LUPIN EX 1002
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`US 8,754,131 B2
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`References Cited
`
`OTHER PUBLICATIONS
`
`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/prophylactic
`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.
`
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`1
`AQUEOUS LIQUID PREPARATION
`CONTAINING
`
`US 8,754,131 B2
`
`2
`
`2-AMINO-3-(4-BROMOBENZOYL)PHENYLACETIC
`ACID
`
`5
`
`TECHNICAL FIELD
`
`The present invention relates to an aqueous liquid prepa-
`ration containing 2-arnino-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 U.S. Pat. No. 4,045,576.
`2-Amino-3-(4-bromobenzoyl)phenylacetic acid, its pharma-
`cologically acceptable salt and a hydrate thereofare known as
`a non-steroidal anti-inflammatory agent, and they are effec-
`tive against inflammatory diseases of anterior or posterior
`segment of the eye, such as blepharitis, conjunctivitis, scleri-
`tis, and postoperative inflammation in the field 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 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.
`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-
`pounds are generally considered to be incompatible with
`ophthalmic compositions of drugs with acidic groups, such as
`nonsteroidal anti-inflammatory drugs. These preservatives
`lose their ability to function as they form complexes with the
`charged drug compounds”.
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`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-arnino-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
`specifically 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 pharrna-
`cologically acceptable salt thereof or a hydrate thereof, the
`aqueous solution becomes stable within a pH range giving no
`irritation to eyes, and change ofthe 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 oftime. The inventors ofthe
`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)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 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) 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
`
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`US 8,754,131 B2
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`3
`aryl polyether alcohol type polymer is selected from a range
`of minimum concentration of 0.01 w/v to maximum concen-
`tration 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-arnino-3-(4-bromobenzoyl)phenylacetic acid is
`a sodium salt,
`(11) 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-
`taining 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a
`pharmacologically acceptable salt
`thereof or a hydrate
`
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`4
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`thereof. Also, an aqueous liquid preparation of the present
`invention, wherein a preservative is incorporated, has a suf-
`ficient 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 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-
`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-23052/1977 (correspond-
`ing to U.S. 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,
`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-
`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-arnino-3-(4-bromobenzoyl)pheny-
`lacetic 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-
`propyl, cyclopropyl, butyl,
`isobutyl, sec-butyl,
`tert-butyl,
`cyclobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethyl-
`propyl, 4-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbu-
`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-
`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-
`able, and 1,1,3,3-tetrarnethylbutyl 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.
`
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`Page 4 of 10
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`US 8,754,131 B2
`
` C(CH3)3
`
`R: (CHZCHZO) xH
`X : 8-10
`In < 6
`
`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.
`Specific 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 maximum content is about 0.05 w/v %,
`0.1 w/v %, 0.3 w/v % or 0.5% w/v, and preferably the mini-
`mum 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 % ofmaximum concentration.
`
`For example, the content (concentration range) of polyethyl-
`ene glycol monostearate is within a range ofabout 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 mini-
`mum content to about 0.05 w/v of the maximum content.
`
`The incorporation ratio of tyloxapol in the aqueous liquid
`preparation ofthe invention is within a range ofthe minimum
`content of about 0.1 or 0.2 part by weight to the maximum
`content ofabout 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 ofthe 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-
`mobenzoyl)phenylacetic
`acid or
`its pharmacologically
`acceptable salt or a hydrate thereof.
`
`Page 5 of10
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`6
`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 ofthe present invention. The
`isotonics include sodium chloride, potassium chloride, glyc-
`erine, marmitol, 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 sulfites such as sodium sulfite 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 ofthe present invention can
`be prepared by per se known method or according to the
`method as described in the Japanese Pharmacopoeia. 14”’
`Edition, General Rules for Preparations, Solutions or Oph-
`thalmic solutions.
`
`The aqueous liquid preparation ofthe 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 ofthe present invention can
`be prepared easily by dissolving the above-mentioned com-
`ponents in, for example, distilled water or sterile purified
`water. For example, the aqueous liquid preparation in the
`form of an eye drop can be used for the treatment of inflam-
`matory diseases in anterior or posterior segment of the eye
`such as blepharitis, conjunctivitis, scleritis, postoperative
`inflammation, and the like. The dose of the aqueous liquid
`preparation containing 0.1 w/v of sodium 2-amino-3-(4-bro-
`mobenzoyl)phenylacetate hydrate is, for example, adminis-
`tered to an adult 3 to 6 times daily in an amount of 1 to 2 drops
`per one time. Depending on the degree of diseases, frequency
`of dosing is appropriately controlled.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`The present invention is illustrated by way ofthe following
`Experimental Examples and Working Examples, but it is not
`restricted by these Examples.
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`7
`Experimental Example 1
`
`8
`Experimental Example 2
`
`US 8,754,131 B2
`
`Stability Test Of S0di11II1
`2-ainino-3-(4-bromobenzoyl)phenylacetate
`
`Stability Test of Sodium
`2-ainino-3-(4-bromobenzoyl)phenylacetate
`
`Five eye drops of sodium 2-amino-3-(4-bromobenzoyl)
`phenylacetate comprising the components as shown in Table
`2 were prepared, filled respectively into apolypropylene con-
`Four eye drops of sodium 2-amino-3-(4-bromobenzoyl)
`phenylacetate comprising the components as shown in Table 10 tainer and preserved at 60° C. for 4 weeks, and then the
`1 were prepared, filled respectively into a polypropylene con-
`content of 2-amino-3-(4-bromobenzoyl)phenylacetic acid
`tainer and subjected to stability test at 60° C.
`and the pH in each eye drop were measured.
`TABLE 2
`
`Components
`
`Sodium 2-amino-3-(4-
`bromobenzoyl)phenyl-
`acetate
`Boricacid
`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
`
`35
`
`A-04
`
`0.1 g
`
`1.1 g
`1.1 g
`0.005 g
`
`0.02 g
`—
`2.0 g
`
`0.02 g
`q.s.
`q.s.
`
`A-05
`
`0.1 g
`
`A-06
`
`0.1 g
`
`A-07
`
`0.1 g
`
`A-08
`
`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
`
`1.1 g
`1.1 g
`0.005 g
`
`0.05 g
`—
`2.0 g
`
`0.02 g
`q.s.
`q.s.
`
`0.03 g
`—
`2.0 g
`
`0.02 g
`q.s.
`q.s.
`
`—
`0.02 g
`2.0 g
`
`0.02 g
`q.s.
`q.s.
`
`—
`0.05 g
`1.0 g
`
`0.02 g
`q.s.
`q.s.
`
`100 mL
`8.17
`92.6
`
`100 mL
`8.16
`90.9
`
`100 mL
`8.15
`92.0
`
`100 mL
`8.19
`93.4
`
`100 mL
`8.19
`93.1
`
`8.15
`
`8.16
`
`8.15
`
`8.13
`
`8.14
`
`Table 2 shows the remaining rate and the pH of sodium
`TABLE 1
`2-amino-3-(4-bromobenzoyl)phenylacetate after storage at
`,
`600 C f
`4
`k
`h
`h
`.
`.
`f
`d.
`Comparison
`A_03
`A_02
`A_01
`Component
`.
`. or wee s, w en t e remaining rate o
`Example 1
`so ium
` 2-amino-3-(4-bromobenzoyl)phenylacetate at
`the time of
`Sfofllgei
`0'1 g
`0'1 g
`0'1 g
`0'1 g
`40 production ofeye drops is set to 100%. The remaining rate is
`acetate
`a value obtained by correcting moisture vaporization from the
`Boric acid
`container. As is apparent from Table 2, the remaining rate of
`o ysor ae
`.
`.
`.
`.
`§’ei‘Za11:’1:‘”§(‘) °h1°“de
`sodium 2-amino-3-(4-bromobenzoyl)phenylacetate in the
`Polyoxyl 40 stearate
`45 compositions A-04, A-05, A-06, A-07 and A-08 contaimng
`Tyloxapol
`0.02 w/v t, 0.03 w/v and 0.05 w/v % oftyloxapol or 0.02 w/v
`O
`.
`.
`.
`Sterile Purified Wat“
`% and 0.05 w/v % ofpolyoxyl 40 stearate is not less than 90%
`Totalvolume
`after storage at 60 C. for.4 weeks‘, which indicates that those
`PH
`compositions have sufficient stability for eye drops.
`Remaining rate (%)
`at 60° C. after
`4 Weeks
`
`1.5 g
`.
`g
`060?: g
`_
`—
`‘1-S-
`100 mL
`7_0
`51.3
`
`1.5 g
`—
`0005 g
`0_15 g
`—
`‘1-S-
`100 mL
`7_0
`63.7
`
`1.5 g
`—
`0005 g
`_
`0.15 g
`‘1-S-
`100 mL
`7_0
`73.8
`
`1.5 g
`—
`0005 g
`_
`0.02 g
`‘1-S
`100 mL
`7_0
`89.6
`
`50
`
`.
`Experimental Example 3
`
`indicates
`The remaining rate (%) in the above Table 1
`values obtained by correcting moisture vaporization from the 55
`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
`Preservative effect test of compositions A-04, A-05 and
`weeks, and sodium 2-amino-3-(4-bromobenzoyl)phenylac-
`A-07 of Experimental Example 2 was carried out against
`etate in each eye drop was stable in the order of tyloxapol-
`containing preparation >polyoxyl 40 stearate-containing 60 Staphylococcus aureus (hereinafter referred to as S. aureus),
`preparation >polysorbate 80-containing preparation.
`Escherichia Coli
`(hereinafter
`referred to as E.
`coli),
`
`Preservative Effect Test ofAqueous Liquid
`Preparation Containing Sodium
`2-ainino-3-(4-bromobenzoyl)phenylacetate
`
`Pseudomonas aeruginosa (hereinafter referred to as P
`Further, with respeet to eye drops eemaining tyloxapol
`aeruginosa), Candida albicans (hereinafter referred to as C.
`(eempesitiens A_02 and A_03), Sodium 2_amine_3_(4_bre_
`mebenzeynphenylaeetate in eempesitien A_03 eemainmg 65 aibicans) and Aspergillus niger (hereinafter referred to as A.
`0.02 w/v of tyloxapol is more stable than that in composition
`W397)‘
`A-02 contaimng 0.15 w/v % of tyloxapol.
`The results are shown in Tables 3-1, 3-2 and 3-3.
`
`Page 6 of10
`
`Page 6 of 10
`
`

`
`US 8,754,131 B2
`
`TABLE 3-1
`
`Cell count (CFU/mL)
`
`A-04
`
`S. aureus
`E. Cali
`
`R aeruginasa
`C. albicans
`
`A. niger
`
`Inoculum
`count
`
`2.1 x 105
`6.5 x 105
`
`5.8 x 105
`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
`—
`
`—
`
`0
`0
`
`0
`—
`
`—
`
`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
`
`S. aureus
`E. Cali
`R aeruginasa
`C. albicans
`A. niger
`
`Inoculum
`count
`
`2.1 x 105
`6.5 x 105
`5.8 x 105
`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
`
`1.7x105
`0
`0
`—
`—
`
`2.0x101
`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 CFU/mL
`
`6 hours
`after
`inoculation
`
`24 hours
`after
`inoculation
`
`7 days
`after
`inoculation
`
`14 days
`after
`inoculation
`
`21 days
`after
`inoculation
`
`28 days
`after
`inoculation
`
`0
`0
`0
`0
`0
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 1/10, and thereaf-
`ter, the cell count keeps the same level as that of 14 days after
`inoculation.
`
`Example 1
`
`Eye Drop
`
`Sodium 2-aInino-3-(4-
`bromobenzoyl)phenylacetate 3/2 hydrate
`Boric acid
`Borax
`Benzalkoniurn chloride
`Tyloxapol
`Polyvinylpyrrolidone (K-30)
`Sodium edetate
`Sodium hydroxide
`Sterile purified Water
`
`0.1 g
`
`1.1 g
`1.1 g
`0.005 g
`0.02 g
`2.0 g
`0.02 g
`q.s.
`to make total volume
`of 100 mL
`pH 8.17
`
`A-07
`
`S. aureus
`E. Cali
`R aeruginasa
`C. albicans
`A. niger
`
`Inoculum
`count
`
`2.7 X106
`7.4 x 105
`8.8 x 105
`4.6 x 105
`1.0 x 105
`
`3.1 x 104
`0
`0
`—
`—
`
`0
`0
`0
`—
`—
`
`0
`0
`0
`0
`0
`
`As is apparent from Tables 3-1, 3-2 and 3-3, the preserva-
`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 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:
`
`Viable cell counts of bacteria (S. aureus, P aeruginosa) 6
`hours, 24 hours, and 28 days after inoculation decrease to not
`more than 1/100, not more than 1/1000, and undetectable, respec-
`tively.
`Viable cell count of fungi (C. albicans, A. niger) 7 hours
`after inoculation decreases to not more than 1/100, and there-
`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
`1/10 and not more than 1/1000, respectively, and thereafter, the
`cell count levels off or decreases.
`
`Page 7 of10
`
`Page 7 of 10
`
`

`
`US 8,754,131 B2
`
`An eye drop is prepared using the above components in a
`conventional manner.
`
`11
`
`Example 2
`
`Eye Drop
`
`Sodium 2-arnino-3-(4-
`bromobenzoy1)pheny1acetate 3/2 hydrate
`Boric acid
`Borax
`Benzalkonium chloride
`Tyloxapol
`Polyvinylpyrrolidone (K-30)
`Sodium edetate
`Sodium hydroxide
`Sterile purified water
`
`0.1 g
`
`1.1 g
`1.1 g
`0.005 g
`0.05 g
`2.0 g
`0.02 g
`q.s.
`to make total volume
`of 100 mL
`pH 8.16
`
`An eye drop is prepared using the above components in a
`conventional manner.
`
`Example 3
`
`Eye Drop
`
`Sodium 2-arnino-3-(4-
`bromobenzoy1)pheny1acetate 3/2 hydrate
`Boric acid
`Borax
`Benzalkonium chloride
`Po1yoxy140 stearate
`Polyvinylpyrrolidone (K-30)
`Sodium edetate
`Sodium hydroxide
`Sterile purified water
`
`0.1 g
`
`1.1 g
`1.1 g
`0.005 g
`0.02 g
`2.0 g
`0.02 g
`q.s.
`to make total volume
`of 100 mL
`pH 8.19
`
`An eye drop is prepared using the above components in a
`conventional manner.
`
`INDUSTRIAL APPLICABILITY
`
`The aqueous liquid preparation of the present invention in
`the form ofeye drops is useful for the treatment ofblepharitis,
`conjunctivitis,
`scleritis, and postoperative inflammation.
`Such preparation is also useful for the treatment ofnasal drop
`for treatment of, for example, allergic rhinitis and inflamma-
`tory rhinitis (e.g. chronic rhinitis, hypertrophic rhinitis, nasal
`polyp, etc.)
`The present application is based on application No. 12427/
`2003 filed in Japan, and includes the entire contents thereof.
`By reference, the references including patents and patent
`applications cited herein are incorporated in the present appli-
`cation at the same level as when the entire contents thereof are
`
`disclosed. Furthermore, since it is obvious that the present
`invention can be carried out beyond the description of the
`above explanation and Working Examples, in light of the
`foregoing description, various other modifications and
`changes can be made to the present invention, and thus these
`modifications and changes should be considered to be within
`the scope of the claims appended hereto.
`
`Page 8 of10
`
`The invention claimed is:
`
`12
`
`1. A stable aqueous liquid preparation comprising: (a) a
`first component; and (b) a second component; wherein the
`first component is 2-arnino-3-(4-bromobenzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a
`hydrate thereof; wherein the hydrate is at least one selected
`from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first com-
`ponent is the sole pharmaceutical active ingredient contained
`in the preparation and is present in the preparation at a con-
`centration from about 0.05 w/v % to about 0.2 w/v %; the
`second component is tyloxapol and is present in said liquid
`preparation in an amount sufiicient to stabilize said first com-
`ponent; and wherein said stable liquid preparation is formu-
`lated for ophthalmic administration.
`2. The aqueous liquid preparation according to claim 1,
`further comprising a quaternary ammonium salt.
`3. The aqueous liquid preparation according to claim 1,
`wherein the first component is a 2-amino-3-(4-bromoben-
`zoyl)phenylacetic acid sodium salt.
`4. The aqueous liquid preparation according to claim 1,
`wherein the concentration oftyloxapol is from about 0.01 w/v
`% to about 0.05 w/v %.
`
`5. The aqueous liquid preparation according to claim 1,
`wherein the pH is from about 7.5 to about 8.5.
`6. The stable aqueous liquid preparation of claim 1;
`wherein the stable aqueous liquid preparation consists essen-
`tially of: (a) 2-arnino-3-(4-bromobenzoyl)phenylacetic acid
`sodium salt, (b) tyloxapol, (c) boric acid, (d) sodium tetrabo-
`rate, (e) EDTA sodium salt, (f) benzalkonium chloride, (g)
`polyvinylpyrrolidone, and (h) sodium sulfite, wherein said
`liquid preparation is formulated for ophthalmic administra-
`tion, wherein the concentration of the 2-amino-3-(4-bro-
`mobenzoyl)phenylacetic acid sodium salt is from about 0.02
`w/v % to about 0.1 w/v %, and wherein the concentration of
`tyloxapol is from about 0.01 w/v % to about 0.05 w/v %.
`7. A stable aqueous liquid preparation comprising: (a) a
`first component; and (b) a second component; wherein the
`first component is 2-arnino-3-(4-bromobenzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a
`hydrate thereof; wherein the hydrate is at least one selected
`from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first com-
`ponent is the sole pharmaceutical active ingredient contained
`in the preparation and is present in the preparation at a con-
`centration from about 0.05 w/v % to about 0.2 w/v %; the
`second component is tyloxapol; wherein said stable liquid
`preparation is formulated for ophthalmic administration; and
`wherein the stable aqueous liquidpreparation is characterized
`in that greater than about 90% of the original amount of the
`first component remains in the preparation after storage at
`about 60° C. for 4 weeks.
`
`8. The aqueous liquid preparation according to claim 7,
`further comprising a quaternary ammonium salt.
`9. The stable aqueous liquid preparation of claim 7;
`wherein the stable aqueous liquidpreparation is characterized
`in that greater than about 92% of the original amount of the
`first component remains in the preparation after storage at
`about 60° C. for 4 weeks.
`
`10. The aqueous liquid preparation according to claim 7;
`wherein the concentration oftyloxapol is from about 0.01 w/v
`% to about 0.05 w/v %; and