(12) United States Patent
`Acheampong et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 8,629,111 B2
`Jan. 14, 2014
`
`US00862911lB2
`
`(54) METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`(71) Applicant: Allergan, Inc., Irvine, CA (US)
`
`(72)
`
`Invc11tors: Andrew Acheampong, Irvinc, CA (US);
`Diane D. Tang-Liu, Las Vegas, NV
`(US); James N. Chang, Newport Beach,
`CA (US); David F. Power, Hubert, NC
`(US)
`
`Assig11ee: Allergan, Inc., Irvine, CA (US)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted 11nder 35
`U.S.C. l54(b) by 0 days.
`
`Appl. N0.: 13/967,163
`
`Filed:
`
`Aug. 14, 2013
`
`Prior Publication Data
`
`US 2013/0331339 A1
`
`Dec. 12, 2013
`
`Related U.S. Application Data
`
`Continuation of application No. 13/961,828, filed on
`Aug. 7, 2013, which is a continuation of application
`No. 11/897,177,
`filed on Aug. 28, 2007, and a
`continuation of application No. 10/927,857, filed on
`Aug. 27, 2004, now abandoned.
`
`Provisional application No. 60/503,137, filed on Sep.
`15, 2003.
`
`(2006.01)
`
`Int. Cl.
`A61K 38/13
`U.S. Cl.
`USPC ....................................................... .. 514/20.5
`Field of Classification Search
`None
`See application file for complete search history.
`
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`(Continued)
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`(Continued)
`
`Primary Examiner — Marcela M Cordero Garcia
`(74) Attorney, Agent, or Firm Laura L. Wine; Joel B.
`German; Debra D. Condino
`
`(57)
`
`ABSTRACT
`
`Mcthods of treating an cyc of a human or animal includc
`administering to an eye of a human or animal a composition
`in the form of an emulsion including water, a hydrophobic
`compone11t and a cyclo sporin component in a therapeutically
`effective amount of less than 0.1% by weight of the compo-
`sition. The weight ratio of the cyclosporin component to the
`hydrophobic component is less than 0.8.
`
`27 Claims, No Drawings
`
`FAMY CARE - EXHIBIT 1001-0001
`
`

`
`US 8,629,111 B2
`Page 2
`
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`Pending U.S. Appl. No. 13/967,168, filed Aug. 14,2013.
`Re-Exam U.S. Appl. No. 90/009,944, filed Aug. 27, 2011.
`
`* cited by examiner
`
`FAMY CARE - EXHIBIT 1001-0003
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`

`
`US 8,629,111 B2
`
`1
`METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COIVIPONENTS
`
`RELATED APPLICATION
`
`This application is a continuation of copendi11g U.S. appli-
`cation Ser. No. 13/961,828 filed Aug. 7, 2013, which is a
`continuation of copending U.S. application Ser. No.
`1 1/897,
`177, filed Aug. 28, 2007, which is a continuation of U.S.
`application Ser. No. 10/927,857, filed Aug. 27, 2004, now
`abandoned, wl1icl1 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 n1ethods 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 cyclosporin A 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 i11 its entirely
`herein by reference. In addition, cyclosporin A compositions
`used in treating ophthahnic conditions is the subject of a
`number of publications. Such publications include,
`for
`example, “Blood concentrations of cyclosporin a during
`long-term treatment with cyclosporin a ophthalmic emul-
`sions in patients with moderate to severe dry eye disease,”
`Small et al, JOculP/zarmacol 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:l001-4;
`“Preclinical safety studies of cyclosporine ophthalmic emul-
`sion,” Angelov et al, Adv Exp A/[ed 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 eflicacy and safety of cyclosporine
`ophthalmic emulsion in moderate to severe dry eye disease.
`CsA Phase 3 Study Group,” Sall et al, Ophzhalmologz, 2000
`April,
`l07(4i):631-9. Each of these publications is incorpo-
`rated in its entirety herein by reference.
`Ir1 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 a11d 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 ca stor oil in each ofthese compositions was
`0.08 or greater, except for Composition B, which included
`0.2% by weight cyclosporin A 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 cyclo sporinA emul-
`sions for ophthalmic use preferably have ess than 0.2% by
`
`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 amormts 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 eflicacy in
`providing desired therapeutic effects.
`In addition, other
`important benefits are obtained employing the present meth-
`ods. For example, patient safety is enhanced. Inparticular, 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 oftl1e 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
`oftl1e composition. The weight ratio ofthe 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, amotmts 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 of0.1% 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 coin-
`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 lea st 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
`eye syndrome, pha coanaphyla ctic endophthalmitis, uveitis,
`vemal conjunctivitis, atopic kerapoconj unctivitis, corneal
`graft rejection and the like conditions. The present invention
`is particularly effective in treating dry eye syndrome.
`Cyclosporin l1as been found as effective i11 treating immune
`mediated keratoconjunctivitis sicca (KCS or dry eye disease)
`in a patient suffering therefrom. The activity of cyclosporine
`
`30
`
`55
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`FAMY CARE - EXHIBIT 1001-0004
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`

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`US 8,629,111 B2
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`3
`is as ar1 in1n1ur1o suppressant and in tlie er1l1ancen1er1t or restor-
`i11g of lacrimal gland tearing. Other conditions that can be
`treated with cyclosporin components include an absolute or
`partial deficiency i11 aqueous tear production (keratoconjunc—
`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 ulceration, inflammation of the cor-
`nea or conjunctiva, filamentary keratisis, mucopurulent dis-
`charge and vascularization of the cornea.
`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 cyclo sporin 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 cl1ror11atograpl1y/n1ass spectrornetry-n1ass
`spectrometry (VLC/MS-MS) analytical method, such as
`described elsewhere herein.
`
`In one embodiment, in the present methods the blood ofthe
`human or animal has concentrations of clyclosporin compo-
`nent of0.1 ng/ml or less.
`Any suitable cyclosporin component effective in the
`present methods may be used.
`Cyclosporins are a group of nonpolar cyclic oligopeptides
`witl1 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
`acid residues with a total molecular weight ofabout 1,200, but
`with different substituents or configurations of some of the
`amino acids.
`The tenn “cyclosporin component” as used herein is
`intended to include any individual member ofthe cyclo sporin
`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 cyclo sporin com-
`ponent is solubilized in the hydrophobic component. The
`hydrophobic component may be considered as comprising a
`discontinuous phase iii 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 of up 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
`usefulness and effectiveness of the compositions. Examples
`
`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 pII 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 iii 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 ofabo11t 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 a11d 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 smile 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
`
`FAMY CARE - EXHIBIT 1001-0005
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`US 8,629,111 B2
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`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
`cyclo sporin components allow for more frequent administra-
`tion of the present compositions to achieve the desired thera-
`peutic effect or effects witl1out substantially increasing the
`risk of side effects and/or eye irritation.
`The present methods are useful in treating any condition
`which is therapeutically sensitive to or treatable with
`cyclo sporin components. Such cond