111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008129431B2
`
`c12) United States Patent
`Sawa et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,129,431 B2
`Mar.6,2012
`
`(54) AQUEOUS LIQUID PREPARATION
`CONTAINING 2-AMIN0-
`3-( 4-BROMOBENZOYL)PHENYLACETIC
`ACID
`
`(75)
`
`Inventors: Shirou Sawa, Kobe (JP); Shuhei Fujita,
`Kakogawa (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 604 days.
`
`(21) Appl. No.:
`
`10/525,006
`
`(22) PCTFiled:
`
`Jan.16,2004
`
`(86) PCTNo.:
`
`PCT I JP2004/000350
`
`§ 371 (c)(l),
`(2), ( 4) Date: Mar. 28, 2005
`
`(87) PCT Pub. No.: W02004/064828
`
`PCT Pub. Date: May 8, 2004
`
`(65)
`
`Prior Publication Data
`
`US 2005/0239895 Al
`
`Oct. 27, 2005
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 21, 2003
`
`(JP) ................................... 2003-12427
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`Int. Cl.
`A01N 37118
`(2006.01)
`A01N 37144
`(2006.01)
`A01N 37110
`(2006.01)
`A61K 311165
`(2006.01)
`A61K 31124
`(2006.01)
`A61K 31119
`(2006.01)
`U.S. Cl. ......... 514/619; 514/535; 514/570; 514/618
`Field of Classification Search .................. 514/567,
`514/619, 535, 570; 424/486
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,045,576 A
`8/1977 Welstead, Jr. et a!.
`7/1987 Poser
`4,683,242 A
`4,910,225 A
`3/1990 Ogawa eta!.
`5,110,493 A
`5/1992 Cherng-Chyi eta!.
`5,475,034 A *
`12/1995 Yanni et al .................... 514/619
`5,540,930 A *
`7/1996 Guy eta!. ..................... 424/427
`111997 Bergamini eta!.
`5,597,560 A
`5,603,929 A *
`2/1997 Desai eta!. ................ 424/78.04
`8/1997 Desai eta!.
`5,653,972 A
`5,998,465 A *
`12/1999 Hellberg et al ............... 514/432
`6,319,513 B1 *
`1112001 Dobrozsi ...................... 424/434
`6,369,112 B1*
`4/2002 Xia ............................... 514/635
`
`6,383,471 B1
`6,395,746 B1
`2007/0082857 A1 *
`
`5/2002 Chen et a!.
`5/2002 Cagle eta!.
`4/2007 Sawa .............................. 514/35
`
`AU
`CA
`JP
`JP
`wo
`wo
`wo
`wo
`wo
`
`FOREIGN PATENT DOCUMENTS
`9/1995
`707 119
`9/1990
`2 013 188
`8/1993
`5-223052
`8/1999
`11-228404
`5/1996
`96/14829
`3/2001
`01115677
`WO 01115677 A2 *
`3/2001
`WO 0115677 A2 *
`3/2001
`02/13804
`212002
`
`OTHER PUBLICATIONS
`
`ISTA Pharmaceuticals; "New Drug Applications: Xibrom", http://
`www.drugs.com/nda/xibrom_040525.html, accessed online Sep.
`19, 2007.*
`Nolan, et al.; The topical anti-inflammatory and analgesic properties
`ofbromfenic in rodents:; Agents and Actions; Aug. 1988; 25( 1-2):77-
`8 5, abstract.*
`Nolan, eta!. ("The topicla anti-inflammatory and analgesic proper(cid:173)
`ties of bromfenac in rodents"; 1988; Agents and Actions; 25(1-2):
`77-85.*
`New Drugs in Japan, 2001, 2001 Edition, Published by Yakuji Nippo
`Ltd., May 11, 2001, pp. 27-29, and its English translation of the
`material portions.
`Corrected partial English translation of New Drugs in Japan, 2001,
`2001 Edition, Published byYakuji 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 connection
`with the corresponding European patent application and Opposition.
`http:/ /medical-dictionary. thefreedictionary.com/prophylactic _ac(cid:173)
`cessed Dec. 15, 2009.
`* cited by examiner
`
`Primary Examiner- Sreeni Padmanabhan
`Assistant Examiner- Layla Soroush
`(7 4) Attorney, Agent, or Firm - Wenderoth, Lind & Ponack,
`L.L.P.
`
`ABSTRACT
`(57)
`An aqueous liquid preparation of the present invention con(cid:173)
`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 mono stearate is stable. Since even in the case where a
`preservative is incorporated into said aqueous liquid prepa(cid:173)
`ration, the preservative exhibits a sufficient 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 inflammation.
`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 inflammatory rhinitis (e.g. chronic rhini(cid:173)
`tis, hypertrophic rhinitis, nasal polyp, etc.).
`
`22 Claims, No Drawings
`
`Page 1 of 8
`
`SENJU EXHIBIT 2001
`LUPIN v. SENJU
`IPR2015-01105
`
`

`
`US 8,129,431 B2
`
`1
`2
`AQUEOUS LIQUID PREPARATION
`nonsteroidal anti-inflannnatory drugs. These preservatives
`CONTAINING
`lose their ability to function as they form complexes with the
`2-AMIN0-3-(4-BROMOBENZOYL)PHENYLACETIC charged drug compounds".
`ACID
`In these prior art references, there is no disclosure that alkyl
`5 aryl polyether alcohol type polymers or polyethylene glycol
`fatty acid esters are able to stabilize an aqueous liquid prepa(cid:173)
`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-
`10 ternary annnonium compounds.
`
`This application is a U.S. national stage of International
`Application No. PCT/JP2004/000350 filed Jan. 16, 2004.
`
`TECHNICAL FIELD
`
`DISCLOSURE OF THE INVENTION
`
`15
`
`The present invention relates to an aqueous liquid prepa(cid:173)
`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(cid:173)
`cally acceptable salt thereof or a hydrate thereof and an alkyl
`aryl poly ether alcohol type polymer or a polyethylene glycol
`fatty acid ester.
`
`BACKGROUND ART
`
`Benzoylphenylacetic acid derivatives including bromfenac
`(generic name) offormula (I):
`
`COOH
`
`Br
`
`It is an object of the present invention to provide an aque-
`ous liquid preparation comprising 2-amino-3-( 4-bromoben(cid:173)
`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
`20 such as benzalkonium chloride is incorporated therein, pre(cid:173)
`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-
`25 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
`30 thereof or a hydrate thereof and a preservative, wherein, when
`specifically a quaternary annnonium salt such as benzalko(cid:173)
`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
`40 2-amino-3-( 4-bromobenzoyl)phenylacetic acid or a pharma(cid:173)
`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(cid:173)
`zoyl)phenylacetic acid over time can be inhibited, and fur-
`45 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 poly ether alcohol type polymer or a polyethylene gly(cid:173)
`col 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 of3 to 10, the alkyl contains 1 to
`18 carbon atoms, the aryl is a phenyl residue, and the
`the
`formula
`represented by
`polyether alcohol
`is
`O(CH2CH20)xH 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 poly(cid:173)
`mer is tyloxapol,
`( 4) The aqueous liquid preparation according to the above (1 ),
`wherein the carbon number of the fatty acid in the polyeth(cid:173)
`ylene glycol fatty acid ester is 12 to 18,
`
`35
`
`of which chemical name is 2-amino-3-( 4-bromobenzoyl)
`phenylacetic acid are known as disclosed in JP-A-23052/
`1977 and its corresponding U.S. Pat. No. 4,045,576.
`2-Amino-3-( 4-bromobenzoyl)phenylacetic acid, its pharma(cid:173)
`cologically acceptable salt and a hydrate thereof are known as
`a non-steroidal anti-inflmatory agent, and they are effec(cid:173)
`tive against inflmatory diseases of anterior or posterior
`segment of the eye, such as blepharitis, conjunctivitis, scleri-
`tis, and postoperative inflannnation in the field of ophthal(cid:173)
`mology, and its sodium salt has been practically used in the
`form of eye drops ("New Drugs in Japan, 2001", 2001 Edi(cid:173)
`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- 50
`done, polyvinyl alcohol, etc.) and a sulfite (e.g. sodium
`sulfite, potassium sulfite, etc.) (Japanese patent No. 2,683,
`676 and its corresponding U.S. 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 U.S. 55
`Pat. Nos. 5,603,929 and 5,653,972) discloses a stable oph(cid:173)
`thalmic composition which comprises incorporating an anti(cid:173)
`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) 60
`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(cid:173)
`lkonium chloride and other quaternary annnonium com(cid:173)
`pounds are generally considered to be incompatible with
`ophthalmic compositions of drugs with acidic groups, such as
`
`65
`
`Page 2 of 8
`
`

`
`US 8,129,431 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 5
`aryl polyether alcohol type polymer is selected from a
`range of minimum concentration of0.01 w/v% to maxi(cid:173)
`mum concentration of0.5 w/v %,
`(7) The aqueous liquid preparation according to any one of
`the above (1), (2) or (4), wherein the concentration of the 10
`polyethylene glycol fatty acid ester is selected from a range
`of minimum concentration of 0.02 w/v % to maximum
`concentration of0.1 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 phar(cid:173)
`macologically 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 20
`contained as a preservative,
`(10) The aqueous liquid preparation according to anyone of
`the above (1) to (9), wherein the pharmacologically accept(cid:173)
`able salt of2-amino-3-( 4-bromobenzoyl)phenylacetic acid
`is a sodium salt,
`(11) The aqueous liquid preparation according to any one of
`the above (1) to (1 0), wherein the pH of the aqueous liquid
`preparation is within a range of7 to 9,
`(12) The aqueous liquid preparation according to the above
`(11 ), wherein the pH of the aqueous liquid preparation is 30
`within a range of7 .5 to 8.5,
`(13) The aqueous liquid preparation according to any one of
`the above (1) to (12), wherein the aqueous liquid prepara(cid:173)
`tion is an eye drop,
`(14) The aqueous liquid preparation according to any one of 35
`the above (1) to (12), wherein the aqueous liquid prepara(cid:173)
`tion is a nasal drop,
`(15) An eye drop comprising sodium 2-amino-3-( 4-bro(cid:173)
`mobenzoyl)phenylacetate hydrate and 0.01 to 0.5 w/v% of
`tyloxapol,
`(16) An eye drop comprising sodium 2-amino-3-( 4-bro(cid:173)
`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 45
`thereof or a hydrate thereof in an aqueous liquid prepara(cid:173)
`tion, which comprises incorporating tyloxapol or polyeth(cid:173)
`ylene glycol mono stearate into an aqueous liquid prepara(cid:173)
`tion containing 2-amino-3-( 4-bromobenzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a 50
`hydrate thereof, and
`(18) A method for inhibiting decrease in preservative effect of
`a preservative in an aqueous liquid preparation of2-amino-
`3-(4-bromobenzoyl)phenylacetic acid or a pharmacologi(cid:173)
`cally acceptable salt thereof or a hydrate thereof, which 55
`comprises incorporating tyloxapol or polyethylene glycol
`monostearate into an aqueous liquid preparation contain(cid:173)
`ing 2-amino-3-( 4-bromobenzoyl)phenylacetic acid or a
`pharmacologically 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(cid:173)
`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 65
`polyethylene glycol fatty acid ester such as polyethylene
`glycol monostearate into an aqueous liquid preparation con-
`
`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(cid:173)
`ficient preservative effect.
`Therefore, the aqueous liquid preparation of the present
`invention is advantageously used as an eye drop for the treat(cid:173)
`ment of, for example, blepharitis, conjunctivitis, scleritis, and
`postoperative inflammation. In addition, such aqueous liquid
`preparation can be used as a nasal drop for the treatment of,
`for example, allergic rhinitis and inflammatory rhinitis (e.g.
`chronic rhinitis, hypertrophic rhinitis, nasal polyp, etc.).
`The pharmacologically acceptable salt of 2-amino-3-(4-
`15 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(cid:173)
`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-23052/1977 (correspond(cid:173)
`ing to U.S. Pat. No. 4,045,576) or by a similar method thereof.
`These compounds can be obtained as their hydrate depending
`25 on synthetic conditions and recrystallization conditions. The
`hydrate includes 1/2 hydrate, 1 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(cid:173)
`mobenzoyl)phenylacetic acid or a pharmacologically accept(cid:173)
`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(cid:173)
`ether alcohol type polymer which is a non-ionic surfactant
`used as a stabilizer for 2-amino-3-(4-bromobenzoyl)pheny-
`40 !acetic acid or a pharmacologically acceptable salt thereof or
`a hydrate thereof is approximately 1 to 18. Specifically, the
`alkyl group includes, for example, methyl, ethyl, propyl, iso(cid:173)
`propyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
`cyclobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethyl(cid:173)
`propyl, 4-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbu(cid:173)
`tyl, 1 ,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(cid:173)
`decyl, isopentadecyl, hexadecyl, isohexadecyl, heptadecyl,
`isoheptadecyl, octadecyl, isooctadecyl, and isomers thereof,
`among which octyl and its isomer (e.g. isooctyl, sec-octyl,
`1-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 1-propylpentyl,
`1,5-dimethylhexyl, 1,1,3,3-tetramethylbutyl, etc.) are prefer(cid:173)
`able, and 1,1,3,3-tetramethylbutyl which is an isomerofoctyl
`groups is especially preferable.
`The aryl in the alkyl aryl polyether alcohol type polymer
`can be preferably a phenyl residue. The poly ether alcohol can
`be represented by the formula O(CH 2CH20)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.
`
`60
`
`Page 3 of 8
`
`

`
`US 8,129,431 B2
`
`5
`
`R ~ (CH2CH20) xH
`X~ 8-10
`m<6
`
`6
`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(cid:173)
`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(cid:173)
`conate, and the like, among which benzalkonium chloride is
`10 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(cid:173)
`ling agents, perfumes and the like may be appropriately added
`15 to the aqueous liquid preparation of the present invention. The
`isotonics include sodium chloride, potassium chloride, glyc(cid:173)
`The fatty acid of the polyethylene glycol fatty acid ester
`erine, mannitol, sorbitol, boric acid, glucose, propylene gly(cid:173)
`which is a non-ionic surfactant used as a stabilizer for
`col and the like. The buffers include, for example, phosphate
`2-amino-3-( 4-bromobenzoyl)phenylacetic acid or a pharma(cid:173)
`buffer, borate buffer, citrate buffer, tartarate buffer, acetate
`20 buffer, boric acid, borax, amino acids, and the like. The thick(cid:173)
`cologically acceptable salt thereof or a hydrate thereof can be
`ners include polyvinylpyrrolidone, carboxymethylcellulose,
`preferably a fatty acid having the carbon number of 12 to 18.
`carboxypropylcellulose, hydroxyethylcellulose, hydrox(cid:173)
`Specific examples of such polyethylene glycol fatty acid
`ypropylcellulose, hydroxypropylmethylcellulose, polyvinyl
`esters are polyethylene glycol monostearate (e.g. polyoxyl 8
`25 alcohol, sodium polyacrylate, and the like. The stabilizers
`stearate, polyoxyl 40 stearate, etc.), polyethylene glycol
`include sulfites such as sodium sulfite and the like. The chelat-
`monolaurate, polyethylene glycol monooleate, polyethylene
`ing agents include sodium edetate, sodium citrate, condensed
`glycol diisostearate, polyethylene glycol dilaurate, polyeth(cid:173)
`sodium phosphate and the like. The pH controlling agents
`ylene glycol dioleate, and the like. Among these compounds,
`include hydrochloric acid, sodium hydroxide, phosphoric
`polyethylene glycol mono stearate is preferable, and polyoxyl
`40 stearate is especially preferable. The polyoxyl 40 stearate 30 acid, acetic acid and the like. The perfumes include !-men(cid:173)
`thol, borneol, camphor, Eucalyptus oil, and the like.
`is a monostearic acid ester of an ethylene oxide condensed
`With respect to the concentrations of the above various
`polymer, and can be represented by the formula C 17H35COO
`additives in the aqueous liquid preparation of the present
`(CH2CH20)nH which is a non-ionic surfactant and n is about
`invention, the isotonic is incorporated into an osmotic pres-
`40.
`35 sure ratio of about 0.8 to 1.2, and the concentrations of the
`Although the content (concentration range) of the alkyl
`buffer and the thickner to be added are about 0.01 to 2 w/v%
`aryl polyether alcohol type polymer in the aqueous liquid
`and 0.1 to 10 w/v %, respectively.
`preparation of the present invention depends on the kind of
`The pH of the aqueous liquid preparation of the present
`compounds used, the minimum concentration is about 0.01
`40 invention is adjusted to about 6 to 9, preferably about 7 to 9,
`w/v % and the maximum concentration is about 0.5 w/v %.
`especially about 7.5 to 8.5.
`With respect to the tyloxapol content (concentration range),
`So long as the purpose of the present invention is achieved,
`for example, the minimum content is about 0.01 w/v %, 0.02
`other same or different kind of active ingredients may be
`w/v % or 0.03 w/v %, and the mamximum content is about
`appropriately added.
`0.05 w/v%, 0.1 w/v%, 0.3 w/v%or0.5%w/v, and preferably
`the minimum content is about 0.02 w/v% and the maximum
`The aqueous liquid preparation of the present invention can
`content is about 0.05 w/v %.
`be prepared by per se known method or according to the
`method as described in the Japanese Pharmacopoeia, 14'h
`Although the content (concentration range) of the polyeth(cid:173)
`Edition, General Rules for Preparations, Solutions or Oph-
`ylene glycol fatty acid ester in the aqueous liquid preparation
`of the present invention depends on the kind of compounds
`50 thalmic solutions.
`used, it is within a range of about 0.02 w/v % of minimum
`The aqueous liquid preparation of the present invention can
`concentration to about 0.1 w/v% of maximum concentration.
`be applied to warm-blooded animals such as human, rat,
`For example, the content (concentration range) of polyethyl(cid:173)
`mouse, rabbit, cow, pig, dog, cat, and the like.
`ene glycol mono stearate is within a range of about 0.02 w/v%
`The aqueous liquid preparation of the present invention can
`of minimum content to about 0.1 w/v of maximum content, 55
`be prepared easily by dissolving the above-mentioned com(cid:173)
`and preferably within a range of about 0.02 w/v % of the
`ponents in, for example, distilled water or sterile purified
`minimum content to about 0.05 w/v % of the maximum
`content.
`water. For example, the aqueous liquid preparation in the
`form of an eye drop can be used for the treatment of inflam-
`The incorporation ratio oftyloxapol in the aqueous liquid
`60 matory diseases in anterior or posterior segment of the eye
`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
`such as blepharitis, conjunctivitis, scleritis, postoperative
`contentofabout0.5, 1, 3 or 5 parts by weight, relative to 1 part
`inflammation, and the like. The dose of the aqueous liquid
`preparation containing 0.1 w/v% of sodium 2-amino-3-(4-
`by weight of 2-amino-3-( 4-bromobenzoyl)phenylacetic acid
`bromobenzoyl)phenylacetate hydrate is, for example, admin-
`or its pharmacologically acceptable salt or a hydrate thereof.
`The incorporation ratio of polyethylene glycol mono stear(cid:173)
`65 istered to an adult 3 to 6 times daily in an amount of 1 to 2
`ate in the aqueous liquid preparation of the present invention
`drops per one time. Depending on the degree of diseases,
`is within a range of the minimum content of about 0.2 part by
`frequency of dosing is appropriately controlled.
`
`45
`
`Page 4 of 8
`
`

`
`7
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`8
`0.02 w/v% oftyloxapol is more stable than that in composi(cid:173)
`tionA-02 containing 0.15 w/v% oftyloxapol.
`
`US 8,129,431 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 1
`
`Stability Test of Sodium
`2-amino-3-( 4-bromo benzoy l)pheny !acetate
`
`Four eye drops of sodium 2-amino-3-( 4-bromobenzoyl)
`phenylacetate comprising the components as shown in Table
`
`EXPERIMENTAL EXAMPLE 2
`
`Stability Test of Sodium
`2-amino-3-( 4-bromo benzoy l)phenylacetate
`
`10
`
`Five eye drops of sodium 2-amino-3-( 4-bromobenzoyl)
`phenylacetate comprising the components as shown in Table
`2 were prepared, filled respectively into a polypropylene con(cid:173)
`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.
`
`TABLE2
`
`Components
`
`A-04
`
`A-05
`
`A-06
`
`A-07
`
`A-08
`
`Sodium 2-amino-3-(4-
`bromobenzoyl)phenyl-
`acetate
`Boric acid
`Borax
`Benzalkonium chloride
`Polysorbate 80
`Tyloxapol
`Polyoxyl40 stearate
`Polyvinyl-pyrrolidone (K-30)
`Sodium edetate
`Sodium hydroxide
`Sterile purified water
`Total volume
`pH
`60° c.,
`4 weeks
`
`Remaining
`rate(%)
`pH
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`l.lg
`l.lg
`0.005 g
`
`l.lg
`l.lg
`0.005 g
`
`l.lg
`l.lg
`0.005 g
`
`l.lg
`l.lg
`0.005 g
`
`l.lg
`l.lg
`0.005 g
`
`0.02 g
`
`0.05 g
`
`0.03 g
`
`2.0g
`0.02 g
`q.s.
`q.s.
`100mL
`8.17
`92.6
`
`2.0g
`0.02 g
`q.s.
`q.s.
`100mL
`8.16
`90.9
`
`2.0g
`0.02 g
`q.s.
`q.s.
`100mL
`8.15
`92.0
`
`0.02 g
`2.0g
`0.02 g
`q.s.
`q.s.
`100mL
`8.19
`93.4
`
`0.05 g
`1.0 g
`0.02 g
`q.s.
`q.s.
`100mL
`8.19
`93.1
`
`8.15
`
`8.16
`
`8.15
`
`8.13
`
`8.14
`
`1 were prepared, filled respectively into a polypropylene con-
`tainer and subjected to stability test at 60° C.
`
`TABLE 1
`
`Component
`
`Comparison
`Example 1
`
`A-01
`
`A-02
`
`A-03
`
`0.1 g
`
`Sodium 2-amino-3-(4-
`bromobenzoyl)
`phenylacetate
`1.5 g
`Boric acid
`Benzalkonium chloride 0.005 g
`Polysorbate 80
`0.15 g
`Polyoxyl40 stearate
`Tyloxapol
`Sterile purified water
`Total volume
`pH
`Remaining rate
`(%)at 60° C.
`after 4 weeks
`
`q.s.
`100mL
`7.0
`51.3
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`1.5g
`0.005 g
`
`1.5 g
`0.005 g
`
`1.5 g
`0.005 g
`
`0.15 g
`
`q.s.
`100mL
`7.0
`63.7
`
`0.15 g
`q.s.
`100mL
`7.0
`73.8
`
`0.02 g
`q.s
`100mL
`7.0
`89.6
`
`40
`
`45
`
`50
`
`55
`
`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 60° C. for 4 60
`weeks, and sodium 2-amino-3-( 4-bromobenzoyl)phenylac(cid:173)
`etate in each eye drop was stable in the order oftyloxapol(cid:173)
`containing preparation>polyoxyl 40 stearate-containing
`preparation>polysorbate SO-containing preparation.
`Further, with respect to eye drops containing tyloxapol 65
`(compositions A-02 and A-03), sodium 2-amino-3-(4-bro(cid:173)
`mobenzoyl)phenylacetate in composition A-03 containing
`
`Table 2 shows the remaining rate and the pH of sodium
`2-amino-3-( 4-bromobenzoyl)phenylacetate after storage at
`60° C. for 4 weeks, when the remaining rate of sodium
`2-amino-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
`container. As is apparent from Table 2, the remaining rate of
`sodium 2-amino-3-( 4-bromobenzoyl)phenylacetate in the
`compositions A-04, A-05, A-06, A-07 and A-08 containing
`0.02 w/v %, 0.03 w/v% and 0.05 w/v% oftyloxapol or 0.02
`w/v% and 0.05 w/v% of polyoxyl40 stearate is not less than
`90% after storage at 60° C. for 4 weeks, which indicates that
`those compositions have sufficient stability for eye drops.
`
`EXPERIMENTAL EXAMPLE 3
`
`Preservative Effect Test of Aqueous Liquid
`Preparation Containing Sodium
`2-amino-3-( 4-bromo benzoy l)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 asS. aureus),
`Escherichia Coli (hereinafter referred to as E. coli),
`Pseudomonas aeruginosa (hereinafter referred to as P.
`aeruginosa), Candida albicans (hereinafter referred to as C.
`albicans) and Aspergillus niger (hereinafter referred to as A.
`niger).
`The results are shown in Tables 3-1, 3-2 and 3-3.
`
`Page 5 of 8
`
`

`
`US 8,129,431 B2
`
`9
`
`TABLE 3-1
`
`Cell count (CFU/mL)
`
`10
`
`6 hours
`
`24 hours
`
`Inoculum
`
`after
`
`after
`
`7 days
`
`after
`
`14 days
`
`21 days
`
`28 days
`
`after
`
`after
`
`after
`
`A-04
`
`cmmt
`
`inoculation
`
`inoculation
`
`inoculation
`
`inoculation
`
`inoculation
`
`inoculation
`
`S. aureus
`
`E. coli
`
`P. aeruginosa
`
`3.0 X 10 1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`2.1 X 106
`6.5 X 106
`5.8 X 106
`3.2 X 105
`1.8 X 105
`
`C. albicans
`
`A. niger
`
`0
`
`0
`
`0
`
`0
`
`TABLE3-2
`
`Cell count (CFU/mL)
`
`A-05
`
`S. aureus
`E. coli
`P. aeruginosa
`C. albicans
`A. niger
`
`Inoculum
`cmmt
`
`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
`
`1.7 X 105
`0
`0
`
`2.0 X 10 1
`0
`0
`
`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
`
`A-07
`
`S. aureus
`E. coli
`P. aeruginosa
`C. albicans
`A. niger
`
`Inoculum
`cmmt
`
`2.7x10 6
`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
`
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`Viable cell count of fungi (C. albicans, A. niger) 14 days
`after inoculation decreases to not more than 1/Jo, and thereaf(cid:173)
`ter, the cell count keeps the same level as that of 14 days after
`50 inoculation.
`
`As is apparent from Tables 3-1, 3-2 and 3-3, the preserva(cid:173)
`tive effect of composition A-04 was found to be compatible
`with EP-criteria A in European Pharmacopoeia (EP), and
`those of compositions A-05 andA-07 were found to be com(cid:173)
`patible with EP-criteria B.
`The EP-criteria A and EP-criteria B are given in the fol(cid:173)
`lowing.
`EP-Criteria A:
`Viable cell counts of bacteria (S. aureus, P. aeruginosa) 6
`hours, 24 hours, and 28 days after inoculation decrease to not
`more than lfwo, not more than lfwoo, and undetectable, respec(cid:173)
`tively.
`Viable cell count of fungi (C. albicans, A. niger) 7 hours 60
`after inoculation decreases to not more than 1/Joo, and there(cid:173)
`after, the cell count levels off or decreases.
`EP-Criteria B
`Viable cell counts of bacteria (S. aureus, P. aeruginosa) 24
`hours and 7 days after inoculation decrease to not more than 65
`1/Jo and not more than 1/Jooo, respectively, and thereafter, the
`cell count levels off or decreases.
`
`55
`
`EXAMPLE 1
`
`Eye Drop
`
`Sodium 2-amino-3-(4-
`bromobenzoyl)phenylacetate 3/2 hydrate
`Boric acid
`Borax
`Benzalkonium chloride
`Tyloxapol
`Polyvinylpyrrolidone (K-30)
`Sodium edetate
`Sodium hydroxide
`Sterile purified water
`
`0.1 g
`
`l.lg
`l.lg
`0.005 g
`0.02 g
`2.0g
`0.02 g
`q.s.
`to make total volume
`of100mL
`pH 8.17
`
`Page 6 of 8
`
`

`
`US 8,129,431 B2
`
`11
`An eye drop is prepared using the above components in a
`conventional marmer.
`
`EXAMPLE2
`
`Eye Drop
`
`Sodium 2-amino-3-(4-
`bromobenzoyl)phenylacetate 3/2 hydrate
`Boric acid
`Borax
`Benzalkonium chloride
`Tyloxapol
`Polyvinylpyrrolidone (K-30)
`Sodium edetate
`Sodium hydroxi