Docket No. 17618CON5B (AP)
`
`IN THE UNITED STATES PATENT
`
`AND
`
`TRADEMARK
`
`OFFICE
`
`Applicant: Acheampong, et al.
`
`Examiner: TBA
`
`Serial No.: TBA
`
`Filed: Herewith
`
`For: METHODS OF PROVIDING
`THERAPEUTIC EFFECTS USING
`CYCLOSPORIN COMPONENTS
`
`Group Art Unit: TBA
`
`Confirmation No. TBA
`
`Customer No.: 51957
`
`PRELIMINARY AMENDMENT
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Dear Sir:
`
`Prior to examining the above-referenced application, please amend the specification as
`
`described on page 2 of this paper, and please amend the claims as described on pages 3-6 of this
`paper. Remarks follow on page 7.
`
`1
`
`0001
`
`TEVA - EXHIBIT 1004 (PART 1 OF 3)
`
`

`
`Docket No. 17618CON5B (AP)
`
`Amendments to the Specification
`
`Please replace page 1, lines 5-10 of
`paragraph:
`
`the
`
`specification
`
`filed herewith with
`
`the
`
`following
`
`This application is a continuation of copending U.S. Application Serial No. 13/961.818
`filed August 7. 2013. which is a continuation of copending U.S. Application Serial No.
`11/897.177. filed August 28. 2007. which is a continuation of U.S. Application Serial No.
`10/927,857, filed August 27, 2004. now abandoned, which claimed the benefit of U.S.
`Provisional Application No. 60/503,137 filed September 15, 2003, which-4s are incorporated in
`its their entirety herein by reference.
`
`2
`
`0002
`
`

`
`Docket No. 17618CON5B (AP)
`
`Amendments to the claims
`
`The following list of claims will
`application:
`1-36. (Canceled)
`
`replace
`
`
`
`
`
`versions all previous of claims presented in this
`
`37.
`(New) A method of treating dry eye disease, the method comprising topically
`administering to the eye of the human an emulsion at a frequency of twice a day, wherein the
`emulsion comprises cyclosporin A in an amount of about 0.05% by weight, polysorbate 80,
`Pemulen, water, and castor oil
`in
`an
`
`amount of about 1.25% by weight; and
`wherein the topical ophthalmic emulsion
`is
`
`effective in treating dry eye disease.
`
`(New) The method of Claim 37, wherein the emulsion further comprises a tonicity agent
`38.
`or a demulcent component.
`
`(New) The method of Claim 38, wherein
`39.
`glycerine.
`
`the
`
`
`
`
`
`agent tonicity or the demulcent component is
`
`40.
`
`
`
`(New) The method of Claim 37, wherein the emulsion further comprises a buffer.
`
`41.
`
`
`
`
`
`the (New) The method of Claim 40, wherein buffer is sodium hydroxide.
`
`(New) The method of Claim 37, wherein the topical ophthalmic emulsion further
`42.
`comprises glycerine and a buffer.
`
`(New) The method of Claim 37, wherein the emulsion comprises polysorbate 80 in an
`43.
`amount of about 1.0%
`by weight.
`
`(New) The method of Claim 37, wherein
`44.
`about 0.05%) by weight.
`
`the
`
`3
`
`
`
`
`
`Pemulen emulsion comprises in an amount of
`
`0003
`
`

`
`Docket No. 17618CON5B (AP)
`
`(New) The method of Claim 37, wherein the emulsion further comprises glycerine in an
`45.
`amount of about 2.2% by weight and a buffer.
`
`46.
`
`
`
`
`
`the (New) The method of Claim 45, wherein buffer is sodium hydroxide.
`
`47.
`(New) The method of Claim 37, wherein, when the emulsion is administered to an eye of
`a human in an effective amount in treating dry eye syndrome, the blood of the human has
`substantially no detectable concentration of
`cyclosporin A.
`
`(New) The method of Claim 42, wherein the emulsion has a pH in the range of about 7.2
`48.
`to about 7.6.
`
`49.
`(New) The method of Claim 37, wherein the emulsion is as substantially therapeutically
`effective as an emulsion comprising cyclosporin A in an amount of 0.1% by weight and castor
`oil in an amount of 1.25% by weight.
`
`50.
`(New) The method of Claim 37, wherein the emulsion achieves at least as much
`therapeutic effectiveness as an emulsion comprising cyclosporin A in an amount of 0.1% by
`weight and castor oil
`in an amount of
`1.25% by weight.
`
`51.
`(New) The method of Claim 37, wherein the emulsion breaks down more quickly in the
`eye of a human, once administered to the eye of
`in
`
`the human, thereby reducing vision distortion
`the eye of the human as compared
`to an emulsion
`that
`contains
`only
`50%
`as
`
`much
`
`(New) The method of Claim 37, wherein the emulsion, when administered to the eye of a
`52.
`human, demonstrates a reduction in adverse events in the human, relative to an emulsion
`comprising cyclosporin A
`
`in an amount of 0.1% by weight and castor oil in an amount of 1.25%
`by weight.
`
`53.
`
`
`
`(New) The method of Claim 52, wherein the adverse events include side effects.
`
`4
`
`0004
`
`

`
`Docket No. 17618CON5B (AP)
`
`by weight;
`
`an
`
`of amount 2.2% by weight;
`
`effects a human suffering from dry eye syndrome, in
`
`
`(New) A method of reducing side
`54.
`method comprising the step of topically administering to the eye of the human an emulsion at a
`frequency of twice a day, wherein
`the
`emulsion
`comprises:
`cyclosporin A in an amount of
`about 0.05% by weight;
`castor oil in an amount of about 1.25% by weight;
`polysorbate 80 in an amount of
`about 1.0%
`Pemulen in an amount of about 0.05% by weight;
`a tonicity component or a demulcent component
`in
`a buffer; and
`water.
`
`the
`
`about
`
`
`
`
`
`55.
`
`
`
`(New) The method of Claim 54, wherein the buffer is sodium hydroxide.
`
`56.
`(New) The method of Claim 54, wherein the tonicity component or the demulcent
`component is glycerine.
`
`is (New) The method of Claim 54, wherein, when the emulsion administered to the eye of
`
`
`57.
`a human in an effective amount in treating dry eye syndrome, the blood of the human has
`substantially no detectable concentration of
`the
`cyclosporin A.
`
`58.
`(New) The method of Claim 54, wherein the emulsion has a pH in the range of about 7.2
`to about 7.6.
`
`59.
`(New) The method of Claim 54, wherein the emulsion is effective in treating dry eye
`disease.
`
`(New) A method of treating dry eye disease, the method comprising the step of topically
`60.
`administering to an eye of a human an emulsion,
`the
`emulsion
`comprising:
`cyclosporin A in an amount of
`
`about 0.05%) by weight;
`castor oil in an amount of about 1.25% by weight;
`polysorbate 80 in an amount of
`about 1.0%
`
`by weight;
`
`5
`
`0005
`
`

`
`Docket No. 17618CON5B (AP)
`
`in
`
`Pemulen in an amount of about 0.05% by weight;
`glycerine in an amount of about 2.2% by weight;
`sodium hydroxide; and
`water;
`wherein the emulsion is effective
`
`
`
`treating dry eye disease.
`
`(New) The method of Claim 60, wherein the emulsion has a pH in the range of about 7.2
`61.
`to about 7.6.
`
`6
`
`0006
`
`

`
`Docket No. 17618CON5B (AP)
`
`REMARKS
`The applicants have canceled Claims 1-36 and have added Claims 37-61. Support for the
`limitations recited in the new claims may be found throughout the specification, and at least at
`page 4, line 25 page 5, line 14, page 10, lines 1-7, page 26, lines 5-19, and page 27, lines 4-31
`of the application specification filed herewith. No new matter
`has
`been
`added.
`The claims of the present application may vary in scope from the claims pursued in the
`parent applications. To the extent any prior amendments or characterizations of the scope of any
`claim, or the specification, or referenced art could be construed as a disclaimer of any subject
`matter supported by the present disclosure, the Applicants hereby rescind and retract such
`disclaimer.
`Specifically, the Applicants would like to bring to the Examiner's attention comments
`made in the Response filed on June 15, 2009 in U.S. Patent Application Serial No. 10/927,857
`(now abandoned) and comments made in the Amendment filed on June 15, 2009 in U.S. Patent
`Application Serial No. 11/897,177 (currently pending) regarding U.S. Patent No. 5,474,979 and
`the present application specification. Since these comments have been filed, the Applicants have
`collected evidence that supports
`
`the patentability of the pending claims.
`The Commissioner is hereby authorized to charge any fees required or necessary for the
`filing, processing or entering of this paper or any of the enclosed papers, and to refund any
`overpayment, to deposit account 01-0885.
`
`Date: August 14, 2013
`
`Respectfully submitted,
`
`/Laura L. Wine/
`
`Laura L. Wine
`Attorney of Record
`Registration Number 68,681
`
`Please direct all inquiries and correspondence
`Laura L. Wine, Esq.
`Allergan, Inc.
`2525 Dupont Drive, T2-7H
`Irvine, California 92612
`Tel: (714) 246-6996 Fax: (714)246-4249
`
`to:
`
`7
`
`0007
`
`

`
`Doc Code: TRACK1.REQ
`Document Description: TrackOne
`
`Request
`
`PTO/AIA/424 (03-13)
`
`REQUEST
`AND
`CERTIFICATION
`UNDER 37 CFR
`1.102(e)
`
`FOR
`
`(Page
`
`PRIORITIZED
`1
`of
`
`1)
`
`Andrew Acheampong
`
`Nonprovisional Application
`known):
`
`Number
`
`(if
`
`METHODS OF PROVIDING
`
`THERAPEUTIC
`
`
`
`EFFECTS CYCLOSPORIN COMPONENTS USING
`
`
`
`First Named
`Inventor:
`Title of
`Invention:
`
`THE
`APPLICANT HEREBY CERTIFIES
`THE ABOVE-IDENTIFIED APPLICATION.
`
`FOLLOWING
`
`
`
`AND PRIORITIZED EXAMINATION REQUESTS
`
`
`
`FOR
`
`CFR
`37
`in
`forth
`set
`fee
`1. The processing
`
`37 CFR 1.17(c), and if not already paid, the publication
`fee
`been filed with
`the
`request. The basic filing
`fee,
`search
`excess claims and application
`size
`fees
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`paid.
`
`the
`1.17(i)(1),
`37
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`set
`forth
`fee,
`examination
`filed
`with
`
`prioritized
`CFR
`1.18(d)
`fee,
`and
`the
`
`2. The application contains
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`total
`
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`claims,
`
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`and
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`|~l Request for Continued Examination
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`/Laura L. Wine/
`Laura L. Wine
`
`Signature
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`(Print/Typed)
`
`August 14, 2013
`Registration Number 68681
`Note: This form must be signed in accordance with 37 CFR 1.33. See 37 CFR 1.4(d) for signature requirements and certifications.
`if more
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`Submit multiple forms
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`Q
`
`Page 2
`
`0009
`
`

`
`Electronic Patent Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`Title of Invention:
`
`METHODS OF PROVIDING
`COMPONENTS
`
`THERAPEUTIC EFFECTS USING
`
`CYCLOSPORIN
`
`First Named Inventor/Applicant Name:
`
`Andrew Acheampong
`
`Filer:
`
`Laura Lee Wine/Lauren
`
`Barberena
`
`Attorney Docket Number:
`
`17618CON5B
`
`(AP)
`
`Filed as Large Entity
`
`Track I Prioritized Examination - Nonprovisional Application under 35 USC 111 (a) Filing Fees
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`Description
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`Claims:
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`1011
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`1311
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`1817
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`Claims in
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`Excess of
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`20
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`1202
`
`Independent
`
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`
`in
`
`3
`
`excess
`
`of
`
`1201
`
`1
`
`1
`
`1
`
`1
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`5
`
`1
`
`280
`
`600
`
`720
`
`280
`
`600
`
`720
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`4000
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`4000
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`80
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`420
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`400
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`420
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`International Application Number:
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`8654
`
`Title of Invention:
`
`METHODS OF PROVIDING
`COMPONENTS
`
`THERAPEUTIC EFFECTS USING
`
`CYCLOSPORIN
`
`First Named Inventor/Applicant Name:
`
`Andrew Acheampong
`
`Customer Number:
`
`51957
`
`Filer:
`
`Laura Lee Wine/Lauren
`
`Barberena
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`Filer Authorized By:
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`Laura Lee Wine
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`17618CON5B
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`0014
`
`

`
`0-311ICON
`METHODS OF PROVIDING THBR&PEOTXC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`5 Related Application
`This application is a continuation of 0.S* Application
`Serial No« 10/927?857, filed August 27, 2004, which claimed
`the benefit of U'."S. Provisional.
`No. 60/503, 137
`Application
`filed September 15, 2003, which is incorporated in its
`10 entirety herein by reference.
`
`Background of the Invention
`The present invention relates to methods of providing
`desired therapeutic effects to humans or animals using
`IS. 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
`20 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 6r254,860; and Garst U.S.
`25 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.
`Such publications
`include,
`for
`"Blood
`example,
`yclospor a
`long-term treatment
`n
`with cyclosporin, a Qphthalmic erftulsions in. patients with
`moderate to severe dry eye disease," Small et al, J Ocul
`Pharmacol Ther, 2002 Octr 18(5);411-8; "Distribution of
`
`30
`
`0015
`
`

`
`2
`ocular tissues after topical
`;
`
`D~311ICON
`cyclosporin
`-»*
`*
`X'
`Acheampong et a1, Curr Eye Res/ 199S Febt 18 (2):91~103b;
`<vCyclospQrine distribution into the conjunctiva, cornea,
`op
`5 lacrimal gland, and systemic blood
`dosing
`of cyclospoyine to rabbit,
`human eyes," Acheampong
`et ai, Adv Exp Med Biol, 19-98, 438:1001-4;
`^Preclinical
`safety studies of cyclosporine ophtha.liril.c emulsion,"
`Angelov et al, Adv Exp Med Biol, 1998, 438:991-5;
`10 ^Cyclosporin & Emulsion & Eye," Stevenson et al.
`and "Two
`Ophthalmology, 2000 May, 107(5) ; 967-7-4;
`raulticenter, .randomized studies of the efficacy and safety
`of cyclosporine aphthaifflic eroulsion in .moderate to severe
`disease. CsA Phase 3
`u
`p," Sail et al.
`IS Ophthalmology, 2000 Apr, 107 (4}.-: 631-9,
`Each of these
`publications is i.ncorporafced in its entirety herein by
`reference. In addition, cyclosporin A:-coni.taining oil-in-
`watet emulsions have been clinically tested, under
`conditions of confidentiality, since the mid 1990's in
`20 order to obtain U.S. Food and Drug Mmnistration
`(FDA)
`regulatory approval.
`Examples of useful cyclosporin A-containing emulsions
`are set out in Ding et al U.S. Patent 5, 474,37EL 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 8,
`which included 0.2% by weight cyclosporin A and 5% by
`weight castor oil.
`The Ding et ai 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
`
`25
`
`30
`
`A
`
`in
`-
`
`than
`
`0.2%
`
`0016
`
`

`
`D-311ICON
`3
`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 soiubilize the cyclosporin h-. Thus, if
`5 reduced amounts of cyclosporin are eittployed, reduced
`amounts of castor oil are needed to provide effective
`solubilization of cyclosporin A.
`There continues to be a need for providing enhanced
`methods of treating ophthalmic or ocular conditions with
`10 eyclosporin-containing emulsions.
`
`Stumaary of the Inventioft
`New methods of treating a human or animal using
`cyclosporin component-containing emulsions have been
`15 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
`20 reduced risks ot 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 risks of harmful side effects and/or drug
`25 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
`30 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
`
`0017
`
`

`
`5
`
`D-311.1 CON
`4
`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,
`It has been found that the relatively increased
`amounts of hydrophobic, component together with relatively
`yet therapeutically effective, amounts of
`reduced,
`cyclosporin component provide substantial and advantageous
`benefits. For example, the overall efficacy of the present
`10 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
`15 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
`2.0 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
`25 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
`without
`dry
`eye
`are.
`limitation,
`syndrome,
`
`30
`
`0018
`
`

`
`15
`
`D-311ICON
`vernal
`uveitis,,
`phaeoanaphylactic
`endophthalmitis r
`conjunctivitis, atopic kerapoconjunctivitis, corneal graft
`rejection and the like conditions. The present invention
`is particularly effective in treating dry eye syndrome.
`Employing reduced eoncentrations 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
`component, preferably with substantially no detectable
`10 concentration of the cyclosporin component»
`The
`cyclosporin component concentration of blood can be
`advantageously measured using a yalidated liquid
`chromatography/mass spectrometEy-mass spectrometry (VLC/MS-
`MSJ analytical Method, such as described elsewhere herein.
`In one embodiment/ in the present methods the blood of
`the human or animal has concentrations of clyciosporin
`component 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 h, along with several other minor metabolites#
`cyclosporin B through 1, 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 irialecular weight of about
`1,200, but with different substituents or configurations of
`30 some of the amino acids.
`The term "cyclosporin component" as used herein is
`intended to include any individual meiiVber of the
`
`20
`
`25
`
`0019
`
`

`
`15
`
`6
`D-311ICON
`cyclosporin group and derivatives thereof, as well as
`mixtures of two or more individual cyclosporins and
`derivatives thereof <
`Particularly preferred cyclosporin components include,
`5 without limitation,. cyclosporin A, derivatives of
`cyclosporin ft and the like and itiixtures thereof.
`Cyclosporin A is an especially useful cyclosporin
`component.
`Any suitable hydrophobic component may be employed in
`10 the present invention. Advantageously, the cyclosporin
`component is solubilized in the hydrophobic component. The
`hydrophobic component may be considered as comprising a
`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
`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.
`Preferahiy, the hydrophobic component comprises one or
`more oily materials. Examples of useful oil materials
`inciude, without limitation, vegetable oils, animal oils,
`mineral oils, synthetic oils and the like and mixtures
`thereof.. In a very useful embodiment, the hydrophobic
`25 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
`30 the usefulness and effectiveness of the compositions.
`Examples of such other components include, without
`limitation, emulsifier components, tonicity components,
`
`20
`
`0020
`
`

`
`n
`
`D~3111C08
`components,
`surfactant
`components,
`polyelectrolyte
`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
`5 are effective to perform two or more functions in the
`presently useful compositions. For example, components
`which are effective as both eroulsifiers and surfactants may
`be employed, and/or components which are effective as both
`polyelectrolyte components and
`viscosity
`inducing
`10 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 achieved, the desired properties
`15 of the compositions to foe 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
`ophtha1mica11y acceptable, A composition, component or
`20 material is Qphthalmically 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
`25 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