111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008629111B2
`
`c12) United States Patent
`Acheampong et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,629,111 B2
`Jan.14,2014
`
`(54) METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`(71) Applicant: Allergan, Inc., Irvine, CA (US)
`
`(72)
`
`Inventors: Andrew Acheampong, Irvine, CA (US);
`Diane D. Tang-Liu, Las Vegas, NV
`(US); James N. Chang, Newport Beach,
`CA (US); David F. Power, Hubert, NC
`(US)
`
`(73) Assignee: Allergan, Inc., Irvine, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 13/967,163
`
`(22) Filed:
`
`Aug. 14, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2013/0331339 Al
`
`Dec. 12, 2013
`
`5,411,952 A
`5,424,078 A
`5,474,919 A
`5,474,979 A
`5,504,068 A
`5,540,931 A
`5,543,393 A
`5,589,455 A
`5,591,971 A
`5,614,491 A
`5,639,724 A
`5,652,212 A
`5,719,123 A
`5,739,105 A
`5,753,166 A
`5,766,629 A
`5,798,333 A
`5,807,820 A
`5,827,822 A
`5,827,862 A
`5,834,017 A
`5,843,452 A
`5,843,891 A
`5,858,401 A
`5,866,159 A
`5,891,846 A
`5,916,589 A
`5,929,030 A
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`7/1999
`(Continued)
`
`Related U.S. Application Data
`
`FOREIGN PATENT DOCUMENTS
`
`(63) 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.
`
`DE
`EP
`
`9/1999
`19810655
`2/1992
`0471293
`(Continued)
`
`OTHER PUBLICATIONS
`
`(60) Provisional application No. 60/503,137, filed on Sep.
`15, 2003.
`
`(51)
`
`(2006.01)
`
`Int. Cl.
`A61K 38113
`(52) U.S. Cl.
`USPC ......................................................... 514/20.5
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
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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
`
`ABSTRACT
`(57)
`Methods of treating an eye of a human or animal include
`administering to an eye of a human or animal a composition
`in the form of an emulsion including water, a hydrophobic
`component and a cyclosporin component in a therapeutically
`effective amount ofless than 0.1% by weight of the compo(cid:173)
`sition. The weight ratio of the cyclosporin component to the
`hydrophobic component is less than 0.8.
`
`27 Claims, No Drawings
`
`APOTEX 1001, pg. 1
`
`

`

`US 8,629,111 B2
`Page 2
`
`(56)
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`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`0547229
`0760237
`95-31211
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`
`APOTEX 1001, pg. 2
`
`

`

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`* cited by examiner
`
`APOTEX 1001, pg. 3
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`

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`US 8,629,111 B2
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`1
`METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`RELATED APPLICATION
`
`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(cid:173)
`ods of treating ophthalmic or ocular conditions with
`cyclosporin-containing emulsions.
`
`SUMMARY OF THE INVENTION
`
`This application is a continuation of copending U.S. appli(cid:173)
`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. 10
`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(cid:173)
`positions including cyclosporin components. More particu(cid:173)
`larly, the invention relates to methods including administer(cid:173)
`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 eta! 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, cyclosporinA compositions
`used in treating ophthalmic 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 ernul- 35
`sions in patients with moderate to severe dry eye disease,"
`Small etai,JOcul Pharmacal Ther, 2002 October, 18(5):411-
`8; "Distribution of cyclosporin A in ocular tissues after to pi-
`cal administration to albino rabbits and beagle dogs,"
`Acheampong eta!, Curr Eye Res, 1999 February, 18(2):91-
`103b; "Cyclosporine distribution into the conjunctiva, cor(cid:173)
`nea, lacrimal gland, and systemic blood following topical
`dosing of cyclosporine to rabbit, dog, and human eyes,"
`Acheampong eta!, Adv Exp Med Biol, 1998, 438:1001-4;
`"Preclinical safety studies of cyclosporine ophthalmic emul(cid:173)
`sion," Angelov eta!, Adv Exp Med Biol, 1998, 438:991-5;
`"Cyclosporin & Emulsion & Eye," Stevenson et a!, Ophthal(cid:173)
`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," Sail et a!, Ophthalmology, 2000
`April, 107 ( 4 ): 631-9. Each of these publications is incorpo(cid:173)
`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 55
`mid 1990's in order to obtain U.S. Food and Drug Adminis(cid:173)
`tration (FDA) regulatory approval.
`Examples of useful cyclosporin A-containing emulsions
`are setoutinDingetal U.S. Pat. No. 5,474,979. Example 1 of
`this patent shows a series of emulsions in which the ratio of 60
`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 a! 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(cid:173)
`sions for ophthalmic use preferably have less than 0.2% by
`
`New methods of treating a human or animal using
`cyclosporin component-containing emulsions have been dis-
`15 covered. Such methods provide substantial overall efficacy in
`providing desired therapeutic effects. In addition, other
`important benefits are obtained employing the present meth(cid:173)
`ods. For example, patient safety is enhanced. In particular, the
`present methods provide for reduced risks of side effects
`20 and/or drug interactions. Prescribing physicians advanta(cid:173)
`geously have increased flexibility in prescribing such meth(cid:173)
`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
`25 practiced. In short, the present methods provide substantial
`and acceptable overall efficacy, together with other advan(cid:173)
`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
`30 composition in the form of an emulsion comprising water, a
`hydrophobic component and a cyclosporin component in a
`therapeutically effective amount ofless 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
`40 in treating dry eye disease, is substantially equal to an iden(cid:173)
`tical composition in which the cyclosporin component is
`present in an amount ofO.l% by weight. Further, a relatively
`high concentration of hydrophobic component is believed to
`provide for a more quick or rapid breaking down or resolving
`45 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 of the com(cid:173)
`position. Additionally, and importantly, using reduced
`amounts of the active cyclosporin component mitigates
`50 against undesirable side effects and/or potential drug interac-
`tions.
`In short, the present invention provides at least one advan(cid:173)
`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 cyclosporin 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, phacoanaphylactic endophthalmitis, uveitis,
`vernal conjunctivitis, atopic kerapoconjunctivitis, corneal
`graft rejection and the like conditions. The present invention
`is particularly effective in treating dry eye syndrome.
`65 Cyclosporin has been found as effective in treating immune
`mediated keratoconjunctivitis sicca (KCS or dry eye disease)
`in a patient suffering therefrom. The activity of cyclosporine
`
`APOTEX 1001, pg. 4
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`US 8,629,111 B2
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`3
`is as an innnunosuppressant and in the enhancement or restor(cid:173)
`ing of lacrimal gland tearing. Other conditions that can be
`treated with cyclosporin components include an absolute or
`partial deficiency in aqueous tear production (keratoconjunc(cid:173)
`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(cid:173)
`val disorders exacerbated by tear deficiency and KCS, such as
`corneal scarring, corneal ulceration, inflannnation of the cor(cid:173)
`nea or conjunctiva, filamentary keratisis, mucopurulent dis(cid:173)
`charge and vascularization of the cornea.
`Employing reduced concentrations of cyclosporin compo(cid:173)
`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(cid:173)
`erably with substantially no detectable concentration of the
`cyclosporin component. The cyclosporin component concen(cid:173)
`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.
`In one embodiment, in the present methods the blood of the
`human or animal has concentrations of clyclosporin compo(cid:173)
`nent of0.1 ng/ml or less.
`Any suitable cyclosporin component effective in the 25
`present methods may be used.
`Cyclosporins are a group of nonpolar cyclic oligopeptides
`with known innnunosuppressant activity. Cyclosporin A,
`along with several other minor metabolites, cyclosporin B
`through I, have been identified. In addition, a number of 30
`synthetic analogs have been prepared.
`In general, connnercially available cyclosporins may con(cid:173)
`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 of about 1 ,200, but 35
`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 of the cyclosporin
`group and derivatives thereof, as well as mixtures of two or 40
`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(cid:173)
`ponent is solubilized in the hydrophobic component. The
`hydrophobic component may be considered as comprising a
`discontinuous phase in the presently useful cyclosporin com- 50
`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 55
`about 1.5% by weight or more of the composition.
`Preferably, the hydrophobic component comprises one or
`more oily materials. Examples of useful oil materials include,
`without limitation, vegetable oils, animal oils, mineral oils,
`synthetic oils and the like and mixtures thereof. In a very 60
`useful 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
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`4
`of such other components include, without limitation, emul(cid:173)
`sifier components, tonicity components, polyelectrolyte
`components, surfactant components, viscosity inducing com(cid:173)
`ponents, acids and/or bases to adjust the pH of the composi(cid:173)
`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(cid:173)
`positions. For example, components which are effective as
`both emulsifiers and surfactants may be employed, and/or
`10 components which are effective as both polyelectrolyte com(cid:173)
`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
`15 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
`20 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 of about 6 to about 10, preferably in a range of about 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(cid:173)
`ing step comprising topically administering the presently use(cid:173)
`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(cid:173)
`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-
`45 istering, preferably topically administering, to an eye of a
`human or animal a cyclosporin component-containing emul(cid:173)
`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