(12) United States Patent
`(10) Patent No.:
`US 7,834,059 B2
`
`Wong
`(45) Date of Patent:
`Nov. 16, 2010
`
`US007834059B2
`
`(54) TOPICAL NEPAFENAC FORMULATIONS
`
`(75)
`
`Inventor: Warren Wonga Fort Worth, TX ms)
`
`( >1: ) NOthCI
`
`(73) Assignee: Alcon Inc. Hunenberg (CH)
`3
`,
`Subject to any disclaimer, the term OfthlS
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 425 days.
`
`.
`(21) Appl’ NO" 11/292’484
`.
`.
`,
`(22) Filed'
`Dec 2 2005
`
`(65)
`
`Prior Publication Data
`
`US 2006/0122277 A1
`
`Jun. 8, 2006
`
`Related US. Application Data
`.
`.
`.
`.
`Pr0V1s10nal application No. 60/632,562, filed on Dec.
`2, 2004~
`
`(60)
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31/195
`(52) US. Cl.
`....................................... 514/567; 424/486
`(58) Field of Classification Search .................. 514/567
`.
`.
`.
`See application file for complete search history.
`-
`References Clted
`U.S. PATENT DOCUMENTS
`
`(56)
`
`3,828,093 A
`4,045,576 A
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`4,313,949 A
`4,503,073 A
`4,568,695 A
`4,683,242 A
`4,783,487 A
`4,851,443 A
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`5,073,641 A
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`5,475,034 A
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`....... 424/309
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`....... 562/441
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`..
`.. 424/309
`
`3/1981 Walsh ..................
`424/309
`2/1982 Shanklin, Jr. et a1.
`..
`.. 424/248
`
`.......
`3/1985 Walsh et a1.
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`
`2/1986 Moran et al.
`514/648
`......................... 514/539
`7/1987 Poser
`11/1988 Brune ........................ 514/563
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`.. 514/563
`
`3/1990 Ogawa et a1.
`514/561
`12/1991 Bundgaard et al
`..... 560/56
`
`.........
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`................. 514/619
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`
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`6,342,524 B1
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`
`.................. 514/772.5
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`...........
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`
`............. 514/530
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`............ 514/532
`
`GB
`GB
`W0
`W0
`
`. 514/619
`. 514/567
`. 514/567
`
`3/2002 Kapin et a1.
`......
`2002/0037929 A1 *
`
`11/2003 Bingaman et al.
`.
`2003/0207941 A1
`10/2005 Sawa et a1.
`.....
`2005/0239895 A1
`FOREIGN PATENT DOCUMENTS
`2 071086 A
`9/1981
`2 093 027 A
`8/1982
`W0 02/13805 A2
`2/2002
`W0 03/092669 A2
`11/2003
`OTHER PUBLICATIONS
`_
`_
`_
`_
`Penn et a1. Studies of the Effect and Mechanism ofAction of Topical
`Nepafenac in Rat Model of ROP. ARVO Annual Meeting, Abstract
`No. 2741, (2002).*
`Sancilio et al., “AHR-10037, anon-steroidal anti-inflammatory com-
`pound of low gastric toxicity,” Agents and Actions, V01. 31, pp.
`117-126 (1990).
`Ke et a1., “Nepafenac, A Unique Nonsteroidal Prodrug with Potential
`Utility in the Treatment of Trauma-Induced Ocular Inflammation,”
`Inflammation, vol. 24(4), pp. 371-384 (2000).
`Walsh et a1., “Antiinflammatory Agents. 3. Synthesis and Pharmaco-
`logical Evaluation of Z-Amin0-3-ben20y1 Phenylacetic Acid and
`$213109“? M??- Chem'V01'27(11)’PP' 13794388 (19.84) .
`sh et a1., Antiinflammatory Agents. 4. Syntheses and Biological
`Evaluation
`of
`Potential
`Prodrugs
`of
`2_Amm0_3_
`benzoylbenzeneacetic
`Acid
`and
`2-Amino-3-(4-
`chlorobenzoyl)benzeneacetic Acid,” J. Med. Chem, V01. 33, pp.
`2296-2304 (1990)
`Penn et a1., “Studies of the Effect and Mechanism of Action of
`Topical Nepafenac in a Rat Model of ROE” ARVO Annual Meeting,
`Abstract No, 2741, 2002,
`.
`.
`* Clted by exammer
`.
`.
`.
`Pr’mary Exammrilake MV11
`(74) AZWWM Agent! or Firmipaka M Ryan
`
`ABSTRACT
`(57)
`.
`.
`.
`.
`.
`Topical suspens1on comp0s1t10ns ofnepafenac are disclosed.
`The compositions are especially suitable for topical oph-
`thalmlc admlmstratlon-
`
`2 Claims, N0 Drawings
`
`Page 1 of4
`
`LUPIN EX 1032
`
`LUPIN EX 1032
`
`Page 1 of 4
`
`

`

`US 7,834,059 B2
`
`1
`TOPICAL NEPAFENAC FORMULATIONS
`
`This application claims priority to US. Provisional appli-
`cation, U.S. Ser. No. 60/632,562 filed Dec. 2, 2004.
`
`BACKGROUND OF THE INVENTION
`
`This invention relates to topically administrable oph-
`thalmic formulations of nepafenac. The formulations of the
`present invention are suspension compositions.
`Nepafenac is also known as 2-amino-3 -benzoylphenylace-
`tic acid. The topical use of nepafenac and other amide and
`ester derivatives of 3-benzoylphenylacetic acid to treat oph-
`thalmic inflammation and pain is disclosed in US. Pat. No.
`5,475,034. According to the ’034 patent, compositions con-
`taining the 3-benzoylphenylacetic acid derivatives can be
`formulated into a variety of topically administrable oph-
`thalmic compositions, such as solutions, suspensions, gels or
`ointments. The compositions optionally contain preserva-
`tives, such as benzalkonium chloride, and thickening agents,
`such as carbomers, hydroxyethylcellulose or polyvinyl alco-
`hol.
`
`SUMMARY OF THE INVENTION
`
`The compositions of the present invention are aqueous
`suspension compositions of nepafenac. The compositions
`contain 009-01 1% (w/v) nepafenac. The compositions con-
`sist essentially of nepafenac, a carbomer, a nonionic surfac-
`tant, a tonicity-adjusting agent, a pH-adjusting agent, purified
`water, and optionally a preservative and a chelating agent.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`.
`.
`.
`.
`.
`.
`Unless indicated otherwrse, all ingredient concentrations
`are presented in units of % weight/volume (% w/v).
`Nepafenac is a known compound. It can be made by known
`methods. See, for example, US. Pat. Nos. 5,475,034 and
`4,313,949. The compositions of the present invention contain 40
`009-01 1% nepafenac, and preferably 0.1% nepafenac.
`In addition to nepafenac, the suspension compositions of
`the present invention also contain a carbomer as a thickening
`or physical stability-enhancing agent. Carbomers suitable for
`use in the present invention are also known as “carboxyvinyl 45
`polymers” or carboxypolymethylene. They are commercially
`available from sources such as Noveon, Inc. (Cleveland,
`Ohio), which distributes them under the trade name Car-
`bopol®. Carbopol polymers are crosslinked, acrylic acid-
`based polymers. They are cross-linked with allyl sucrose or 50
`allylpentaerythritol. Carbopol copolymers are polymers of
`acrylic acid, modified by C10_3O alkyl acrylates, and
`crosslinked with allylpentaerythritol. A preferred carbomer
`for use in the compositions of the present invention is a
`polymer of acrylic acid cross-linked with allyl sucrose or 55
`allylpentaerythritol, which is commercially available as Car-
`bopol® 974P. The concentration of carbomer in the compo-
`sitions of the present invention will generally range from
`04-06%, and will preferably be 0.5%.
`The compositions of the present invention also contain an 60
`ophthalmically acceptable nonionic surfactant. Many oph-
`thalmically acceptable nonionic surfactants are known. Suit-
`able nonionic surfactants include, but are not limited to tylox-
`apol; polyoxyethylene sorbitan esters, such as polysorbate
`20, polysorbate 60, and polysorbate 80; polyethoxylated cas-
`tor oils, such as Cremophor EL; polyethoxylated hydroge-
`nated castor oils, such as HCO-40; and poloxamers. The most
`
`65
`
`2
`
`preferred surfactant is tyloxapol. In the case of tyloxapol, the
`surfactant is generally present in an amount of 0.001 -0.05%,
`and preferably 0.01%.
`In addition to nepafenac, a carbomer, and a nonionic sur-
`factant, the compositions of the present invention contain an
`ophthalmically acceptable tonicity-adjusting agent. Oph-
`thalmically acceptable tonicity adjusting agents include, but
`are not limited to, metal chloride salts and non-ionic tonicity-
`adjusting agents such as mannitol. Preferred metal chloride
`salts are those found in human tears, such sodium chloride,
`potassium chloride, calcium chloride and magnesium chlo-
`ride. The amount of tonicity adjusting agent contained in the
`compositions of the present invention is an amount sufficient
`to cause the composition to have an osmolality of about
`250-350 mOsm/kg, preferably 270-315 mOsm/kg. Most pre-
`ferred is a combination of sodium chloride and mannitol. For
`
`the most preferred embodiment where the tonicity adjusting
`agent is a combination of sodium chloride and mannitol, the
`amount of sodium chloride is preferably 0.3-0.5% and the
`amount of mannitol is 2-3%, and the most preferred amount
`of sodium chloride is 0.4% and the most preferred amount of
`mannitol is 2.4%.
`
`The compositions of the present invention have a pH from
`7.0-7.8. Preferably, the pH ofthe compositions is 7.3-7.7, and
`most preferably 7.5. The compositions contain an ophthalmi-
`cally acceptable pH-adjusting agent in order to achieve the
`desired pH. Ophthalmically acceptable pH adjusting agents
`are known and include, but are not limited to, hydrochloric
`acid (HCl) and sodium hydroxide (NaOH).
`The compositions of the present invention optionally con-
`tain an ophthalmically acceptable preservative ingredient.
`Ophthalmically acceptable preservative ingredients are
`known and include, but are not limited to, benzalkonium
`halides, such as benzalkonium chloride, polyquaternium-l,
`and chlorine dioxide. Most preferred are benzalkonium chlo-
`ride and polyquatemium-l . In the case ofbenzalkonium chlo-
`ride, the preservative is preferably present in an amount from
`0.001-0.01%, and most preferably 0.005%.
`A chelating agent is also optionally included in the suspen-
`sion compositions ofthe present invention. Suitable chelating
`agents include edetate disodium; edetate trisodium; edetate
`tetrasodium; and diethyleneamine pentaacetate. Most pre-
`ferred is edetate disodium. If included, the chelating agent
`will typically be present in an amount from 0.001-0.1%. In
`the case of edetate disodium, the chelating agent is preferably
`present at a concentration of 0.01%.
`The following examples are intended to illustrate, but not
`limit, the present invention.
`
`EXAMPLE 1
`
`The formulations shown in Table 1A below were prepared
`and their in vitro corneal penetration rates compared. Corneal
`penetration rates were assessed in a perfusion bath using
`freshly isolated rabbit corneas according to the method
`described in Ke, et al., Inflammation, 24(4):371-384 (2000).
`The corneal penetration results are shown in Table 1B.
`
`TABLE 1A
`
`FORMULATION
`
`A
`% (w/v)
`
`0.1
`0.35
`
`B
`% (w/v)
`
`0.1
`0.5
`
`INGREDIENT
`
`Nepafenac
`Carbopol 9741’
`
`Page 2 of 4
`
`Page 2 of 4
`
`

`

`US 7,834,059 B2
`
`3
`
`TABLE 1A-c0ntinued
`
`INGREDIENT
`
`Sodium Chloride
`Mannitol
`
`Tyloxapol
`Edetate Disodium
`Benzalkonium Chloride
`
`NaOH/HCl
`Purified Water
`
`FORMULATION
`
`A
`
`% (w/V)
`
`B
`
`% (w/V)
`
`0.4
`2.4
`
`0.01
`0.01
`0.01
`
`0.4
`2.4
`
`0.01
`0.01
`0.01
`
`q.s. pH 7.5
`q.s. 100
`
`q.s. pH 7.5
`q.s. 100
`
`10
`
`15
`
`20
`
`TABLE 3A
`
`FORMULATION
`
`F
`% (w/V)
`
`0.1
`0.35
`0.4
`2.4
`0.01
`0.01
`0.005
`q.s. pH 7.5
`q.s. 100
`
`G
`% (w/V)
`
`0.1
`0.35
`0.4
`2.4
`0.01
`0.01
`0.01
`q.s. pH 7.5
`q.s. 100
`
`H
`% (w/V)
`
`0.1
`0.5
`0.4
`2.4
`0.01
`0.01
`0.01
`q.s. pH 7.5
`q.s. 100
`
`INGREDIENT
`
`Nepafenac
`Carbopol 974P
`Sodium Chloride
`Mannitol
`Tyloxapol
`Edetate Disodium
`Benzalkonium Chloride
`NaOH/HCl
`Purified Water
`
`TABLE 3B
`
`FORMULATION
`
`RATE OF CORNEAL PENETRATION
`(nM/min) (Mean 1 SD)
`
`F
`G
`H
`
`13.9144 (n=4)*
`9.915.87 (n=4)**
`20.8124 (n=5)
`
`25
`
`*Statistically significant difference between formulations F and H (p = 0.02).
`**Statistically significant difference between Formulations G and H (p = 0.007).
`No statistically significant difference between Formulations F and G.
`
`EXAMPLE 4
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`The formulations shown in Table 4A below were prepared
`and their in Vitro corneal penetration rates compared. The
`corneal penetration results are shown in Table 4B.
`
`TABLE 4A
`
`FORMULATION
`
`I
`J
`INGREDIENT
`% (w/V)
`% (w/V)
`
`
`Nepafenac
`Carbopol 974P
`Sodium Chloride
`Mannitol
`Tyloxapol
`Edetate Disodium
`Benzalkonium Chloride
`NaOH/HCl
`Purified Water
`
`0.1
`0.35
`0.4
`2.4
`0.01
`7
`7
`q.s. pH7.5
`q.s. 100
`
`0.1
`0.5
`0.4
`2.4
`0.01
`7
`7
`q.s. pH7.5
`q.s. 100
`
`TABLE 4B
`
`FORMULATION
`
`RATE OF CORNEAL PENETRATION
`(nM/min) (Mean 1 SD)
`
`I
`J
`
`12.0: 1.9 (n=4)*
`18.3 12.2 (n=4)*
`
`*Statistically significant difference (p = 0.005).
`
`The data in Examples 1-4 demonstrate that for composi-
`tions with nepafenac concentrations of 0.3%, the amount of
`carbomer had no statistically significant effect on the rate of
`corneal penetration.
`In contrast,
`for compositions with
`nepafenac concentrations of 0.1%, the amount of carbomer
`had a statistically significant effect. For compositions con-
`taining 0.1% nepafenac, those with a carbomer concentration
`of 0.5% had a superior rate of corneal penetration compared
`to compositions containing a carbomer concentration of
`0.35%.
`
`TABLE 1B
`
`FORMULATION
`
`RATE OF CORNEAL PENETRATION
`(nM/min) (Mean 1 SD)
`
`A
`B
`
`10.7:0.6(n=4)*
`17.2:1.2(n=4)*
`
`*Statistically significant difference (p < 0.001).
`
`EXAMPLE 2
`
`The formulations shown in Table 2A below were prepared
`and their in Vitro corneal penetration rates compared. The
`corneal penetration results are shown in Table 2B.
`
`TABLE 2A
`
`FORMULATION
`
`C
`% (w/V)
`
`0.3
`0.35
`0.4
`2.4
`0.01
`0.01
`0.005
`q.s. pH 7.5
`q.s. 100
`
`D
`% (w/V)
`
`0.3
`0.35
`0.4
`2.4
`0.01
`0.01
`0.01
`q.s. pH 7.5
`q.s. 100
`
`E
`% (w/V)
`
`0.3
`0.5
`0.4
`2.4
`0.01
`0.01
`0.01
`q.s. pH 7.5
`q.s. 100
`
`INGREDIENT
`
`Nepafenac
`Carbopol 974P
`Sodium Chloride
`Mannitol
`Tyloxapol
`Edetate Disodium
`Benzalkonium Chloride
`NaOH/HCl
`Purified Water
`
`TABLE 2B
`
`FORMULATION
`
`RATE OF CORNEAL PENETRATION
`(anUmin) (Mean 1 SD)
`
`C
`D
`E
`
`63.8 18.9 (n=4)*
`65.2 115.0(H=3)*
`61.41105 (n=5)*
`
`*No statistical difference among Formulations C, D, and E.
`
`EXAMPLE 3
`
`The formulations shown in Table 3A below were prepared
`and their in Vitro corneal penetration rates compared. The
`corneal penetration results are shown in Table 3B.
`
`Page 3 of 4
`
`Page 3 of 4
`
`

`

`US 7,834,059 B2
`
`6
`
`5
`
`EXAMPLE 5
`
`Topical Ophthalmic Composition
`
`a) 0.1% (w/v) nepafenac;
`b) 0.5% (w/v) carbomer;
`c) 0.01% (w/v) tyloxapol;
`d) 0.4% (w/v) sodium chloride;
`e) 2.4% (w/v) mannitol;
`f) a pH-adjusting agent in an amount sufficient to cause the
`composition to have a pH of 7.3-7.7;
`g) 0.005% (w/v) benzalkonium chloride;
`h) 0.01% edetate disodium; and
`i) purified water.
`2. In a method of treating ophthalmic inflammatory disor-
`ders in a human patient comprising topically administering to
`the patient an aqueous suspension composition comprising
`nepafenac; the improvement wherein the composition con-
`sists of
`
`a) 0.1% (w/v) nepafenac;
`b) 0.5% (w/v) carbomer;
`c) 0.01% (w/v) tyloxapol;
`d) 0.4% (w/v) sodium chloride;
`e) 2.4% (w/v) mannitol;
`f) a pH-adjusting agent in an amount sufficient to cause the
`composition to have a pH of 7.3-7.7;
`g) 0.005% (w/v) benzalkonium chloride;
`h) 0.01% edetate disodium; and
`i) purified water.
`
`10
`
`15
`
`20
`
`25
`
`Ingredient
`
`Nepafenac
`Benzalkonium Chloride
`Carbomer 9741’
`Tyloxapol
`Edetate Disodium
`Mannitol
`Sodium Chloride
`NaOH/HCl
`Purified Water
`
`% (W/v)
`
`0.1
`0.005
`0.5
`0.01
`0.01
`2.4
`0.4
`q.s. pH 7.3-7.7
`q.s. to 100
`
`The invention has been described by reference to certain
`preferred embodiments; however, it should be understood
`that it may be embodied in other specific forms or variations
`thereof without departing from its spirit or essential charac-
`teristics. The embodiments described above are therefore
`
`considered to be illustrative in all respects and not restrictive,
`the scope of the invention being indicated by the appended
`claims rather than by the foregoing description.
`What is claimed is:
`
`1. A method oftreating ophthalmic inflammatory disorders
`in a human patient comprising topically administering to the
`patient a composition consisting of
`
`Page 4 of 4
`
`Page 4 of 4
`
`