(12) United States Patent
`Bowman et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,265,444 B1
`*Jul. 24, 2001
`
`US006265444B1
`
`(54) OPHTHALMIC COMPOSITION
`
`(75) Inventors: Lyle M. Bowman, Pleasanton; James
`E Pfei?'er, Oakland; Eric B_
`Memarzadeh, San Carlos; Samir Roy,
`San Ramon, all Of CA (US)
`
`(73) Assignee: InSite Vision Incorporated, Alameda,
`CA (Us)
`
`(*) Notice:
`
`This patent issued on a continued pros-
`ecution application ?led under 37 CFR
`1.53(d), and is subject to the twenty year
`patent term provisions of 35 USC.
`l54(a)(2)-
`_
`_
`_
`_
`Sub]ect to any dlsclalmer> the term of thls
`patent is extended or adjusted under 35
`U'S'C' 154(k)) by 0 days‘
`
`(21) Appl. N0.: 09/074,419
`-
`_
`(22) Flled'
`
`May 8’ 1998
`Related US. Application Data
`
`(63) g/lzrgltiggiatligrgl
`
`.
`
`.
`
`_. _
`
`.
`
`.
`
`part of application No. 08/863,015, ?led on
`
`12/1992 MiZushima etal..
`5,171,566
`3/1993 Davis et al. .
`5,192,535
`3/1994 Chang et a1. .
`5,296,228
`8/1994 Patel et al. .
`5,340,572
`11/1996 Mam“ et a1‘ '
`5’576’028
`FOREIGN PATENT DOCUMENTS
`
`28 39 752
`WO 94/10976
`WO 95/31968
`
`11/1977 (DE) .
`5/1994 (WO) .
`11/1995 (W0) .
`OTHER PUBLICATIONS
`
`LasZlo Borka, The Polymorphism Of Indomethacine,AC1I4
`Pharm. Suecica 11., pp. 295—303 (1974).
`P.S. WeisWeiler, et al., Journal Of Clinical Research and
`Drug Development, Dec. 1998, vol. 2, No. 4, pp. 234—238.
`International Journal of Pharmaceutics, 1989, vol. 55/2.3,
`pp. 124—128.
`Patent Abstracts of Japan, vol. 8, No. 7 (C—204) correspond
`ing to JP58—174309 published Oct. 1983 entitled Antiphlo
`gistic Eye Drop.
`DerWent Publications Ltd., Section Ch, Week 8347, AN
`83—823242, XP002078183 for (JP 58 174309 A) Wakamoto
`Pharm CO Ltd’ Oct‘ 13’ 1983'
`
`Primary Examiner—Zohreh Fay
`
`(74) Attorney) Agent) Or Firm
`
`n01 d & Porter
`
`(51) Int. c1.7 ................................................... .. A61K 31/19
`
`(57)
`
`ABSTRACT
`
`(52) US. Cl. ........................................... .. 514/570; 514/912
`Fleld Of Search .................................. ..
`L,
`,
`References Clted
`U5, PATENT DOCUMENTS
`
`(56)
`
`,
`
`,
`
`4,960,799
`5,102,666
`5,110,493
`
`ou a as .
`
`ganlei‘? '
`1%;
`10/1990 Nagy .
`4/1992 Acharya.
`5/1992 Cherng-Chyi et al. .
`
`An 0 hthalmic Com Osition Containin a divalent Salt and a
`P
`P
`g
`norksteroidal antidn?ammatoly agent as a precipitate‘ The
`composition reduces or eliminates the risk of stinging and
`burning the eye from topical application. Additionally a
`preservative system comprising a perborate salt, a polyphos
`phonic acid peroXy stabiliZer and EDTA provides stable
`preservation of a variety of aqueous ophthalmic composi
`Hons‘
`
`-
`
`31 Claims, 1 Drawing Sheet
`
`

`
`U.S. Patent
`
`Jul. 24, 2001
`
`US 6,265,444 B1
`
`2 COMPOSITION A 0 COMPOSITION B
`
`TIME(hr)
`
`FIG.1
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`l
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`n
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`o
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`O
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`(In/611’) 31w asvt-naa
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`Page 2
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`

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`US 6,265,444 B1
`
`1
`OPHTHALMIC COMPOSITION
`
`This application is a Continuation-in-Part of prior
`co-pending application Ser. No. 08/863,015, ?led May 23,
`1997, the entire contents of Which are incorporated herein by
`reference.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`The present invention relates to ophthalmic compositions
`and more particularly, to ophthalmic compositions contain
`ing a divalent cation and a non-steroidal anti-in?ammatory
`agent and/or to ophthalmic compositions containing a pre
`servative system.
`2. Description of the Related Art
`Non-steroidal anti-in?ammatory agents can be used in a
`variety of ophthalmic treatments such as for treating ocular
`tissue in?ammation and its associated pain. Additional uses
`include
`preventing particular side-effects from surgical
`trauma (e.g., on the pupil preventing surgical meiosis), (ii)
`preventing ?uid accumulation in the back of the eye after
`cataract surgery (post-surgical macular edema) and (iii)
`preventing the appearance of in?ammatory cells and vessel
`leakage in the anterior chamber. Diclofenac, suprofen, and
`?urbipro?n are speci?c examples of non-steroidal anti
`in?ammatory agents that have been used for the treatment of
`postoperative in?ammation in patients Who have undergone
`cataract extraction. Topical application of non-steroidal anti
`in?ammatory agents in the eye also appears to relieve some
`of the itching due to allergic conjunctivitis.
`In the past, anti-in?ammatory agents, in general, have
`been administered in solutions at neutral pH. Injection of
`anti-in?ammatory agents in the form of a suspension has
`also been proposed. Suspensions have been used for topical
`ophthalmic applications When the drug is not very soluble.
`HoWever, When the drug is soluble, at an acceptable pH,
`solutions are normally used to avoid potential irritation
`caused by the particles of the suspension. The folloWing
`patents illustrate ophthalmic solutions containing non
`steroidal anti-in?ammatory agents, including diclofenac.
`US. Pat. No. 4,960,799 to Nagy concerns a storage stable
`aqueous solution of sodium ortho-(2,6-dichlorophenyl)
`aminophenylacetate acid, Which is the chemical name for
`diclofenac sodium, for topical treatment of ocular in?am
`mation. The solution taught by Nagy has a pH of about 7.0
`to 7.8.
`US. Pat. No. 4,829,088 to Doulakas also relates to an
`ophthalmic medicament containing diclofenac sodium in
`aqueous solution. The solution contains 2-amino-2
`hydroxymethyl-1,3-propanediol as a preservative.
`US. Pat. No. 5,110,493 to Cherng-Chyi et al. relates to
`ophthalmic non-steroidal anti-in?ammatory drug formula
`tions containing a quaternary ammonium preservative and a
`non-ionic surfactant.
`Patent Abstracts of Japan, Vol. 8, No. 7, Abs. Gp. C-204,
`concerning Japanese published application 58-174309 (pub.
`Oct. 13, 1983) relates to an antiphlogistic eye drop compo
`sition containing (1) a non-steroidal antiphlogistic agent
`having a carboxyl group in its structure and (2) a physi
`ologically permissible calcium or magnesium salt. The salt
`is described as an irritation mitigating agent and is normally
`added in an amount of 1—1.5 mol per 1 mol of the non
`steroidal agent. Sodium diclofenac is speci?cally mentioned
`as the non-steroidal antiphlogistic agent and the pH of the
`composition is preferably maintained in the 7—8 range.
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`HoWever, a problem With the use of non-steroidal anti
`in?ammatory agents, as recogniZed in the above-mentioned
`Japanese published application, is that stinging or burning
`sensations are commonly experienced during the ?rst feW
`minutes after topical administration on the eye. Not only are
`patients Who experience such stinging likely to avoid regu
`larly taking their medication, they also receive less bene?t
`from each application. Speci?cally, the stinging causes
`tearing Which Washes aWay the drug. Having physically
`removed a portion of the drug from the eye by tearing, the
`bioavailability of the drug is reduced.
`In addressing the stinging problem, it has been proposed
`to supply a portion of the non-steroidal anti-in?ammatory
`agent in suspension form, as is described in commonly
`assigned co-pending application Ser. No. 08/248,500, ?led
`May 24, 1994 (the entire contents of Which are hereby
`incorporated by reference). The particle must dissolve
`before it can treat the eye. By providing some of the active
`agent as a particle, the ?oW of the drug onto the eye is
`delayed; i.e., providing some of the active agent as a particle
`reduces the initial concentration of the drug contacting the
`eye. This delay in drug delivery contrasted With the prior
`compositions Wherein all of the agent Was in solution, oWing
`to a pH of 7—8, thereby immediately providing to the cornea
`a high concentration of the drug. The high concentration of
`the drug on the eye Was believed to aggravate the burning
`and stinging effects of the drug.
`While some improvements have been made With respect
`to the stinging problem by such a technique, there is still a
`segment of the population that Will experience stinging
`When topically administering non-steroidal anti
`in?ammatory ophthalmic compositions. Accordingly, fur
`ther improvements are desirable.
`Additionally, preserving an ophthalmic composition that
`contains a non-steroidal anti-in?ammatory agent can be
`problematic. Conventional broad spectrum antimicrobial
`agents like benZalkonium chloride (BAK) tend to interact
`With the non-steroidal anti-in?ammatory agents over time
`and thereby reduce the ef?cacy of the medication. Indeed, as
`a general matter, preservatives in ophthalmic compositions
`are not entirely satisfactory. Effective, broad spectrum anti
`microbials tend to reduce the storage stability of the com
`position and/or have adverse interactions With other com
`ponents.
`Auseful preservative system that seeks to overcome some
`of these de?ciencies is disclosed in US. Pat. Nos. 5,576,028
`and 5,607,698. These systems use a loW amount of hydrogen
`peroxide, or a hydrogen peroxide source, as a preservative in
`combination With a peroxy stabiliZer. The stabiliZer is pref
`erably a phosphonic acid such as diethylene triamine penta
`(methylene-phosphonic acid) and the like Which are com
`mercially available from Monsanto under the DEQUEST
`brand name. Although this system is quite useful, certain
`improvements in storage stability Would be desirable.
`SUMMARY OF THE INVENTION
`It is an object of the present invention to provide an
`ophthalmic composition that contains a topically effective
`amount of a non-steroidal anti-in?ammatory agent and that
`is no more irritating than conventional eye drops.
`It is another object of the present invention to provide a
`non-steroidal anti-in?ammatory agent-containing oph
`thalmic composition that can be taken by a large segment of
`the population Without experiencing stinging or irritation.
`A further object of the present invention is to provide a
`preserved ophthalmic composition that exhibits good stabil
`ity during storage.
`
`Page 3
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`

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`US 6,265,444 B1
`
`3
`Another object of the present invention is to provide a
`method for treating diseases of the eye, including
`in?ammation, by topically applying to eyes in need of such
`treatment a non-steroidal anti-in?ammatory agent
`containing ophthalmic composition.
`Preferred forms of the invention contemplated accom
`plish at least some of the above objects. One embodiment of
`the invention is an ophthalmic composition comprising an
`aqueous medium containing an effective amount of a non
`steroidal anti-in?ammatory agent, Wherein at least about 80
`mol. % of said agent is in the form of a precipitate, and at
`least about 0.5 equivalents of a pharmacologically accept
`able divalent cation per mole of said non-steroidal anti
`in?ammatory agent; said aqueous medium having a pH of
`from about 4.0 to 6.7. Another embodiment of the invention
`relates to a method for treating an eye, Which comprises
`administering to an eye in need thereof an effective amount
`of such an ophthalmic composition. A further aspect of the
`present invention relates to a method for making such an
`ophthalmic composition. Another preferred embodiment of
`the present invention relates to an ophthalmic composition
`that is formed by combining at least (1) sodium diclofenac,
`(2) a divalent metal salt, (3) a Water insoluble, Water
`sWellable polymer, and (4) Water.
`A further embodiment of the invention is an ophthalmic
`composition Which comprises Water, about 0.01 to 0.5 Wt. %
`of a perborate salt, about 0.001 to 0.06 Wt. % of a poly
`phosphonic acid peroXy stabiliZer, and about 0.01 to 0.1 Wt.
`% of ethylenediaminetetraacetic acid. The composition in
`this embodiment may further comprise a pharmaceutically
`active agent such as a non-steroidal anti-in?ammatory agent.
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`BRIEF DESCRIPTION OF THE DRAWING
`
`FIG. 1 shoWs the illustrious results of EXample 21 regard
`ing release rate curves for an inventive and a comparative
`ophthalmic composition.
`
`35
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present inventors have discovered that by providing
`the non-steroidal anti-in?ammatory (NSAI) agent as a solid
`and in the presence of a divalent cation, the dissolution of the
`NSAI agent during the ?rst several minutes at neutral pH is
`sufficiently sloWed so as to further avoid stinging the eye.
`For reasons that are not entirely clear, stinging and burning
`irritation are typically only induced during the ?rst minutes
`after contact With a suf?ciently high concentration of NSAI
`agent. After this initial time period, the eye is apparently no
`longer sensitive to the NSAI agent, regardless of its con
`centration level. Thus, by delaying the dissolution of the
`NSAI agent during the ?rst feW minutes, the initial NSAI
`agent concentration on the eye can be sufficiently loW to
`avoid irritation. AfterWard, the high concentration caused by
`the dissolution of the solid NSAI agent precipitate is too late
`to cause irritation. In this Way the stinging problem is
`effectively avoided While still providing a topically effective
`dose of NSAI agent.
`In contrast, the typical prior art composition Would supply
`all of the NSAI agent as a solute and thus apply an
`immediate high concentration to the surface of the eye. Such
`a technique has the greatest chance of inducing stinging in
`the patient. While the use of sodium diclofenac in both
`suspension and solution form, simultaneously, is described
`in the above-mentioned co-pending application and provides
`good results, the presence of a divalent cation in accordance
`With the present invention improves the avoidance of sting
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`ing. The divalent cation reduces the solubility of the NSAI
`agent in the aqueous medium and thus reduces the dissolu
`tion rate of the solid NSAI agent precipitate during the ?rst
`several minutes after administration.
`As used in this application, the term “divalent cation”
`means a cation having a +2 charge. The divalent cation can
`be in either solid or dissolved form, or both. In solid form,
`the cation is ionically bonded to an anion thereby making a
`salt. When in solution, the cation is not required to be
`directly associated With a speci?c anion. Typically the cation
`is, or contains, a metal; i.e., a “metal divalent cation”.
`EXamples of suitable divalent cations include Group IIA
`elements (alkaline earth metals) such as calcium,
`magnesium, barium, etc. Particularly preferred divalent cat
`ions are Ca++ and Mg“. The divalent cation and any salts
`thereof in the composition are pharmacologically acceptable
`so as to not harm the eye or the patient. Typical anions
`include chlorides, sulfates, and the NSAI agent.
`The divalent cation is only required to be present in the
`composition and is not necessarily associated or otherWise
`bonded With the NSAI agent. In one embodiment, all or
`essentially all of the divalent cation is in solution With no
`cation present in the solid NSAI agent.
`The amount of divalent cation is at least about 0.5
`equivalents and generally Within the range of from about 0.5
`to about 10 equivalents, more preferably 1.0 to about 5.0
`equivalents, per mole of NSAI. Note that molar equivalents
`are speci?ed since NSAI agents may be monovalent and
`hence stoichiometrically require only half as many moles of
`the divalent cation. Thus, for eXample, one mole of Mg++ per
`one mole of diclofenac anion Would be 2.0 equivalents of
`Mg++ (tWice as much cation as is required).
`“Non-steroidal anti-in?ammatory agents” as used herein
`are intended to mean any non-narcotic analgesic/non
`steroidal anti-in?ammatory compound useful in treating or
`ameliorating a disease or medical condition. They include
`drugs intended to therapeutically treat conditions of the eye
`itself or the tissue surrounding the eye and drugs adminis
`tered via the ophthalmic route to treat therapeutically a local
`condition other than that involving the eye. Preferably the
`NSAI agent is useful as a cyclooXygenase inhibitor.
`CyclooXygenase is essential in the biosynthesis of prostag
`landins Which have been shoWn in many animal models to
`be mediators of intraocular in?ammation. The NSAI agent
`typically contains at least one carboXy group in its molecule.
`EXamples of NSAI agents that are useful in the present
`invention include aspirin, benoXaprofen, benZofenac,
`bucloXic acid, butibufen, caiprofen, cicloprofen, cinmetacin,
`clidanac, clopirac, diclofenac, etodolac, fenbufen,
`fenclofenac, fenclorac, fenoprofen, fentiaZac,
`?unoXaprofen, furaprofen, ?urbiprofen, furobufen,
`furofenac, ibuprofen, ibufenac, indomethacin, indoprofen,
`isoXepac, ketorolac, ketroprofen, lactorolac, lonaZolac,
`metiaZinic, miroprofen, naproXen, oXaproZin, oXepinac,
`phenacetin, pirprofen, piraZolac, protiZinic acid, sulindac,
`suprofen, tiaprofenic acid, tolmetin, and Zomepirac.
`Preferably, the NSAI agent is selected from the group
`consisting of diclofenac, suprofen, ?urbiprofen and miXtures
`thereof.
`The composition of the present invention contains at least
`80% of the NSAI agent in precipitate form. This means that
`80%, by mole, of the NSAI is in a solid state. The remainder,
`if any, is in solution. In this regard the term “precipitate” is
`not meant to require that the solid Was formed by a precipi
`tation process, although such is usually the case. Preferably,
`85% to 95% of the NSAI agent is in precipitate form. The
`
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`US 6,265,444 B1
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`precipitate is usually dispersed in the aqueous medium or
`carried on a dispersed carrier such as a polymer particle, but
`such a dispersed form is not required.
`In one embodiment of the invention, the precipitate is the
`free-acid form (or free-base form) and not a salt form of the
`NSAI agent. Generally, the free-acid is almost alWays
`formed, even if formed from an NSAI divalent salt solution.
`For example, originally, a calcium or magnesium salt of
`diclofenac Was believed to have been formed as the precipi
`tate. HoWever, subsequent investigations shoWed that the
`precipitate Was in fact the free-acid of diclofenac. The
`divalent cation remained in solution. The presence of this
`divalent cation serves to reduce the solubility of the NSAI
`agent; thereby causing the desired delayed release.
`Alternatively, the precipitate can be a salt of the divalent
`cation and the NSAI agent or a mixture of salt and the
`free-acid forms.
`The remaining portion, if any, of the NSAI agent is in
`solution (a solute) and is typically in a salt form such as
`sodium diclofenac or magnesium diclofenac for example.
`The total amount of NSAI agent present in the composi
`tion is an amount effective to treat the selected target
`condition. Generally the concentration Will be about 0.001 to
`about 5.0% by Weight of the composition. Preferably, the
`drug is about 0.005 to about 3.0% by Weight of the
`composition, and more preferably about 0.1 to about 1.0%
`by Weight of the composition. These same ranges of drug
`concentrations are believed to be appropriate for treating a
`Wide range of conditions, such as those discussed above, in
`addition to treating in?ammation.
`The pH of the aqueous medium is set to be Within the
`range of 4.0 to 6.7. Importantly the pH is beloW that of the
`pH of the eye. In this Way, upon topical application of the
`composition to the eye, an increase in pH occurs thereby
`changing the solubility equilibrium of the NSAI agent and
`causing the precipitate to dissolve. As sloW dissolution
`during the ?rst minutes after administration is desired, the
`use of a loWer pH is preferred, such as from 4.0 to 6.5.
`The most preferred composition contains solid diclofenac
`in free-acid form and all of the divalent cation as Well as the
`remaining diclofenac in solution. The divalent cation is
`preferably calcium or magnesium. One of the advantages of
`this composition is the ability to fully (100%) redissolve at
`pH 7.0 or above With adequate residence time in the eye.
`This means that all of the diclofenac is recovered and made
`bioavailable When the composition is placed into the eye.
`The aqueous medium used in the present invention is
`made of Water that has no physiologically or ophthalmo
`logically harmful constituents. Typically puri?ed or deion
`iZed Water is used. The pH is adjusted by adding any
`physiologically and ophthalmologically acceptable pH
`adjusting acids, bases or buffers. Examples of acids include
`acetic, boric, citric, lactic, phosphoric, hydrochloric, and the
`like, and examples of bases include sodium hydroxide,
`sodium phosphate, sodium borate, sodium citrate, sodium
`acetate, sodium lactate, tromethamine, THAM
`(trishydroxymethylamino-methane), and the like. Salts and
`buffers Would include citrate/dextrose, sodium bicarbonate,
`ammonium chloride and mixtures of the aforementioned
`acids and bases.
`of the present composition is
`The osmotic pressure
`preferably from about 10 milliosmolar (mOsM) to about 400
`mOsM. If necessary, the osmotic pressure can be adjusted by
`using appropriate amounts of physiologically and ophthal
`mologically acceptable salts or excipients. When needed,
`sodium chloride is preferred to approximate physiologic
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`?uid, and amounts of sodium chloride ranging from about
`0.01% to about 1% by Weight, and preferably from about
`0.05% to about 0.45% by Weight, based on the total Weight
`of the composition, are typically used. Equivalent amounts
`of one or more salts made up of cations such as potassium,
`ammonium and the like and anions such as chloride, citrate,
`ascorbate, borate, phosphate, bicarbonate, sulfate,
`thiosulfate, bisulfate, sodium bisulfate, ammonium sulfate,
`and the like can also be used in addition to or instead of
`sodium chloride to achieve osmolalities Within the above
`stated range. Sugars like mannitol, dextrose, glucose or
`other polyols may be added to adjust osmolarity.
`The composition of the present invention may contain
`Water soluble polymers or Water insoluble polymers as a
`suspending agent. Examples of such soluble polymers are
`dextran, polyethylene glycols, polyvinylpyrolidone,
`polysaccaride gels, Gelrite®, and cellulosic polymers like
`hydroxypropyl methylcellulose as Well as other polymeric
`demulcents. Water insoluble polymers are preferably
`crosslinked carboxy-vinyl polymers.
`A preferred embodiment of the invention provides the
`ophthalmic composition as either gel or liquid drops that
`contain Water insoluble, Water-sWellable polymers Which
`release the drug over time; i.e., over one or more hours.
`Preferably, the polymer is contained in an amount of about
`0.1 to about 6.5%, more preferably about 0.5 to about 1.3%
`by Weight based on the total Weight of the composition.
`These polymer carriers include lightly crosslinked carboxy
`containing polymers (such as polycarbophil (Noveon AA-1)
`or Carbopol®) Which typically have an average dry particle
`siZe of not more than about 50 pm in equivalent spherical
`diameter, more preferably not more than 20pm in equivalent
`spherical diameter. The crosslinked carboxy-containing
`polymers can be formed from carboxy-containing monoet
`hylenically unsaturated monomers such as acrylic acid,
`methacrylic acid, crotonic acid, and the like and from
`suitable crosslinking agents such as difunctional crosslink
`ers including divinyl glycol, divinyl benZene, 2,5-dimethyl
`1,5-hexadiene, and polyalkenyl polyether compounds. The
`carboxy-containing polymer backbone can be a homopoly
`mer or a copolymer comprised of tWo or more monomer
`species. When tWo or more monomers are used, non
`carboxy-containing monomers may be employed, such as
`acrylic acid esters and methacrylic acid esters (ethyl
`acrylate, methyl methacrylate, etc.), vinyl acetate,
`N-vinylpyrrolidone, and the like. These non-carboxy
`containing comonomers are preferably present in an amount
`of not more than 40 Wt. %, more preferably 0 to 20 Wt. %,
`based on the total Weight of monomers present. The amount
`of crosslinker employed is preferably from about 0.01 to
`5%, more preferably from 0.1 to 1.0%, based on the total
`Weight of monomers present. Suitable carboxy-containing
`polymers for use in the present invention and methods for
`making them are described in US. Pat. No. 5,192,535 to
`Davis et al. Which is hereby incorporated by reference. A
`suitable carboxy-containing polymer system for use in the
`present composition is knoWn by the tradename DuraSite®,
`containing polycarbophil, Which is a sustained release topi
`cal ophthalmic delivery system that releases the drug at a
`controlled rate.
`The ophthalmic compositions of the present invention
`have a viscosity that is suited for the selected route of
`administration. Aviscosity up to about 30,000 centipoise is
`useful for a drop. About 30,000 to about 100,000 centipoise
`is an advantageous viscosity range for ophthalmic adminis
`tration in ribbon form. The viscosity can be controlled in
`many Ways knoWn to the Worker skilled in the art.
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`US 6,265,444 B1
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`7
`In one embodiment, the amount of insoluble lightly
`crosslinked polymer particles, the pH, and the osmotic
`pressure can be correlated With each other and With the
`degree of crosslinking to give a composition having a
`viscosity in the range of from about 500 to about 100,000
`centipoise, and preferably from about 1,000 to about 30,000
`or about 1,000 to about 10,000 centipoise, as measured at
`room temperature (about 25° C.) using a Brook?eld Digital
`LVT Viscometer equipped With a number 25 spindle and a
`13R small sample adapter at 12 rpm. Alternatively, When
`Water soluble polymers are used, such as hydroxypropyl
`methylcellulose, the viscosity Will typically be about 10 to
`about 400 centipoise, more typically about 10 to about 200
`centipoises or about 10 to about 25 centipoise.
`Ophthalmic compositions of the present invention may be
`formulated so that they retain the same or substantially the
`same viscosity in the eye that they had prior to administra
`tion to the eye. Alternatively, ophthalmic compositions of
`the present invention may be formulated so that there is
`increased gelation upon contact With tear ?uid. For instance,
`When a formulation containing DuraSite® is administered to
`the eye at a loWer pH, the DuraSite® system sWells upon
`contact With tears. This gelation or increase in gelation leads
`to entrapment of the suspended drug particles, thereby
`extending the residence time of the composition in the eye.
`The drug is released sloWly as the suspended particles
`dissolve over time as the solubility of the drug is higher in
`the tear ?uid. All these events eventually lead to increased
`patient comfort, increase in the time the drug is in contact
`With the eye tissues, thereby increasing the extent of drug
`absorption and duration of action of the formulation in the
`eye.
`The viscous gels that result from ?uid eye drops typically
`have residence times in the eye ranging from about 2 to
`about 12 hours, e.g., from about 3 to about 6 hours. The
`agents contained in these drug delivery systems Will be
`released from the gels at rates that depend on such factors as
`the drug itself and its physical form, the extent of drug
`loading and the pH of the system, as Well as on any drug
`delivery adjuvants, such as ion exchange resins compatible
`With the ocular surface, Which may also be present.
`Preferably, the compositions provide a sustained concentra
`tion of the NSAI agent of betWeen 10-8 and 10-4 M, and
`more preferably betWeen 10'7 and 10'5 M, in the aqueous or
`treated tissue of the eye for at least tWo hours, preferably at
`least three hours.
`The composition of the present invention Will ordinarily
`contain surfactants and, if desired, adjuvants, including
`additional medicaments, buffers, antioxidants, tonicity
`adjusters, preservatives, thickeners or viscosity modi?ers,
`and the like. Additives in the formulation may desirably
`include sodium chloride, EDTA (disodium edetate), phos
`phonic acid, BAK (benZalkonium chloride), perborate salt,
`sorbic acid, methyl paraben, propyl paraben, and/or chlo
`rhexidine. It should be noted that BAK Was found to be
`unexpectedly compatible With diclofenac in the present
`ophthalmic composition. While the reasons for this are not
`entirely clear, and Without Wishing to be bound by any
`theory, the presence of the divalent cation is believed to
`prevent the BAK from complexing the diclofenac out of the
`system.
`The preferred preservative in the divalent cation non
`steroidal anti-in?ammatory ophthalmic composition is
`sodium perborate in an amount of from about 0.01 to 0.5 Wt.
`%, more preferably from 0.03 to 0.3 Wt. %.
`In this connection, applicants have also discovered that a
`perborate salt can be effectively stabiliZed by the presence of
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
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`55
`
`60
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`65
`
`8
`both a polyphosphonic acid peroxy stabiliZer and EDTA.
`This discovery Was surprising in that the presence of EDTA
`Would have been expected to interfere With the complexing
`action of the polyphosphonic acid stabiliZer. Moreover, the
`presence of EDTA surprisingly enhances the stability of the
`composition. This three component preservative system is
`applicable to any aqueous ophthalmic composition includ
`ing saline solutions, eye lubricants, medicated compositions,
`etc. and is not limited to use in combination With a non
`steroidal anti-in?ammatory agent. The preservative system
`comprises (1) about 0.01 to 0.5 Wt. %, preferably 0.03 to 0.3
`Wt. %, of a perborate salt; (2) about 0.001 to 0.06 Wt. %,
`preferably 0.003 to 0.03 Wt. %, of a polyphosphonic acid
`peroxy stabiliZer; and (3) about 0.01 to 0.1 Wt. % of EDTA,
`based on the total Weight of the composition. The preser
`vative system may additionally comprise 0.05 to 0.2 parts of
`BAK. The perborate salt is preferably sodium perborate.
`A “polyphosphonic acid peroxy stabiliZer” means any
`compound containing at least tWo —PO3H2 moieties or the
`pharmacologically acceptable salt thereof, and that is
`capable of stabiliZing a peroxy compound. Such compounds
`are generally Well knoWn in the prior art. Preferably the
`polyphosphonic acid peroxy stabiliZer is a compound of the
`formula I or II or a pharmacologically acceptable salt
`thereof:
`
`Wherein x is an integer of 0 to 3 and k, m, n, o, and p are
`each independently an integer of 1 to 4. Preferably x is
`2 and k, m, n, o, and p are each 1 or 2.
`
`CH3
`
`Wherein q, r, s, and t are each independently an integer of
`0 to 4. Preferably q, r, s, and t are 0 or 1, and most
`preferably all are Zero.
`Many of the compounds of formulas I and II are sold by
`Monsanto under the DEQUEST brand name. A preferred
`compound is diethylene triamine penta(methylene
`phosphonic acid), Which corresponds to formula I, and is
`sold as DEQUEST 2060.
`The Water used in the preserved ophthalmic composition
`of the present invention is normally steriliZed. The preserved
`ophthalmic composition can contain additional ingredients
`including any of the ingredients discussed previously. For
`example, sodium chloride can be present as part of a saline
`solution; a carboxy-containing polymer, such as
`polycarbophil, can be present to form a stably preserved
`suspension; etc. With respect to the latter composition, a
`preferred form further includes magnesium ions (Mg++) in
`addition to the polymer and the perborate/polyphosphonic
`acid peroxy stabilizer/EDTA system. The amount of mag
`
`Page 6
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`
`US 6,265,444 B1
`
`nesium is not particularly limited, but typically ranges from
`about 0.005 to 0.5Wt. %, preferably 0.02 to 0.2 Wt. % (the
`amount of polymer being the same as described above).
`Such a composition is Well preserved and also exhibits a
`stable viscosity during storage.
`Alternatively, a pharmaceutically active agent may be
`present as part of a medicated composition. In this regard, a
`“pharmaceutically active agent” is broader in scope than an
`NSAI agent and embraces any agent With pharmaceutical
`utility that can be used to treat the eye or administered via
`the eye in treating a disease or condition of the patient.
`The preservative system can used in a variety of aqueous
`ophthalmic compositions such as saline solutions for clean
`ing contact lenses, as an eye Wash, as an eye lubricating or
`Wetting composition, and as a medicated composition. The
`preservative system of the present invention is preferably
`combined With the above-described divalent cation
`containing ophthalmic composition.
`The compositions of the present invention can be pre
`pared from knoWn materials through the application of
`knoWn techniques by Workers of ordinary skill in the art
`Without undue