11111111111111111111111111#1111)11111111111111111111111111111111111
`
`(12) United States Patent (cid:9)
`Acheampong et al. (cid:9)
`
`(10) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`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: (cid:9)
`* )
`
`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: (cid:9)
`
`Aug. 14, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2013/0331339 Al (cid:9)
`
`Dec. 12, 2013
`
`5,411,952
`5,424,078
`5,474,919
`5,474,979
`5,504,068
`5,540,931
`5,543,393
`5,589,455
`5,591,971
`5,614,491
`5,639,724
`5,652,212
`5,719,123
`5,739,105
`5,753,166
`5,766,629
`5,798,333
`5,807,820
`5,827,822
`5,827,862
`5,834,017
`5,843,452
`5,843,891
`5,858,401
`5,866,159
`5,891,846
`5,916,589
`5,929,030
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`Related U.S. Application Data
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`FOREIGN PATENT DOCUMENTS
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`(63) Continuation of application No. 13/961,828, filed on
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`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 (cid:9)
`2/1992
`0471293 (cid:9)
`(Continued)
`
`OTHER PUBLICATIONS
`
`(60) Provisional application No. 60/503,137, filed on Sep.
`15, 2003.
`
`(2006.01)
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`(51) Int. Cl.
`A61K 38/13 (cid:9)
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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) (cid:9)
`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 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
`
`ARGENTUM - EX. 1001, p. 001
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`US 8,629,111 B2
`Page 2
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`(56) (cid:9)
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`Tsubota, Kazuo et al, Use of Topical Cyclosporin A in a Primary
`Sjogren's Syndrome Mouse Model, Invest Ophthalmol Vis Sci, Aug.
`1998, 1551-1559, 39(9).
`Van Der Reijden, Willy et al, Treatment of Oral Dryness Related
`Complaints (Xerostomia) in Sjogren's Syndrome, Ann Rheum Dis,
`1999, 465-473, 58.
`Winter, T.A. et al, Cyclosporin A Retention Enemas in Refractory
`Distal Ulcerative Colitis and Touchitis', Scand J Gastroenterol,
`1993, 701-704, 28.
`Pending U.S. Appl. No. 13/967,189, filed Aug. 14, 2013.
`Pending U.S. Appl. No. 13/976,179, filed Aug. 14, 2013.
`Pending U.S. Appl. No. 13/961,818, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/961,835, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/961,808, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/961,828, filed Aug. 7, 2013.
`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
`
`ARGENTUM - EX. 1001, p. 003
`
`

`
`US 8,629,111 B2
`
`1
`METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`RELATED APPLICATION
`
`5 (cid:9)
`
`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. 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
`
`15
`
`25
`
`The present invention relates to methods of providing
`desired therapeutic effects to humans or animals using com-
`positions including cyclosporin components. More particu- 20
`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. (cid:9)
`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 in its entirely 30
`herein by reference. In addition, cyclosporin A 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 emul- 35
`sions in patients with moderate to severe dry eye disease,"
`Small et al, J Ocul Pharmacol Ther, 2002 October, 18(5):411 -
`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- 40
`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- 45
`sion," Angelov et al, Adv Exp Med Biol, 1998, 438:991-5;
`"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. so
`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 55
`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 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 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. (cid:9)
`Over time, it has become apparent that cyclo sporinA emul-
`sions for ophthalmic use preferably have less than 0.2% by
`
`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 of the 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 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.
`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
`
`ARGENTUM - EX. 1001, p. 004
`
`

`
`US 8,629,111 B2
`
`4
`3
`is as an immunosuppressant and in the enhancement or restor- (cid:9)
`of such other components include, without limitation, emul-
`ing of lacrimal gland tearing. Other conditions that can be (cid:9)
`sifier components, tonicity components, polyelectrolyte
`treated with cyclosporin components include an absolute or (cid:9)
`components, surfactant components, viscosity inducing com-
`partial deficiency in aqueous tear production (keratoconjunc- (cid:9)
`ponents, acids and/or bases to adjust the pH of the composi-
`tivitis sicca, or KCS). Topical administration to a patient's 5 tion, buffer components, preservative components and the
`tear deficient eye can increase tear production in the eye. The (cid:9)
`like. Components may be employed which are effective to
`treatment can further serve to correct corneal and conjuncti- (cid:9)
`perform two or more functions in the presently useful com-
`val disorders exacerbated by tear deficiency and KCS, such as (cid:9)
`positions. For example, components which are effective as
`corneal scarring, corneal ulceration, inflammation of the cor- (cid:9)
`both emulsifiers and surfactants may be employed, and/or
`nea or conjunctiva, filamentary keratisis, mucopurulent dis- 10 components which are effective as both polyelectrolyte com-
`charge and vascularization of the cornea. (cid:9)
`ponents and viscosity inducing components may be
`Employing reduced concentrations of cyclosporin compo- (cid:9)
`employed. The specific composition chosen for use in the
`nent, as in the present invention, is advantageously effective (cid:9)
`present invention advantageously is selected taking into
`to provide the blood of the human or animal under treatment (cid:9)
`account various factors present in the specific application at
`with reduced concentrations of cyclosporin component, pref-
`15 hand, for example, the desired therapeutic effect to be
`erably with substantially no detectable concentration of the (cid:9)
`achieved, the desired properties of the compositions to be
`cyclosporin component. The cyclosporin component concen- (cid:9)
`employed, the sensitivities of the human or animal to whom
`tration of blood can be advantageously measured using a (cid:9)
`the composition is to be administered, and the like factors.
`validated liquid chromatography/mass spectrometry-mass (cid:9)
`The presently useful compositions advantageously are
`spectrometry (VLC/MS-MS) analytical method, such as 20 ophthalmically acceptable. A composition, component or
`described elsewhere herein. (cid:9)
`material is ophthalmically acceptable when it is compatible
`In one embodiment, in the present methods the blood of the (cid:9)
`with ocular tissue, that is, it does not cause significant or
`human or animal has concentrations of clyclosporin compo- (cid:9)
`undue detrimental effects when brought into contact with
`nent of 0.1 ng/ml or less. (cid:9)
`ocular tissues.
`Any suitable cyclosporin component effective in the 25 (cid:9)
`Such compositions have pH's within the physiological
`present methods may be used. (cid:9)
`range of about 6 to about 10, preferably in a range of about 7.0
`Cyclosporins are a group of nonpolar cyclic oligopeptides (cid:9)
`to about 8.0 and more preferably in a range of about 7.2 to
`with known immunosuppressant activity. Cyclosporin A, (cid:9)
`about 7.6.
`along with several other minor metabolites, cyclosporin B
`The present methods preferably provide for an administer-
`through I, have been identified. In addition, a number of 30 ing step comprising topically administering the presently use-
`synthetic analogs have been prepared. (cid:9)
`ful compositions to the eye or eyes of a human or animal.
`In general, commercially available cyclosporins may con- (cid:9)
`Each and every feature described herein, and each and
`tain a mixture of several individual cyclosporins which all (cid:9)
`every combination of two or more of such features, is
`share a cyclic peptide structure consisting of eleven amino (cid:9)
`included within the scope of the present invention provided
`acid residues with a total molecular weight of about 1,200, but 35 that the features included in such a combination are not mutu-
`with different substituents or configurations of some of the (cid:9)
`ally inconsistent.
`amino acids. (cid:9)
`These and other aspects and advantages of the present
`The term "cyclosporin component" as used herein is (cid:9)
`invention are apparent in the following detailed description,
`intended to include any individual member of the cyclosporin (cid:9)
`example and claims.
`group and derivatives thereof, as well as mixtures of two or 40
`more individual cyclosporins and derivatives thereof. (cid:9)
`Particularly preferred cyclosporin components include,
`The present methods are effective for treating an eye of a
`without limitation, cyclosporin A, derivatives of cyclosporin
`human or animal. Such methods, in general, comprise admin-
`A and the like and mixtures thereof. Cyclosporin A is an
`especially useful cyclosporin component. (cid:9)
`45 istering, preferably topically administering, to an eye of a
`Any suitable hydrophobic component may be employed in
`human or animal a cyclosporin component-containing emul-
`the present invention. Advantageously, the cyclosporin com- (cid:9)
`sion. The emulsion contains water, for example U.S. pure
`ponent is solubilized in the hydrophobic component. The (cid:9)
`water, a hydrophobic component and a cyclosporin compo-
`hydrophobic component may be considered as comprising a (cid:9)
`nent in a therapeutically effective amount of less than 0.1% by
`discontinuous phase in the presently useful cyclosporin com- so weight of the emulsion. In addition, beneficial results have
`ponent-containing emulsions. (cid:9)
`been found when the weight ratio of the cyclosporin compo-
`The hydrophobic component preferably is present in the (cid:9)
`nent to the hydrophobic component is less than 0.08.
`emulsion compositions in an amount greater than about
`As noted above, the present administering step preferably
`0.625% by weight. For example, the hydrophobic component
`includes topically administering the emulsion to the eye of a
`may be present in an amount of up to about 1.0% by weight or 55 patient of a human or animal. Such administering may
`about 1.5% by weight or more of the composition. (cid:9)
`involve a single use of the presently useful compositions, or
`Preferably, the hydro