3-(4-bro
`mobenZoyl)phenylacetate in composition A-03 containing
`
`55
`
`60
`
`65
`
`Table 2 shoWs the remaining rate and the pH of sodium
`40 2-amino-3-(4-bromobenZoyl)phenylacetate after storage at
`600 C. for 4 Weeks, When the remaining rate of sodium
`.
`.
`2-am1no-3-(4-bromobenZoyl)phenylacetate at the time of
`production of eye drops is set to 100%. The remaining rate is
`a value obtained by correcting moisture vaporiZation from the
`45 container. As is apparent from Table 2, the remaining rate of
`S°d1um_ 2911111106-(4-br0m0benzoyhphenylacewre 11} The
`compos1t1ons A-04, A-05, A-06, A-07 and A-08 conta1mng
`0.02 W/v %, 0.03 W/v % and 0.05 W/v % oftyloxapol or 0.02
`50 W/v % and 0.05 W/v % ofpolyoxyl 40 stearate is not less than
`0
`o
`.
`.
`.
`90%) after storage at 60 C. for4 Weeks, vvhich 1nd1cates that
`those compos1t1ons have su?iclent stab1l1ty for eye drops.
`
`Experimental Example 3
`
`Preservative Effect Test of Aqueous Liquid
`Preparation Containing Sodium
`2-amino-3-(4-bromobenZoyl)phenylacetate
`
`Preservative effect test of compositions A-04, A-05 and
`A-07 of Experimental Example 2 Was carried out against
`Staphylococcus aureus (hereinafter referred to as S. aureus),
`Escherichia Cali (hereinafter referred to as E. coli),
`Pseudomonas aeruginosa (hereinafter referred to as R
`aeruginosa), Candida albicans (hereinafter referred to as C.
`albicans) and Aspergillus niger (hereinafter referred to as A.
`niger).
`
`Metrics EX1001, Page 6
`
`

`
`9
`The results are shown in Tables 3-1, 3-2 and 3-3.
`
`10
`
`US 8,669,290 B2
`
`TABLE 3-1
`
`Cell count (CFU/mL)
`
`A-04
`
`5. 611478143
`E. COZi
`P aeruginosa
`c. albicans
`A. niger
`
`Inoculum
`count
`
`2.1 X 106
`6.5 X 106
`5.8 X 106
`3.2 X 105
`1.8 X 105
`
`6 hours
`after
`inoculation
`
`24 hours
`after
`inoculation
`
`7 days
`after
`inoculation
`
`14 days
`after
`inoculation
`
`21 days
`after
`inoculation
`
`28 days
`after
`inoculation
`
`3.0 X101
`0
`0
`i
`i
`
`0
`0
`0
`i
`i
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`TABLE 3-2
`
`Cell count (CFU/mL)
`
`A-05
`
`5. 611478143
`E. COZi
`P aeruginosa
`c. albicans
`A. niger
`
`Inoculum
`count
`
`2.1><106
`6.5 X 106
`5.8 X 106
`3.2 X 105
`1.8 X 105
`
`6 hours
`after
`inoculation
`
`24 hours
`after
`inoculation
`
`7 days
`after
`inoculation
`
`14 days
`after
`inoculation
`
`21 days
`after
`inoculation
`
`28 days
`after
`inoculation
`
`1.7><105
`0
`0
`i
`i
`
`2.0><10l
`0
`0
`i
`i
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`TABLE 3-3
`
`Cell count (CFU/mL)
`
`A-07
`
`5. 611478143
`E. COZi
`P aeruginosa
`c. albicans
`A. niger
`
`Inoculum
`count
`
`2.7 ><106
`7.4 X 106
`8.8 X 106
`4.6 X 105
`1.0 X 105
`
`6 hours
`after
`inoculation
`
`24 hours
`after
`inoculation
`
`7 days
`after
`inoculation
`
`14 days
`after
`inoculation
`
`21 days
`after
`inoculation
`
`28 days
`after
`inoculation
`
`3.1 X 104
`0
`0
`i
`i
`
`0
`0
`0
`i
`i
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`50
`
`Example 1
`
`Eye Drop
`
`.
`
`.
`
`55
`
`Viable cell count of fungi (C. albicans, A. niger) 14 days
`_
`AS 15 apparent from Tables 3'1’ 3'2 and 3'3’ the Preserve" 4 after inoculation decreases to not more than 1/ 10, and there
`tiVe effect of Composition A'04 Was found to be Compatible
`after, the cell count keeps the same level as that of 14 days
`With EP-criteria A in European Pharmacopoeia (EP), and
`after inoculation
`those of compositions A-05 and A-07 Were found to be com
`patible With EP-criteria B.
`The EP-criteria A and EP-criteria B are given in the fol
`lowing.
`EP-Criteria A:
`V1able cell counts of bacteria (S. aureus, P aeruginosa) 6
`hours, 24 hours, and 28 days after 1noculat1on decrease to not
`more than 1/100, not more than 1/ 1000, and undetectable,
`.
`1
`respecnve y‘
`V1able cell count of fungi (C. albicans, A. niger) 7 hours
`ft
`.
`1 t.
`d
`t
`t
`th 1/100
`dth
`a er 1nocu a 1on ecreases o no more an
`, an
`ere-
`after, the cell count levels off or decreases.
`.
`.
`EP-Cr lter 121 B
`V1able cell counts of bacteria (S. aureus, R aeruginosa) 24
`.
`.
`hours and 7 days after 1noculat1on decrease to not more than 65
`1/ 10 and not more than 1/ 1000, respectively, and thereafter,
`the cell count levels off or decreases.
`
`Sodlum 2'am1n°'3'(4'
`brornobenzoyl)phenylacetate 3/2 hydrate
`Boric acid
`I
`Borax
`I
`60 Benzalkonium chloride
`Tyloxapol
`Polyvinylpyrrolidone (K-30)
`Sodium edetate
`Sodium hydroxide
`Sterile puri?ed Water
`
`0-1 g
`1.1 g
`1-1 g
`0.005 g
`002 g
`2.0 g
`0.02 g
`q.s.
`to make total volume
`of 100 mL
`PH 817
`
`M