111111111111111111111111111!91111,11111,11111111111111111111111111111
`
`(12) United States Patent
`Acheampong et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,633,162 B2
`*Jan. 21, 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.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 13/967,179
`
`(22) Filed: (cid:9)
`
`Aug. 14, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2013/0338083 Al (cid:9)
`
`Dec. 19, 2013
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 13/961,818, filed on
`Aug. 7, 2013, which is a continuation of application
`No. 11/897,177, filed on Aug. 28, 2007, which is a
`continuation of application No. 10/927,857, filed on
`Aug. 27, 2004, now abandoned.
`
`(60) Provisional application No. 60/503,137, filed on Sep.
`15, 2003.
`
`(2006.01)
`
`(51) Int. Cl.
`A 61K 38/13 (cid:9)
`(52) U.S. Cl.
`USPC (cid:9)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
` 514/20.5
`
`(56)
`
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`FOREIGN PATENT DOCUMENTS
`
`DE
`EP
`
`19810655 (cid:9)
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`0471293 (cid:9)
`2/1992
`(Continued)
`
`OTHER PUBLICATIONS
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`(Continued)
`
`Primary Examiner — Marcela M Cordero Garcia
`(74) Attorney, Agent, or Firm Laura L. Wine; Joel
`German
`
`(57) (cid:9)
`
`ABSTRACT
`
`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.
`
`24 Claims, No Drawings
`
` EXHIBIT 1001
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`US 8,633,162 B2
`Page 2
`
`(56) (cid:9)
`
`References Cited
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`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 'Pouchitis', Scand J Gastroenterol,
`1993, 701-704, 28.
`Pending U.S, Appl. No. 13/967,189, filed Aug. 14, 2013.
`Pending U.S. Appl. No. 13/961,818, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/961,828, 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. 13/967,163, filed Aug. 14, 2013.
`Pending U.S. Appl. No. 13/967,168, filed Aug. 14, 2013.
`U.S. Re-Examination Application: 90/009,944 Filed on Aug. 27,
`2011.
`
`* cited by examiner
`
`

`
`US 8,633,162 B2
`
`1
`METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`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
`5 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
`
`RELATED APPLICATION
`This application is a continuation of copending U.S. appli- (cid:9)
`cation Ser. No. 13/961,818 filed Aug. 7, 2013, which is a (cid:9)
`continuation of copending U.S. application Ser. No. 11/897, (cid:9)
`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. (cid:9)
`
`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
`BACKGROUND OF THE INVENTION
`important benefits are obtained employing the present meth-
`The present invention relates to methods of providing (cid:9)
`ods. For example, patient safety is enhanced. In particular, the
`desired therapeutic effects to humans or animals using com- (cid:9)
`present methods provide for reduced risks of side effects
`positions including cyclosporin components. More particu- 20 and/or drug interactions. Prescribing physicians advanta-
`larly, the invention relates to methods including administer- (cid:9)
`geously have increased flexibility in prescribing such meth-
`ing to an eye of a human or animal a therapeutically effective (cid:9)
`ods and the compositions useful in such methods, for
`amount of a cyclosporin component to provide a desired
`example, because of the reduced risks of harmful side effects
`therapeutic effect, preferably a desired ophthalmic or ocular (cid:9)
`and/or drug interactions. The present methods can be easily
`therapeutic effect. (cid:9)
`25 practiced.
`The use of cyclosporin-A and cyclosporinA derivatives to
`In short, the present methods provide substantial and
`treat ophthalmic conditions has been the subject of various (cid:9)
`acceptable overall efficacy. together with other advantages,
`patents, for example Ding et al U.S. Pat. No. 5,474,979: Garst (cid:9)
`such as increased safety and/or flexibility.
`U.S. Pat. No. 6,254,860; and Garst U.S. Pat. No. 6,350,442, (cid:9)
`In one aspect of the present invention, the present methods
`this disclosure of each of which is incorporated in its entirely 30 comprise administering to an eye of a human or animal a
`herein by reference. In addition, cyclosporinA compositions (cid:9)
`composition in the form of an emulsion comprising water, a
`used in treating ophthalmic conditions is the subject of a
`hydrophobic component and a cyclosporin component in a
`number of publications. Such publications include, for (cid:9)
`therapeutically effective amount of less than 0.1% by weight
`example, "Blood concentrations of cyclosporin a during (cid:9)
`of the composition. The weight ratio of the cyclosporin com-
`long-term treatment with cyclosporin a ophthalmic emul- 35 ponent to the hydrophobic component is less than 0.08.
`It has been found that the relatively increased amounts of
`sions in patients with moderate to severe dry eye disease,"
`Small et al, J Ocul Pharmacol Ther, 2002 October, 18(5): 411 - (cid:9)
`hydrophobic component together with relatively reduced, yet
`8; "Distribution of cyclosporin A in ocular tissues after topi- (cid:9)
`therapeutically effective, amounts of cyclosporin component
`provide substantial and advantageous benefits. For example,
`cal administration to albino rabbits and beagle dogs,"
`Acheampong et al, Curr Eye Res, 1999 February, 18(2):91- 40 the overall efficacy of the present compositions, for example
`103b; "Cyclosporine distribution into the conjunctiva, cor- (cid:9)
`in treating dry eye disease, is substantially equal to an iden-
`tical composition in which the cyclosporin component is
`nea, lacrimal gland, and systemic blood following topical
`present in an amount of 0.1% by weight. Further, a relatively
`dosing of cyclosporine to rabbit, dog, and human eyes,"
`Acheampong et al, Adv Exp Med Biol, 1998, 438:1001-4;
`high concentration of hydrophobic component is believed to
`"Preclinical safety studies of cyclosporine ophthalmic emul- 45 provide for a more quick or rapid breaking down or resolving
`sion," Angelov et al, Adv Exp Med Biol, 1998. 438:991-5; (cid:9)
`of the emulsion in the eye, which reduces vision distortion
`"Cyclosporin & Emulsion & Eye," Stevenson et al, Ophthal- (cid:9)
`which may be caused by the presence of the emulsion in the
`mology, 2000 May, 107(5):967-74; and "Two multicenter, (cid:9)
`eye and/or facilitates the therapeutic effectiveness of the com-
`randomized studies of the efficacy and safety of cyclosporine (cid:9)
`position. Additionally, and importantly, using reduced
`ophthalmic emulsion in moderate to severe dry eye disease. 50 amounts of the active cyclosporin component mitigates
`CsA Phase 3 Study Group." Sall et al, Ophthalmology. 2000
`against undesirable side effects and/or potential drug interac-
`April, 107(4):631 -9. Each of these publications is incorpo- (cid:9)
`tions.
`rated in its entirety herein by reference. In addition, (cid:9)
`In short, the present invention provides at least one advan-
`cyclosporin A-containing oil-in-water emulsions have been (cid:9)
`tageous benefit, and preferably a plurality of advantageous
`clinically tested, under conditions of confidentiality, since the 55 benefits.
`mid 1990's in order to obtain U.S. Food and Drug Adminis- (cid:9)
`The present methods are useful in treating any suitable
`tration (FDA) regulatory approval. (cid:9)
`condition which is therapeutically sensitive to or treatable
`Examples of useful cyclosporin A-containing emulsions (cid:9)
`with cyclosporin components. Such conditions preferably are
`are set out in Ding et al U.S. Pat. No. 5,474,979. Example 1 of
`ophthalmic or ocular conditions, that is relating to or having
`this patent shows a series of emulsions in which the ratio of 60 to do with one or more parts of an eye of a human or animal.
`cyclosporin A to castor oil in each of these compositions was
`Included among such conditions are, without limitation, dry
`0.08 or greater, except for Composition B, which included
`eye syndrome, phacoanaphylactic endophthalmitis, uveitis,
`0.2% by weight cyclosporinA and 5% by weight castor oil. (cid:9)
`vernal conjunctivitis, atopic kerapoconjunctivitis, corneal
`The Ding et al patent placed no significance in Composition (cid:9)
`graft rejection and the like conditions. The present invention
`13 relative to Compositions A, C and D of Example 1. (cid:9)
`65 is particularly effective in treating dry eye syndrome.
`Over time, it has become apparent that cyclosporinA emul- (cid:9)
`Employing reduced concentrations of cyclosporin compo-
`sions for ophthalmic use preferably have less than 0.2% by (cid:9)
`nent, as in the present invention, is advantageously effective
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`(cid:9)
`(cid:9)
`(cid:9)
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`(cid:9)
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`

`
`US 8,633,162 B2
`
`3
`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.
`In one embodiment, in the present methods the blood of the
`human or animal has concentrations of clyclosporin compo-
`nent of 0.1 ng/ml or less.
`Any suitable cyclosporin component effective in the
`present methods may be used.
`Cyclosporins are a group of nonpolar cyclic oligopeptides
`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
`acid residues with a total molecular weight of about 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 of the 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 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 of useful oil materials include,
`without limitation, vegetable oils, animal oils, mineral oils,
`synthetic oils and the like and mixtures thereof. In a very
`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
`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-
`
`4
`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
`10 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
`15 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-
`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
`35 invention are apparent in the following detailed description,
`example and claims.
`
`20 (cid:9)
`
`30
`
`25 (cid:9)
`
`DETAILED DESCRIPTION
`
`5 4
`
`40 (cid:9)
`
`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 of less than 0.1% by
`weight of the emulsion. In addition, beneficial