(tee 10/96)
`
`PTO/SB/16/(6-95)
`Approved for use through 04/11/98. OMB 0651-0037
`Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`
`PROVISIONAL APPLICATION COVER SHEET
`
`This is a request for filing a PROVISIONAL APPLICATION under 37 CFR 1.53 (b)(2).
`
`Docket Number
`
`D-3111 P
`
`INVENTOR(s)/APPLICANT(s)
`
`l Type a plus sign(+)
`
`inside this box -
`
`I+
`
`LAST NAME
`
`FIRST NAME
`
`MIDDLE
`INITIAL
`
`RESIDENCE (CITY AND EITHER STATE OR FOREIGN
`COUNTRY)
`
`Acheampong
`Tang-Liu
`Chang
`Power
`
`Andrew
`Diane
`James
`David
`
`N.
`F.
`
`Irvine, CA
`Newport Beach, CA
`Newport Beach, CA
`Trabuco Canyon, CA
`
`TITLE OF THE INVENTION (280 characters max)
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`CORRESPONDENCE ADDRESS
`
`FRANK J. UXA
`4 VENTURE, SUITE
`IRVINE, CA 92618
`
`STATE
`
`CA
`
`I ZIP I
`
`CODE
`
`92618
`
`COUNTRY I
`
`USA
`
`ENCLOSED APPLICATION PARTS (check all that apply)
`
`X
`
`Specification
`
`-
`
`Drawing(s)
`
`Number of
`Pages
`
`Number of
`Sheets
`
`33
`
`f----
`
`Small Entity Statement
`
`Other(specify) I
`
`A check or money order is enclosed to cover the Provisional filing fee
`
`METHOD OF PAYMENT (check one)
`
`X
`
`The Commissioner is hereby
`authorized to charge filing fees and
`credit deposit Account Number:
`
`01-0885
`
`PROVISIONAL
`FILING FEE
`AMOUNT($)
`
`$160.00
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States Government.
`• No.
`o Yes, the name of the U.S. Government agency and the Government contract number a re : - - - - - - - - - -
`
`I hereby appoint the following attorney(s) and/or agent(s) to prosecute this application and to transact all business in the Patent and
`Trademark Office connected therewith
`Martin A. Voet. Reg. No. 25.208. Robert Baran. Reg. No. 25.806, Carlos A. Fisher, Reg. No. 36,510. Stephen Donovan. Reg.
`No. 33.433, and Frank J. Uxa. Reg. No. 25,612. Donald E. Stout. Reg. No. 34,493; Robert D. Buyan, Reg. No. 32.460; Kenton
`R. Mullins. Reg. No. 36.331; JoAnne M. Ybaben. Reg. No. 42.243. Linda Allvson Fox. Reg. No. 38,883. Kyle D. Yesland.
`Reg. No.45,526, Greg S. Hollrigel, Reg. No. 45,374. LouseS. Heim, Reg. No. 32.337.
`
`Respectfully submitted,
`
`o Additional inventors are being named on separately numbered sheets attached hereto
`
`PROVISIONAL APPLICATION FILING ONLY
`SEND TO: Commissioner of Patents, PO Box 1450, Alexandria, VA 22313-1450
`
`APOTEX 1019, pg. 3252
`
`

`
`I ,
`
`DOCKET NO.: D-3111P
`
`THE ENCLOSED PROVISIONAL PATENT APPLICATION OF ACHEAMPONG
`ET AL IS BEING FILED IN ACCORDANCE WITH SECTION 37 CFR
`1.10 BY EXPRESS MAIL AND SHOULD BE ACCORDED A FILING DATE
`
`September 15, 2003
`
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION.
`
`APOTEX 1019, pg. 3253
`
`

`
`D-3111P
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`PATENT
`
`In re application of:
`ACHEAMPONG ET AL.
`
`Serial No. N/A
`
`) Group Art Unit: N/A
`)
`) Examiner: N/A
`)
`)
`)
`For: METHODS OF PROVIDING THERAPEUTIC)
`EFFECTS USING CYCLOSPORIN
`)
`COMPONENTS
`) ATTN: MS PROVISIONAL
`PATENT APPLICATION
`
`Dated: Submitted herewith
`
`Express Mail Mailing Label No.
`
`EV 059889887US
`
`Date of Deposit: SEPTEMBER 15, 2003
`
`I hereby certify that the following documents as identified
`below are being deposited with the United States Postal Service
`"Express Mail Post Office to Addressee" service under 37 CFR 1.10
`on the date indicated above and are addressed to the Commissioner
`for Patents, MS Provisional Patent Application, PO Box 1450,
`Alexandria, VA 22313-1450.
`
`Provisional Application Cover Sheet;
`1.
`2. Application Data Sheet
`3. Application
`4.
`Return receipt postcard.
`
`The 4 above-identified documents are enclosed herewith.
`
`- Resp~2b;nt~
`
`Janet E. McGhee, Office of
`Frank J. Uxa
`Attorney for Applicant
`Reg. No. 36,331
`4 Venture, Suite 300
`Irvine, CA
`92618
`(949) 450-1750
`Facsimile (949) 450-1764
`
`APOTEX 1019, pg. 3254
`
`

`
`D-3111
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`
`USING CYCLOSPORIN COMPONENTS
`
`The present invention relates to methods of providing
`desired therapeutic effects to humans or animals using
`compositions
`including cyclosporin components.
`More
`particularly, the invention relates to methods including
`administering
`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. Patent
`5,474,979; Garst U.S. Patent 6,254,860; and Garst U.S.
`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.
`publications
`Such
`include,
`for
`example,
`"Blood
`concentrations of cyclosporin a during long-term treatment
`with cyclosporin a ophthalmic emulsions in patients with
`moderate to severe dry eye disease," Small et al, J Ocul
`
`A
`
`Pharmacol Ther, 2002 Oct, 18 (5) :411-8; "Distribution of
`cyclosporin
`in
`ocular
`tissues
`after
`topical
`administration
`to albino
`rabbits
`and beagle dogs,"
`Acheampong et al, Curr Eye Res, 1999 Feb, 18(2) :91-103b;
`"Cyclosporine distribution into the conjunctiva, cornea,
`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 emulsion,"
`
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`APOTEX 1019, pg. 3255
`
`

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`D-3111
`
`2
`
`1998,
`
`438:991-5;
`
`Angelov et al, Adv Exp Med Biol,
`"Cyclosporin
`& Emulsion
`& Eye, " Stevenson et al,
`and
`"Two
`Ophthalmology,
`2000 May,
`107(5) :967-74;
`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,
`Each of these
`Ophthalmology, 2000 Apr, 107(4) :631-9.
`publications is incorporated 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 Administration (FDA)
`regulatory approval.·
`Examples of useful cyclosporin A-containing emulsions
`are set out in Ding et al U.S. Patent 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 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 cyclosporin A
`emulsions for ophthalmic use preferably have less than 0.2%
`by 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
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`APOTEX 1019, pg. 3256
`
`

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`D-3111
`
`3
`
`methods 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
`discovered.
`Such methods provide substantial overall
`efficacy in providing desired therapeutic effects.
`In
`addition, other important benefits are obtained employing
`the present methods.
`For example, patient safety is
`enhanced.
`In particular, the present methods provide for
`reduced risks of side effects and/or drug interactions.
`Prescribing physicians advantageously have
`increased
`flexibility
`in prescribing
`such methods
`and
`the
`compositions useful in such methods, for example, because
`of the reduced
`sks 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
`advantages, 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 component to the hydrophobic component is less
`than 0.08.
`the relatively increased
`that
`found
`It has been
`amounts of hydrophobic component together with relatively
`reduced,
`yet
`therapeutically effective,
`amounts of
`cyclosporin component provide substantial and advantageous
`
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`APOTEX 1019, pg. 3257
`
`

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`D-3111
`
`4
`
`benefits. For example, the overall efficacy of the present
`compositions, for example in treating dry eye disease, is
`substantially equal to an identical 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
`composition. Additionally, and importantly, using reduced
`amounts of
`the active cyclosporin component mitigates
`against undesirable side effects and/or potential drug
`interactions.
`In short, the present invention provides at least one
`advantageous benefit,
`and preferably a plurality of
`advantageous benefits.
`treating any
`in
`The present methods are useful
`sui table 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.
`Employing
`reduced concentrations of cyclosporin
`component, as in the present invention, is advantageously
`effective to provide the blood of the human or animal under
`treatment with
`reduced concentrations of cyclosporin
`
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`APOTEX 1019, pg. 3258
`
`

`
`D-3111
`
`5
`
`component, preferably with substantially no detectable
`concentration of
`the
`cyclosporin
`component.
`The
`cyclosporin component concentration of blood can be
`advantageously measured
`using
`a
`validated·
`liquid
`chromatography/mass spectrometry-mass spectrometry (VLC/MS(cid:173)
`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
`component of 0.1 ng/ml or less.
`Any suitable cyclosporin component effective in the
`present methods may be used.
`group
`Cyclosporins
`are
`a
`of nonpolar
`cyclic
`immunosuppressant activity.
`oligopeptides with
`known
`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
`contain 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.
`
`5
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`
`APOTEX 1019, pg. 3259
`
`

`
`D-3111
`
`6
`
`Any suitable hydrophobic component may be employed in
`
`the present invention. Advantageously,
`
`the cyclosporin
`
`component is solubilized in the hydrophobic component. The
`
`hydrophobic component may be considered as comprising a
`
`5
`
`discontinuous phase in the presently useful cyclosporin
`
`component-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
`
`10
`
`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,
`
`15
`
`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.
`
`20
`
`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, emulsifier components,
`
`tonicity components,
`
`2 5
`
`polyelectrolyte
`
`components,
`
`surfactant
`
`components,
`
`viscosity inducing components, acids and/or bases to adjust
`
`the pH of the composition, buffer components, preservative
`
`components and the like. Components may be employed which
`
`are effective to perform two or more functions in the
`
`3 0
`
`presently useful compositions.
`
`For example, components
`
`which are effective as both emulsifiers and surfactants may
`
`be employed, and/or components which are effective as both
`
`APOTEX 1019, pg. 3260
`
`

`
`D-3111
`
`7
`
`inducing
`viscosity
`and
`components
`polyelectrolyte
`The specific composition
`components may be employed.
`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 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.
`an
`for
`The present methods preferably provide
`administering step comprising topically administering the
`presently useful 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
`mutually inconsistent.
`These and other aspects and advantages of the present
`invention are
`apparent
`in
`the
`following detailed
`description, example and claims.
`
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`
`APOTEX 1019, pg. 3261
`
`

`
`D-3111
`
`8
`
`Detailed Description
`
`The present methods are effective for treating an eye
`
`of a human or animal. Such methods, in general, comprise
`
`administering, preferably topically administering, to an
`
`5
`
`eye of a human or animal a cyclosporin component-containing
`
`emulsion. The emulsion contains water, for example U.S.
`
`pure water,
`
`a hydrophobic component and a cyclosporin
`
`component in a therapeutically effective amount of less
`
`than 0.1% by weight of
`
`the emulsion.
`
`In addition,
`
`10
`
`beneficial results have been found when the weight ratio of
`
`the cyclosporin component to the hydrophobic component is
`
`less than 0.08.
`
`As noted above,
`
`the present administering step
`
`preferably includes topically administering the emulsion to
`
`15
`
`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
`
`20
`
`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
`
`25
`
`effective in providing the desired therapeutic effect or
`
`fects 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 animal being treated, and eye
`
`30
`
`irritation which,
`
`in the past, has been caused by the
`
`presence of certain components in prior art cyclosporin(cid:173)
`
`containing emulsions.
`
`Also,
`
`the use of
`
`the present
`
`APOTEX 1019, pg. 3262
`
`

`
`D-3111
`
`9
`
`compositions which
`
`include
`
`reduced
`
`amounts of
`
`the
`
`cyclosporin
`
`components
`
`allow
`
`for more
`
`frequent
`
`administration of the present compositions to achieve the
`
`desired therapeutic effect or effects without substantially
`
`5
`
`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 cyclosporin components.
`
`Such conditions
`
`preferably are ophthalmic or ocular conditions, that is
`
`10
`
`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
`
`15
`
`rejection and the like conditions. The present invention
`
`is particularly effective in treating dry eye syndrome.
`
`The frequency of administration and the amount of the
`
`presently useful
`
`composition
`
`to
`
`use
`
`during
`
`each
`
`administration varies depending upon the therapeutic effect
`
`20
`
`to be obtained, the severity of the condition being treated
`
`and the like factors. The presently useful compositions
`
`are designed to allow the prescribing physician substantial
`
`flexibility
`
`in
`
`treating various ocular conditions
`
`to
`
`achieve the desired therapeutic effect or effects with
`
`25
`
`reduced risk of side effects and/or eye irritation. Such
`
`administration may occur on an as needed basis,
`
`for
`
`example, in treating or managing dry eye syndrome, on a one
`
`time basis or on a repeated or periodic basis once, twice,
`
`thrice or more times daily depending on the needs of the
`
`30
`
`human or animal being treated. and other factors involved in
`
`the application at hand.
`
`One of
`
`the
`
`important advantages of
`
`the present
`
`APOTEX 1019, pg. 3263
`
`

`
`D-3111
`
`10
`
`invention is the reduced concentration of the cyclosporin
`component in the blood of the human or animal as a result
`of administering
`the present composition as described
`herein.
`One very useful embodiment of
`the present
`administering step provides no substantial detectable
`concentration of cyclosporin component in the blood of the
`human or animal. Cyclosporin component concentration in
`blood
`preferably
`is
`determined
`using
`a
`liquid
`chromatography-mass spectroscopy-mass spectroscopy
`(LC-
`MS/MS), which test has a cyclosporin component detection
`
`limit of 0.1 ng/ml. Cyclosporin component concentrations
`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
`solution, then extracted with 5 ml of methyl t-butyl ether.
`After separation from the acidified aqueous layer,
`the
`organic phase is neutralized with 2 ml of 0.1 N NaOH,
`evaporated, reconstituted in a water/acetonitrile-based
`mobil phase, and injected onto a 2.1 x 50 mm, 3~-tm pore size
`C-8 reverse phase high pressure liquid chromatography
`(HPLC)
`column
`(Keystone Scientific, Bellefonte, PA).
`Compounds are gradient-eluted at 0.2 mL/min and detected
`using an API III triple quadrupole mass spectrometer with
`a
`turbo-ionspray source
`(PE-Sciex, Concord, Ontario,
`Canada). Molecular reaction monitoring enhances
`the
`sensitivity and selectivity of this assay.
`Protonated
`molecules for the analyte and an internal standard are
`collisionally dissociated and product ions at m/z 425 are
`monitored for the analyte and the internal standard. Under
`these conditions, cyclosporin A and the internal standard
`cyclosporin G elute with retention times of about 3. 8
`
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`
`APOTEX 1019, pg. 3264
`
`

`
`D-3111
`
`11
`
`minutes. The lower limit of quantitation is 0.1 ng/mL, at
`
`the coefficient of variation and
`which concentration
`deviation from nominal concentration is <15%.
`As
`noted previously,
`any
`suitable cyclosporin
`
`5
`
`component effective in the present methods may be employed.
`
`Very useful cyclosporin
`
`components
`
`include, without
`
`limitation, cyclosporin A, derivatives of cyclosporin A and
`the like and mixtures thereof.
`
`The
`
`structure
`represented by Formula 1
`
`chemical
`
`10
`
`for
`
`cyclosporin A
`
`is
`
`FORMULA I
`
`As used herein the term "derivatives" of a cyclosporin
`
`refer to compounds having structures sufficiently similar
`
`to
`
`the cyclosporin so as
`
`to
`
`function
`
`in
`
`a manner
`
`15
`
`substantially similar to or substantially identical to the
`
`in the present
`cyclosporin, for example, cyclosporin A,
`methods.
`Included, without limitation, within the useful
`
`( (R)(cid:173)
`cyclosporin A derivatives are those sel.ected from
`methylthio-Sar) 3
`( (R)
`- (4' -hydroxy-MeLeu) cyclosporin A,
`(Cyclo)alkylthio-Sar) 3 (4'-hydroxy-MeLeu) 4-cyclosporin A,
`
`20
`
`APOTEX 1019, pg. 3265
`
`

`
`D-3111
`
`12
`
`and ((R)-(Cyclo)alkylthio-Sar) 3-cyclosporin A derivatives
`described below.
`
`These cyclosporin derivatives are represented by the
`
`following general
`respectively:
`
`5
`
`formulas
`
`(II) I
`
`(III) I
`
`and
`
`(IV)
`
`APOTEX 1019, pg. 3266
`
`

`
`D-3111
`
`13
`
`(II)
`
`(UI)
`
`(I)
`
`APOTEX 1019, pg. 3267
`
`

`
`D-3111
`
`14
`
`is 2-6C alkylene or 3-
`is methyl; Alk
`wherein Me
`6C cycloalkylene; R is OH, COOH, alkoxycarbonyl, -NR1R2 or
`is H,
`3-6C
`N(R3 )-(CH2 )-NR1R2 ; wherein
`alkyl,
`R1 ,R2
`cycloalkyl, phenyl (optionally substituted by halo, alkoxy,
`
`5
`
`alkoxycarbonyl, amino, alkylamine or dialkylamino), benzyl
`
`10
`
`or saturated or unsaturated heterocyclyl having 5 or 6
`members and 1-3 heteroatoms; or NR1R2 is a 5 or 6 membered
`heterocycle which may contain a
`further N,
`0 or S
`heteroatom and may be alkylated; R3 is H or alkyl and n is
`2-4; and the alkyl moieties contain 1-4C.
`
`In one embodiment,
`
`the cyclosporin component
`
`is
`
`effective as an immunosuppressant. Without wishing to be
`
`limited to any particular theory of operation, it is
`
`believed that,
`
`in certain embodiments of
`
`the present
`
`15
`
`invention,
`
`the cyclosporin component acts to enhance or
`
`restore lacrimal gland tearing in providing the desired
`
`therapeutic effect.
`
`One important feature of the present invention is that
`
`the presently useful compositions contain less than 0. 1% by
`weight of the cyclosporin component.
`The advantages of
`
`20
`
`such low-concentrations of cyclosporin components have been
`
`discussed
`
`in
`
`some detail
`
`elsewhere herein.
`
`Low
`
`concentrations of cyclosporin component,
`
`together with
`
`concentrations of the hydrophobic component such that .the
`
`25
`
`weight ratio of cyclosporin component
`
`to hydrophobic
`
`component is greater than 0. 08, provides one or more
`
`substantial advantages in the present methods.
`
`Any suitable hydrophobic component may be employed in
`
`the present invention. Such hydrophobic component may be
`
`30
`
`considered as comprising a discontinuous phase in the
`
`presently
`
`useful
`
`cyclosporin
`
`component-containing
`
`emulsio~s, with the water or aqueous phase being considered
`
`the continuous phase in such emulsion.
`
`The hydrophobic
`
`APOTEX 1019, pg. 3268
`
`

`
`D-3111
`
`15
`
`component is preferably selected so as to solubilize the
`cyclosporin
`component, which
`is often substantially
`insoluble in the aqueous phase.
`Thus, with a sui table
`hydrophobic component included in the presently useful
`emulsions,
`the
`cyclosporin
`component
`is preferably
`
`solubilized in the emulsions.
`In one very useful embodiment,
`component comprises an oily material,
`
`the hydrophobic
`in particular, a
`
`material which is substantially not miscible in water.
`Examples of useful oily materials
`include, without
`limitation, vegetable oils, animal oils, mineral oils,
`synthetic oils, and the like and mi~tures thereof. Thus,
`the present hydrophilic components may comprise naturally
`occurring oils,
`including, without
`limitation refined
`
`naturally occurring oils, or naturally occurring oils which
`have been processed to alter their chemical structures to
`some extent or oils which are substantially entirely
`synthetic. One very useful hydrophobic component includes
`
`higher fatty acid glycerides.
`Examples of useful hydrophobic components include,
`without limitation, olive oil, arachis oil, castor oil,
`mineral oil, silicone fluid and the like and mixtures
`thereof. Higher fatty acid glycerides such as olive oil,
`peanut oil, castor oil and the like and mixtures thereof
`are particularly useful
`in
`the present
`invention.
`Excellent
`results are obtained using
`a ~ydrophobic
`component comprising castor oil. Without wishing to limit
`the invention to any particular theory of operation, it is
`believed
`that castor oil
`includes a
`relatively high
`concentration of ricinoleic acid which itself may be useful
`in benefitting ocular tissue and/or in providing one or
`more therapeutic effects when administered to an eye.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 3269
`
`

`
`D-3111
`
`16
`
`The hydrophobic component is preferably present in the
`
`presently useful cyclosporin component-containing emulsion
`
`compositions in an amount greater than about 0. 62 5% by
`
`weight.
`
`For example,
`
`the hydrophobic component may be
`
`5
`
`present in an amount up to about 0.75% by weight or about
`
`1. 0% by weight or about 1. 5% by weight or more of the
`
`presently useful emulsion compositions.
`
`The presently useful compositions may include one or
`
`more other components in amounts effective to facilitate
`
`10
`
`the usefulness and effectiveness of the present methods
`
`and/or the presently useful compositions. Examples of such
`
`other components include, without limitation, emulsifier
`
`components, surfactant components,
`
`tonicity components,
`
`poly electrolyte components, emulsion stability components,
`
`15
`
`viscosity inducing components, demulcent components, acid
`
`and/or bases to adjust the pH of the composition, buffer
`
`components, preservative components and the like.
`
`In one very useful embodiment, the presently useful
`
`compositions are substantially free of preservatives.
`
`20
`
`Thus, the presently useful compositions may be sterilized
`
`and maintained in a sterile condition prior to use, for
`
`example, provided
`
`in a
`
`sealed package or otherwise
`
`maintained in a substantially sterile condition.
`
`Any suitable emulsifier component may be employed in
`
`25
`
`the presently useful compositions, provided,
`
`that such
`
`emulsifier component is effective in forming maintaining
`
`the emulsion and/or
`
`in
`
`the hydrophobic component
`
`in
`
`emulsion, while having no significant or undue detrimental
`
`effect or effects on the compositions during storage or
`use.
`
`30
`
`In addition,
`
`the presently useful compositions, as
`
`well as each of the components of the present compositions
`
`APOTEX 1019, pg. 3270
`
`

`
`D-3111
`
`17
`
`composition
`
`the
`in
`concentration present
`the
`in
`advantageously are ophthalmically acceptable.
`Useful emulsifier components may be selected from such
`component which are conventionally used and well known in
`the art. Examples of such emulsifier components include,
`without limitation, surface active components or surfactant
`components which may be anionic, cationic, nonionic or
`amphorteric
`in nature.
`In general,
`the emulsifier
`component
`includes
`a hydrophobic constituent and
`a
`hydrophilic constituent. Advantageously,
`the emulsifier
`component
`is water soluble
`in
`the presently useful
`compositions.
`Preferably,
`the emulsifier component is
`nonionic.
`Specific examples of suitable emulsifier
`components include, without limitation, polysorbate 80,
`polyoxyalkylene alkylene ethers, polyalkylene oxide ethers
`of
`alkyl
`alcohols,
`polyalkylene
`oxide
`ethers
`of
`alkylphenols, other emulsifiers/surfactants, preferably
`nonionic emulsifiers/surfactants, useful
`in ophthalmic
`compositions, and the like and mixtures thereof.
`The emulsifier component is present in an amount
`effective
`in
`forming
`the present emulsion and/or
`in
`maintaining the hydrophobic component in emulsion with the
`water or aqueous component.
`In one preferred embodiment,
`the emulsifier component is present in an amount in a range
`of about 0.1% to about 5%, more preferably about 0.2% to
`about 2% and still more preferably about 0.5% to about 1.5%
`by weight of the presently useful compositions.
`Polyelectrolyte or emulsion stabilizing components may
`be included in the presently useful compositions.
`Such
`components are believed to be effective in maintaining the
`electrolyte balance in the presently useful emulsions,
`thereby stabilizing
`the emulsions and preventing
`the
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 3271
`
`

`
`D-3111
`
`18
`
`emulsions
`
`from breaking down prior
`
`to use.
`
`In one
`
`embodiment,
`
`the presently useful compositions include a
`
`polyanionic component effective as an emulsion stabilizing
`
`component.
`
`Examples of suitable polyanionic components
`
`5
`
`in
`useful
`without limitation, anionic cellulose derivatives, anionic
`
`the presently useful compositions
`
`include,
`
`acrylic acid-containing polymers, anionic methacrylic acid(cid:173)
`
`containing polymers, anionic amino acid-containing polymers
`
`and the like and mixtures thereof.
`
`10
`
`A particularly useful class of polyanionic components
`
`include one or more polymeric materials having multiple
`
`anionic charges. Examples include, but are not limited to:
`
`metal carboxy methylcelluloses
`
`metal carboxy methylhydroxyethylcelluloses
`
`15
`
`metal carboxy methylstarchs
`
`metal carboxy methylhydroxyethylstarchs
`
`hydrolyzed polyacrylamides and polyacrylonitriles
`
`heparin
`gucoaminoglycans
`
`20
`
`hyaluronic acid
`
`chondroitin sulfate
`
`dermatan sulfate
`
`peptides and polypeptides
`
`alginic acid
`
`25
`
`metal alginates
`
`homopolymers and copolymers of one or more of:
`
`acrylic and methacrylic acids
`
`metal acrylates and methacrylates
`
`30
`
`vinylsulfonic acid
`
`metal vinylsulfonate
`
`amino acids, such as aspar.tic acid, glutamic
`
`APOTEX 1019, pg. 3272
`
`

`
`D-3111
`
`19
`
`acid and the like
`metal salts of amino acids
`
`p-styrenesulfonic acid
`
`metal p-styrenesulfonate
`
`5
`
`2-methacryloyloxyethylsulfonic acids
`
`metal 2-methacryloyloxethylsulfonates
`
`3-methacryloyloxy-2-hydroxypropylsulonic acids
`
`metal 3-methacryloyloxy-2-
`
`hydroxypropylsulfonates
`
`10
`
`2-acrylamido-2-methylpropanesulfonic acids
`
`metal 2-acrylamido-2-methylpropanesulfonates
`allylsulfonic acid
`
`metal allylsulfonate and the like.
`
`One particularly useful emulsion stabilizing component
`includes crosslinked polyacrylates, such as carbomers and
`
`15
`
`Pemulen® materials. Pemu