US 8,629,111 B2
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`References Cited
`U.S. PATENT DOCUMENTS
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`5t962t0 l4 A
`5t962t0l7 A
`5t962t0l9 A
`5t977t066 A
`5t98lt479 A
`5t98lt607 A
`5t998t365 A
`6t004t566 A
`6t007t840 A
`6t008tl9l A
`6,008,192 A
`6,022,852 A
`6,024,978 A
`6,046,163 A
`6,057,289 A
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`Ep
`EP
`wo
`wo
`W0
`wo
`wo
`wo
`wo
`wo
`
`0547229
`0760237
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`00-00179
`01-32142
`01-41571
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`
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`3/1997
`11/1995
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`5/2001
`5/2001
`2/2002
`5/2002
`4/2003
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`
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`hlhal
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`P
`.
`’
`f
`2 H ’dr P
`l’
`l d
`.
`’C
`l
`f
`¢m£$1R3§31f°:§««‘3~¢
`' Y °x“”°PY 'I3'°y° ° em“
`°mP ex“ °
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`TEVA - EXHIBIT 1004 (PART 4 OF 4)
`
`0503
`
`TEVA - EXHIBIT 1004 (PART 4 OF 4)
`
`

`
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`
`* cited by examiner
`
`0504
`
`0504
`
`

`
`US 8,629,111 B2
`
`1
`METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`RELATED APPLICATION
`
`This application is a continuation of copending U.S. appli-
`cation Ser. No. 13/961,828 filed Aug. 7, 2013, which is a
`continuation of copending U.S. application Ser. No. 11/897,
`177, filed Aug. 28, 2007, which is a continuation of U.S.
`application Ser. No. 10/927,857, filed Aug. 27, 2004, now
`abandoned, which claimed the benefit of U.S. Provisional
`Application No. 60/503,137 filed Sep. 15, 2003, which are
`incorporated in their entirety herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to methods of providing
`desired therapeutic effects to humans or animals using com-
`positions including cyclosporin components. More particu-
`larly, the invention relates to methods including administer-
`ing to an eye of a human or animal a therapeutically effective
`amount of a cyclosporin component to provide a desired
`therapeutic effect, preferably a desired ophthalmic or ocular
`therapeutic effect.
`The use of cyclosporin-A and cyclosporinA derivatives to
`treat ophthalmic conditions has been the subject of various
`patents, for example Ding et al U.S. Pat. No. 5,474,979; Garst
`U.S. Pat. No. 6,254,860; and Garst U.S. Pat. No. 6,350,442,
`this disclosure of each of which is incorporated in its entirely
`herein by reference. In addition, cyclosporin A compositions
`used in treating ophthalmic conditions is the subject of a
`number of publications. Such pub§Liga1;ion\s““LngLL§ie,
`for
`example, “Blood concentrations of §cyclosporin a§during
`long-term treatment with§B§E‘i8§i33B*fi"§“fpritnaimi€ emul-
`sions in patients with moétera‘te“to“s‘e‘v‘ere“dry eye disease,”
`Small et al, J Ocul Pharmacol Ther, 2002 October, 18(5):41 1-
`8; “Distribution of cyclosporin A in ocular tissues after topi-
`cal administration to albino rabbits and beagle dogs,”
`Acheampong et al, Curr Eye Res, 1999 February, 18(2):91-
`103b; “Cyclosporine distribution into the conjunctiva, cor-
`nea, lacrimal gland, and systemic blood following topical
`dosing of cyclosporine to rabbit, dog, and human eyes,”
`Acheampong et al, Adv Exp Med Biol, 1998, 438:1001-4;
`“Preclinical safety studies of cyclosporine ophthalmic emul-
`sion,” Angelov et al, Adv Exp Med Biol, 1998, 4382991-5;
`“Cyclosporin & Emulsion & Eye,” Stevenson et al, Ophthal-
`mology, 2000 May, 107(5):967-74; and “Two multicenter,
`randomized studies of the efficacy and safety of cyclosporine
`ophthalmic emulsion in moderate to severe dry eye disease.
`CsA Phase 3 Study Group,” Sall et al, Ophthalmology, 2000
`April, 107(4):631-9. Each of these publications is incorpo-
`rated in its entirety herein by reference.
`In addition,
`cyclosporin A-containing oil-in-water emulsions have been
`clinically tested, under conditions of confidentiality, since the
`mid 1990’s in order to obtain U.S. Food and Drug Adminis-
`tration (FDA) regulatory approval.
`Examples of useful cyclosporin A-containing emulsions
`are set out in Ding et al U.S. Pat. No. 5,474,979. Example 1 of
`this patent shows a series of emulsions in which the ratio of
`cyclosporin A to castor oil in each of these compositions was
`0.08 or greater, except for Composition B, which included
`0.2% by weight cyclosporinA and 5% by weight castor oil.
`The Ding et al patent placed no significance in Composition
`B relative to Compositions A, C and D of Example 1.
`Over time, it has become apparent that cyclosporinA emul-
`sions for ophthalmic use preferably have less than 0.2% by
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`weight of cyclosporin A. With cyclosporin A concentrations
`less than 0.2%, the amount of castor oil employed has been
`reduced since one of the functions of the castor oil is to
`
`solubilize the cyclosporin A. Thus, if reduced amounts of
`cyclosporin are employed, reduced amounts of castor oil are
`needed to provide effective solubilization of cyclosporin A.
`There continues to be a need for providing enhanced meth-
`ods of treating ophthalmic or ocular conditions with
`cyclosporin-containing emulsions.
`
`SUMMARY OF THE INVENTION
`
`New methods of treating a human or animal using
`cyclosporin component-containing emulsions have been dis-
`covered. Such methods provide substantial overall efficacy in
`providing desired therapeutic effects.
`In addition, other
`important benefits are obtained employing the present meth-
`ods. For example, patient safety is enhanced. In particular, the
`present methods provide for reduced risks of side effects
`and/or drug interactions. Prescribing physicians advanta-
`geously have increased flexibility in prescribing such meth-
`ods and the compositions useful
`in such methods,
`for
`example, because of the reduced risks of harmful side effects
`and/or drug interactions. The present methods can be easily
`practiced. In short, the present methods provide substantial
`and acceptable overall efficacy, together with other advan-
`tages, such as increased safety and/or flexibility.
`In one aspect of the present invention, the present methods
`comprise administering to an eye of a human or animal a
`composition in the form of an emulsion comprising water, a
`hydrophobic component and a cyclosporin component in a
`therapeutically effective amount of less than 0.1% by weight
`of the composition. The weight ratio of the cyclosporin com-
`ponent to the hydrophobic component is less than 0.08.
`It has been found that the relatively increased amounts of
`hydrophobic component together with relatively reduced, yet
`therapeutically effective, amounts of cyclosporin component
`provide substantial and advantageous benefits. For example,
`the overall efficacy of the present compositions, for example
`in treating dry eye disease, is substantially equal to an iden-
`tical composition in which the cyclosporin component is
`present in an amount of 0. 1% by weight. Further, a relatively
`high concentration of hydrophobic component is believed to
`provide for a more quick or rapid breaking down or resolving
`of the emulsion in the eye, which reduces vision distortion
`which may be caused by the presence of the emulsion in the
`eye and/or facilitates the therapeutic effectiveness ofthe com-
`position. Additionally, and importantly, using reduced
`amounts of the active cyclosporin component mitigates
`against undesirable side effects and/or potential drug interac-
`tions.
`
`In short, the present invention provides at least one advan-
`tageous benefit, and preferably a plurality of advantageous
`benefits.
`
`The present methods are useful in treating any suitable
`condition which is therapeutically sensitive to or treatable
`with cyclo sporin components. Such conditions preferably are
`ophthalmic or ocular conditions, that is relating to or having
`to do with one or more parts of an eye of a human or animal.
`Included among such conditions are, without limitation, dry
`.
`.
`.
`.
`.
`\\\\\\\\\\\\\\\\\\\\\ ,“m““,“,“,“\
`eye syndrome, phacoanaphylactic endophthalmitis ‘uveitis,
`vernal conjunctivitis, atOp1Cil(eI‘apOCOI1]11I1Ct1V1t1S,§COI‘I1eal
`graft rejection and the like coiiEti?fi§T“I‘Ii‘é‘pFe‘sefit‘i?ivention
`is particularly effective in treating dry eye syndrome.
`Cyclosporin has been found as effective in treating immune
`.
`mediated keratoconjunctivitis sicca (KCS or drygye disease)‘
`\\\\\\\\\\\\\\\\\\\\\V:\\\\
`in a patient suffering therefrom. The activity of§cyc osporineg
`
`0505
`
`0505
`
`

`
`US 8,629,111 B2
`
`sEsss.
`
`N
`3
`\\\\\\\\\\V:‘
`\
`\\\\\\\\\\\\
`is as:$1n immuno suppressant and in the enhancement or restor-
`1ng of lacrimal gland tearing. Other conditions that can be
`treated with cyclosporin components include an absolute or
`partial deficiency in aqueous tear production (keratocor1junc-
`tivitis sicca, or KCS). Topical administration to a patient’s
`tear deficient eye can increase tear production in the eye. The
`treatment can further serve to correct corneal and conjuncti-
`val disorders exacerbated by tear deficiency and KCS, such as
`corneal scarring, corneal ulcerat‘i“o‘g,‘i‘rl_11a‘r‘I_1rnation of the cor-
`nea or conjunctiva, filamentaryikeratisis,gmucopurulent dis-
`charge and vascularization of th\‘€‘C‘t‘f‘f‘IT€"2I‘.‘§
`Employing reduced concentrations of cyclosporin compo-
`nent, as in the present invention, is advantageously effective
`to provide the blood of the human or animal under treatment
`with reduced concentrations of cyclosporin component, pref-
`erably with substantially no detectable concentration of the
`cyclosporin component. The cyclosporin component concen-
`tration of blood can be advantageously measured using a
`validated liquid chromatography/mass spectrometry-mass
`spectrometry (VLC/MS-MS) analytical method, such as
`described elsewhere herein.
`
`4
`
`of such other components include, without limitation, emul-
`sifier components,
`tonicity components, polyelectrolyte
`components, surfactant components, viscosity inducing com-
`ponents, acids and/or bases to adjust the pH of the composi-
`tion, buffer components, preservative components and the
`like. Components may be employed which are effective to
`perform two or more functions in the presently useful com-
`positions. For example, components which are effective as
`both emulsifiers and surfactants may be employed, and/or
`components which are effective as both polyelectrolyte com-
`ponents
`and viscosity inducing components may be
`employed. The specific composition chosen for use in the
`present
`invention advantageously is selected taking into
`account various factors present in the specific application at
`hand,
`for example,
`the desired therapeutic effect
`to be
`achieved, the desired properties of the compositions to be
`employed, the sensitivities of the human or animal to whom
`the composition is to be administered, and the like factors.
`The presently useful compositions advantageously are
`ophthalmically acceptable. A composition, component or
`material is ophthalmically acceptable when it is compatible
`with ocular tissue, that is, it does not cause significant or
`undue detrimental effects when brought into contact with
`ocular tissues.
`
`Such compositions have pH’s within the physiological
`range ofabout 6 to about 10, preferably in a range ofabout 7.0
`to about 8.0 and more preferably in a range of about 7.2 to
`about 7.6.
`
`The present methods preferably provide for an administer-
`ing step comprising topically administering the presently use-
`ful compositions to the eye or eyes of a human or animal.
`Each and every feature described herein, and each and
`every combination of two or more of such features,
`is
`included within the scope of the present invention provided
`that the features included in such a combination are not mutu-
`
`ally inconsistent.
`These and other aspects and advantages of the present
`invention are apparent in the following detailed description,
`example and claims.
`
`DETAILED DESCRIPTION
`
`The present methods are effective for treating an eye of a
`human or animal. Such methods, in general, comprise admin-
`istering, preferably topically administering, to an eye of a
`human or animal a cyclosporin component-containing emul-
`sion. The emulsion contains water, for example U.S. pure
`water, a hydrophobic component and a cyclosporin compo-
`nent in a therapeutically effective amount ofless than 0.1% by
`weight of the emulsion. In addition, beneficial results have
`been found when the weight ratio of the cyclosporin compo-
`nent to the hydrophobic component is less than 0.08.
`As noted above, the present administering step preferably
`includes topically administering the emulsion to the eye of a
`patient of a human or animal. Such administering may
`involve a single use of the presently useful compositions, or
`repeated or periodic use of such compositions, for example,
`as required or desired to achieve the therapeutic effect to be
`obtained. The topical administration of the presently useful
`composition may involve providing the composition in the
`form of eye drops or similar form or other form so as to
`facilitate such topical administration.
`The present methods have been found to be very effective
`in providing the desired therapeutic effect or effects while, at
`the same time, substantially reducing, or even substantially
`eliminating, side effects which may result from the presence
`of the cyclosporin component in the blood of the human or
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`0506
`
`In one embodiment, in the present me:‘th‘qd“s“tli‘e‘:‘:t3‘l‘o‘od ofthe
`human or animal has concentrations of§clyclosporin\§compo-
`nent of 0.1 ng/ml or less.
`K“““““““““““‘§
`Any suitable cyclosporin component effective in the
`present methods may be used.
`Cyclosporins are a group of nonpolar cyclic oligopeptides
`with known immunosuppressant activity. Cyclosporin A,
`along with several other minor metabolites, cyclosporin B
`through I, have been identified. In addition, a number of
`synthetic analogs have been prepared.
`In general, commercially available cyclosporins may con-
`tain a mixture of several individual cyclosporins which all
`share a cyclic peptide structure consisting of eleven amino
`acidresidues with a total molecular weight ofabout 1,200, but
`with different substituents or configurations of some of the
`amino acids.
`
`The term “cyclosporin component” as used herein is
`intended to include any individual member ofthe cyclosporin
`group and derivatives thereof, as well as mixtures of two or
`more individual cyclosporins and derivatives thereof.
`Particularly preferred cyclosporin components include,
`without limitation, cyclosporin A, derivatives of cyclosporin
`A and the like and mixtures thereof. Cyclosporin A is an
`especially useful cyclosporin component.
`Any suitable hydrophobic component may be employed in
`the present invention. Advantageously, the cyclosporin com-
`ponent is solubilized in the hydrophobic component. The
`hydrophobic component may be considered as comprising a
`discontinuous phase in the presently useful cyclosporin com-
`ponent-containing emulsions.
`The hydrophobic component preferably is present in the
`emulsion compositions in an amount greater than about
`0.625% by weight. For example, the hydrophobic component
`may be present in an amount ofup to about 1.0% by weight or
`about 1.5% by weight or more of the composition.
`Preferably, the hydrophobic component comprises one or
`more oily materials. Examples ofuseful oil materials include,
`without limitation, vegetable oils, animal oils, mineral oils,
`synthetic oils and the like and mixtures thereof. In a very
`usefiil embodiment, the hydrophobic component comprises
`one or more higher fatty acid glycerides. Excellent results are
`obtained when the hydrophobic component comprises castor
`oil.
`
`The presently useful compositions may include one or
`more other components in amounts effective to facilitate the
`usefiilness and effectiveness of the compositions. Examples
`
`0506
`
`

`
`US 8,629,111 B2
`
`6
`copy (LC-MS/MS), which test has a cyclosporin component
`detection limit of 0.1 ng/ml. Cyclosporin component concen-
`trations below or less than 0.1 ng/ml are therefore considered
`substantially undetectable.
`The LC-MS/MS test is advantageously run as follows.
`One ml of blood is acidified with 0.2 ml of 0.1 N HCl
`
`5
`animal being treated, and eye irritation which, in the past, has
`been caused by the presence ofcertain components in prior art
`cyclosporin-containing emulsions. Also,
`the use of the
`present compositions which include reduced amounts of the
`cyclosporin components allow for more frequent administra-
`tion of the present compositions to achieve the desired thera-
`solution, then extracted with 5 ml of methyl t-butyl ether.
`peutic effect or effects without substantially increasing the
`After separation from the acidified aqueous layer, the organic
`risk of side effects and/or eye irritation.
`phase is neutralized with 2 ml of 0.1 N NaOH, evaporated,
`The present methods are useful in treating any condition
`which is therapeutically sensitive to or treatable with 10 reconstituted in a water/acetonitrile-basedfifitilgahase, and
`cyclosporin components. Such conditions preferably are oph-
`injected onto a 2.lx50 mm, 3 pm pore size C-8 reverse phase
`thalmic or ocular conditions, that is relating to or having to do
`high pressure liquid chromatography (HPLC) colunm (Key-
`with one or more parts of an eye of a human or animal.
`stone Scientific, Bellefonte, Pa.). Compounds are gradient-
`Included among such conditions are, without limitation, dry 15 eluted at 0.2 mL/min and detected using an API Ill triple
`eye syndrome, phacoanaphylgctig“en\dophthalrnjti§,‘ uveitis,
`quadrupole mass spectrometer with a turbo-ionspray source
`vernal conjunctivitis, atopic§kerapoconjunctivitis, gcomeal
`(PE-Sciex, Concord, Ontario, Canada). Molecular reaction
`graft rejection and the like conditions. The present invention
`monitoring enhances the sensitivity and selectivity of this
`is particularly effective in treating dry eye syndrome.
`assay. Protonated molecules for the analyte and an internal
`The frequency of administration and the amount of the 20 standard are collisionally dissociated and product ions at n1/z
`presently useful composition to use during each administra-
`425 are monitored for the analyte and the internal standard.
`tion varies depending upon the therapeutic effect
`to be
`Under these conditions, cyclosporinA and the internal stan-
`obtained, the severity of the condition being treated and the
`dard cyclosporin G elute with retention times of about 3.8
`like factors. The presently useful compositions are designed
`minutes. The lower limit of quantitation is 0.1 ng/mL, at
`to allow the prescribing physician substantial flexibility in 25 which concentration the coefficient ofvariation and deviation
`treating various ocular conditions to achieve the desired
`from nominal concentration is <l5%.
`thera eutic effect or effects with reduced risk of side effects
`As noted reviousl , an suitable c clos orin com onent
`p
`.
`.
`.
`.
`.
`.
`.
`.
`p
`y
`y
`y
`p
`p
`and’or eye irritation. Such administration may occur on an as
`effective in the present methods may be employed. Very use-
`needed basis, for example, in treating or managing dry eye
`ful cyclosporin components include, without
`limitation,
`syndrome, on a one time basis or on a repeated or periodic 30 cyclosporin A, derivatives of cyclosporinA and the like and
`basis once, twice, thrice or more times daily depending on the
`mixtures thereof.
`needs of the human or animal being treated and other factors
`The chemical structure for cyclosporin A is represented by
`involved in the application at hand.
`Formula 1
`
`Formula l
`
`0H3
`
`H30
`H30
`
`\N
`
`H30
`
`CH3
`
`H30
`
`HO,,,,
`
`o
`TH3
`N\)k
`E
`5
`H30/\0H3
`
`o
`
`T
`CH3
`
`CH3
`
`0
`CH3
`NHA 0H3
`E
`N/
`2
`\0H3
`
`o
`
`0
`
`0
`0H3
`
`0
`
`H30
`
`0
`
`N—0H3
`
`CH3
`
`N
`
`H3C/
`
`N
`H
`
`o
`
`N
`
`‘
`
`0H3
`
`o
`
`N
`I
`CH
`3
`H3C
`
`N
`
`O
`
`0H
`
`3
`
`0H3
`
`As used herein the term “derivatives” ofa cyclo sporin refer
`One of the important advantages of the present invention is
`the reduced concentration of the cyclosporin component in 50 to compounds having structures sufiicjenfly sjmflar to the
`the blood of the human or animal as a result of administering
`cyclosporin so as to function in a manner substantially similar
`the present composition as described herein. One very useful
`to or substantially identical to the cyclosporin, for example,
`embod