liii
`
`11111
`
`Iii
`
`111111
`
`11111
`
`11111
`
`1111111111
`
`11111
`
`11111
`
`11111
`
`1110
`
`US005578586A
`Patent Number
`
`Date of Patent
`
`1111111 III
`
`11111
`
`United States Patent
`
`Glonek et
`
`5578586
`Nov 26 1996
`
`424/1.1
`
`514/78
`
`424/450
`
`424/427
`
`424/450
`
`514/169
`
`252/3 14
`
`514/76
`
`424/450
`
`DRY EYE TREATMENT PROCESS AN
`SOLUTION
`
`Inventors
`
`Thomas Glonek Oak Park Ill
`Greiner Winchester Donald
`Korb Boston both of Mass
`
`Jack
`
`Assignee Ocular Research of Boston Inc
`Boston Mass
`
`Notice
`
`The term of this patent shall not extend
`beyond the expiration date of Pat No
`5294607
`
`Appl No 192051
`Feb
`
`Filed
`
`1994
`
`Related U.S Application Data
`
`1992 Pat No
`Continuation of Set No 898375 Jun
`of Set No 529
`5294607 which is
`continuation-in-part
`657 May 29 1990 abandoned Ser No 457086 Dec 26
`1989 abandoned Ser No 111874 Oct 23 1987 Pat No
`4914088 and Set No 33185 Apt
`1987 abandoned
`mt Cl.6
`
`A61K 311685 A61K 31/66
`A61K 31/20
`
`U.S Cl
`
`Field of Search
`
`514/76 514/75 514/78
`514/558 514/912
`514176 75 558
`514/912
`
`References Cited
`
`U.S PATENT DOCUMENTS
`
`4522803
`4677099
`4804539
`4818537
`4839175
`4866049
`4908154
`4914088
`4938965
`
`6/1985
`
`Lenk et al
`
`6/1987
`
`2/1989
`
`4/1989
`
`Shinitzky et al
`Quo et al
`Quo
`Gun
`6/1989
`9/1989 Maumenee et al
`
`Cook et al
`3/1990
`4/1990 Ginneketal
`Shek et al
`
`7/1990
`
`FOREIGN PATENT DOCUMENTS
`
`16149
`0241376
`0391369
`
`1/1978
`
`10/1987
`
`4/1990
`
`Australia
`European Pat Off
`European Pat Off
`
`OTHER PUBLICATIONS
`
`Hardberger Hanna and Boyd Effects of Drug Vehicles on
`Ocular Contact Time Arch Ophthalmol vnl 93 Jan
`1975
`
`Primaty ExaminerZohreh Fay
`Attorney Agent or FinnRobert
`
`Goldberg
`
`ABSTRACT
`
`method and composition for reducing evaporation of an
`the eye The method
`from the surface of
`aqueous
`layer
`comprises applying an admixture of
`charged phospholipid
`and
`non-polar oil over the eye preferably in the form of
`dosage not exceed
`in water emulsion in
`meta-stable oil
`ing 100 microliters
`
`4421748
`
`12/1983
`
`Trager et al
`
`424/199
`
`22 Claims No Drawings
`
`FAMY CARE - EXHIBIT 1009-0001
`
`

`
`5578586
`
`DRY EYE TREATMENT PROCESS AND
`SOLUTION
`
`CROSS REFERENCE TO RELAThD
`APPLICATIONS
`
`This is continuation of applications Set No 07/898375
`1992 now U.S Pat No 5294607 which is
`filed on Jun
`of U.S patent application Set No
`continuation-in-part
`filed May 29 1990 now abandoned
`and
`07/529657
`of U.S patent application Set No
`continuation-in-part
`filed Dec 26 1989 now abandoned
`and
`07/45708
`of U.S patent application Set No
`07/111874 filed Oct 23 1987 now U.S Pat No 4914088
`continuation-in-part of U.S patent application Set No 15
`and
`1987 now abandoned
`07/033185 filed Apt
`
`continuation-in-part
`
`10
`
`BACKGROUND OF THE INVENTION
`
`Introduction
`
`20
`
`to ocular
`
`is the
`
`is known that reported relief of
`inaccurate For this reason it
`known tear substitutes
`dry eye symptoms using
`varies
`to subject and regardless of the
`considerably from subject
`method used to quantify relief using
`tear substitute relief
`often does not exceed several minutes
`The symptoms associated with dry eye are often exacer
`such as contact
`bated with subjects using ocular prostheses
`lenses In some cases contact
`lens intolerance is caused in
`part or in total by the condition of dry eye and its symp
`toms Further the rate of evaporation from the eye is
`lens surface and the
`accelerated by the nature of the contact
`physical presence of the contact
`lens results in meaiscii
`formation with additional physical and evaporative
`effects
`film For many
`even with subjects having
`an adequate tear
`lens intolerance is not overcome by topical
`subjects contact
`need for
`application of tear substitutes Therefore there is
`for treatment of the
`improved compositions and processes
`dry eye condition and for improving tolerance
`prostheses
`An improved composition for dry eye treatment
`subject of U.S Pat No 4914088 incorporated herein by
`teaches the use of charged phospho
`reference This patent
`lipids for the treatment of dry eye symptoms The addition
`of
`charged phospholipid to the eye assists in replicating the
`tear film that would naturally occur
`in the eye In accordance
`with the patent
`the phospholipid composition preferably in
`the form of an aqueous emulsion is topically applied to the
`the ocular surface
`is believed to disperse over
`eye where it
`lipid layer that would be
`and form film that
`replicates
`formed by the spreading of
`naturally occurring lipid
`secreted principally from the Meibomian
`glands during
`blinldng Because the phospholipid when applied to the eye
`is believed that aligned molecules
`net charge it
`carries
`formation
`repel each other preventing complex aggregate
`stable phospholipid film The patent
`thereby resulting in
`the film formed from the charged phospho
`speculates that
`in the formation of
`bather
`film reducing
`lipid assists
`evaporation of the aqueous layer thereby preserving the tear
`film
`In copending U.S patent application Set No 07/529657
`filed May 29 1990
`in dry eye
`improvement
`treatment is disclosed In accordance with the disclosure of
`said application the dry eye treatment composition of U.S
`Pat No 4914088 is
`improved by the addition of an
`to the eye treatment composition
`essentially non-polar oil
`The oil
`is added to improve the performance of
`dry eye
`treatment composition by increasing the longevity of the tear
`film formed on the eye following addition of the dry eye
`thick
`treatment solution presumably by providing and/or
`layer on the outer
`the oil
`eaing the dehydration barrier
`surface of the tear film Thus the oil
`the efficacy
`increases
`of the dry eye treatment solution and reduces performance
`variability from subject
`to subject
`The
`the referenced
`use of
`the dry eye treatment of
`application assists in overcoming dry eye symptoms as
`reported in the application However when using the pro
`cedures and composition of the application some subjects
`addition of
`the treatment
`experience
`blurring following
`composition containing the oil The time required for the
`blur to clear is often unpredictable In addition relief of dry
`eye symptoms was found to vary somewhat from patient to
`
`further
`
`patient
`
`SUMMARY OF THE INVENTION
`
`The invention disclosed herein is
`further improvement
`in the above referenced U.S
`
`over the inventions disclosed
`
`cant
`
`It
`
`over
`
`This invention relates to wetting the surface of the eye
`lubrica
`an ocular prosthesis providing mechanical
`and/or
`reducing the evaporation of fluid from the
`tion therefor
`surface of the eye and if desired delivering medicant to the
`ocular surface More particularly the invention relates to
`composition capable of augmenting and maintaining
`stable
`tear film over the ocular surface and/or delivering medi
`to said surface without causing substantial blurring of
`the invention
`preferred embodiment of
`vision In
`the
`invention relates to an ophthalmic composition for dry eye 30
`treatment The invention is especially useful for treatment of
`lenses
`individuals wearing ocular prostheses such as contact
`the invention wets and provides
`of
`the composition
`as
`lubrication for both the ocular surface and the surface of the
`prosthesis in contact with the ocular surfaces
`Description of the Prior Art
`is known in the art
`tear film extends
`that an aqueous
`the ocular surfaces and maintains the ocular surface
`is also known that dehydration of
`moist and lubricated It
`moisture from the eye may result in discomfort Further it
`is known that compositions are available in the market
`intended for dry eye treatment These
`compositions are
`primarily aqueous materials that supplement the tear film
`resulting from dry eye con
`The feeling of discomfort
`dition may include ocular dryness grittiness burning sore
`and the
`upon the subject
`ness or scratching
`dependent
`condition of
`causes for dry eye
`the subject Proposed
`compendium of
`treatment and symptoms are described in
`papers edited by Holly The Preocular Tear Film in Health
`Disease and Contact Lens Wear The Dry Eye Institute
`Lubbock Tex 1986 incorporated herein by reference
`for dry eye involves tem
`The most common treatment
`porary alleviation of dry eye symptoms by topical applica
`tear substitute that adds
`large volume of liquid to
`tion of
`the anterior surface of the eye and related adnexa Typical
`tear substitute compositions comprise water soluble polymer
`solutions Examples of such solutions include saline solu
`tions of polyvinyl alcohol hydroxypropylmethyl
`cellulose
`celluloses U.S Pat No 4421748
`or carboxymethyl
`tear composition comprising an aqueous
`teaches an artificial
`hypotonic solution of lecithin and
`viscosity adjusting agent
`such as
`solution soluble cellulose
`
`25
`
`35
`
`40
`
`45
`
`50
`
`60
`
`of tear sub
`Methods used to quantify the effectiveness
`stitutes for dry eye treatment solutions have not been stan-
`dardized and many methods used to quantify the results
`obtained using such tear substitute compositions are often
`
`65
`
`FAMY CARE - EXHIBIT 1009-0002
`
`

`
`5578586
`
`application Ser No
`Pat No 4914088
`and copending
`071529657
`In accordance with the invention
`disclosed
`herein dry eye treatment compositions and processes
`are
`controlled means for appli
`further improved by providing
`cation of dry eye treatment composition to the eye whereby
`blurred vision is reduced or eliminated and the residence
`time of tear film on the eye is prolonged
`The invention herein is the result of several discoveries
`it has been discovered
`that
`the total quantity of oil
`First
`the ocular surface should be
`available to form film over
`closely controlled Secondly and contrary to prior under
`standing it has been found that when the dry eye treatment
`composition is in the form of an emulsion the emulsion is
`preferably added to the eye as meta-stable emulsion not as
`finely divided stable emulsion Finally it has been dis
`covered that
`used in the preparations of the
`the surfactant
`preferred treatment composition be one that cnables control
`of the amount of oil contained
`in an emulsion and enables
`the ocular surface
`rapid formation of an oil film over
`how the treatment compositions of
`and the basis
`invention function
`for the improvements
`is desirable to understand the mechanism
`described herein it
`by which
`barrier film over the eye is capable of alleviating
`thy eye symptoms The description that
`follows is based
`upon belief and that reported in the literature
`
`To understand
`
`the
`
`It
`
`polar
`
`naturally occurring tear film comprises
`is reported that
`complex coating with three separate layers The inner layer
`in contact with the ocular surface of the eye is said to be
`composed primarily of mucous and renders the hydropho
`bic epithelial cell surface hydrophilic The middle layer of
`the tear film is an aqueous layer This layer is the thickest
`source of moisture and lubri
`portion of the tear film is
`for the eye and functions as an optical planarizing
`cation
`layer The outer layer of the tear film at
`the interface with
`the atmosphere is
`non-polar oily naturally occurring lipid
`layer This oily lipid layer is reported to act as
`barrier that
`layer Mishima and
`of
`the aqueous
`evaporation
`prevents
`Maurice The oily layer of the tear film and evaporation
`from
`the corneal surface Exp Eye Res 1961 13945 Finally
`the oily layer is bound to the aqueous layer through
`interfacial phospholipid layer
`The polar phospholipid and non-polar oily lipid compo
`nents of the tear film are thought to originate primarily from
`secretions of the Meibomian glands The oily layer of the
`tear film is formed from these secretions
`and is constantly
`replenished during blinking by expression of the secretions
`from the Meibomian glands and then spreading of the same
`over
`the surface of the eye by the eyelids By constantly
`spreading the polar and non-polar lipids over
`the eye during
`blinking the tear film is maintained and evaporation
`of the
`film is minimized
`aqueous middle layer of the tear
`cause of dry eye is believed to be
`deficiency in the
`quantity or quality of secretions from the Meibomian glands
`cause of dry eye is
`is postulated herein that
`deficiency
`in the polar lipid layer of the tear
`film the non-polar oily
`lipid layer or both Regardless of the cause of the deficiency
`the compromised lipid layer
`to act as an adequate
`barrier against evaporation of the aqueous portion of the tear
`film resulting in one form of the dry eye condition
`In accordance with the invention of U.S Pat No 4914
`088
`charged phospholipid is added to the eye preferably
`as an oil-in-water emulsion Upon contact of the emulsion
`with the eye it was thought that the phospholipid dispersed
`over
`the ocular surface to form film replicating the lipid
`formed by spreading
`naturally occurring lipid
`layer
`secreted from the Meibomian glands during blinking Where
`
`It
`
`fails
`
`net
`
`the phospholipid applied to the eye preferably carries
`the aligned molecules repel each
`charge it
`is believed
`that
`other such that complex aggregate
`formation is prevented
`and the integrity of the phospholipid film is maintained It
`was believed that
`the film formed from the phospholipid
`layer acted as barrier reducing evaporation of the aqueous
`layer thereby preserving the tear film
`In practice it was found that treatment of dry eye symp
`toms with the phospholipid compositions claimed in U.S
`Pat No 4914088
`resulted in substantial
`improvement
`relative to treatment with prior art compositions Films
`formed by the application of the phospholipid to the eye
`were found to be long lasting and application of the treat
`ment composition did not cause blurring of vision any more
`severe than the blurring resulting from the application of
`prior art compositions for dry eye treatment or even physi
`ological saline
`
`Though the use of the dry eye treatment compositions of
`U.S Pat No.4914088 provided relief of dry eye symptoms
`in the majority of patients
`treated as stated in said patent
`with improved testing procedures
`subsequent
`developed
`the filing of the application leading to the grant of said
`from
`it was found that there was variance in efficacy
`
`patent
`
`to
`
`10
`
`15
`
`20
`
`25
`
`30
`
`patient to patient
`In copending U.S patent application Ser No 07/529657
`an improved dry eye treatment composition is disclosed The
`invention of the application was the discovery of the desir
`ability of adding an oil
`to the eye for treatment of the dry eye
`condition Thus the invention of the copending
`application
`involved supplementing dry eye treatment by addition of an
`preferred embodi
`to the eye In
`essentially non-polar oil
`ment of the invention dry eye treatment involved adding
`combination of
`charged phospholipid and an essentially
`to the eye In accordance with said application
`non-polar oil
`though the charged phospholipid and the non-polar oil could
`be separately applied to the eye it was preferred that
`the two
`be combined in
`single treatment composition
`components
`most preferably in the form of
`finely divided stable
`oil-in-water emulsion
`stable emulsion was desired for
`container Upon application of the
`long term storage in
`phospholipid and oil
`to the eye whether as separate addi
`single treatment composition it was postulated
`tions or as
`the negatively charged phospholipid layer formed an
`tear film with charged ends
`aligned film over
`the aqueous
`dissolved in the aqueous layer and hydrophobic ends fur
`thest removed from the aqueous layer available to bond with
`layer This caused the oil
`the non-polar oil
`layer to disperse
`over
`the top surface of the eye as
`thin continuous
`and
`functioned as an evaporation barrier Rec
`stable layer that
`50 ognizing that
`the tear film naturally occurring in the eye may
`be deficient in the phospholipid component
`the oil compo
`nent or both the preferred embodiment of the treatment
`composition of said application replenished both compo
`nents of the tear film thereby reducing variations in efficacy
`from patient to patient
`
`40
`
`that
`
`Use of
`the treatment compositions of
`the copending
`application results in formation of
`tear film over
`the eye
`that alleviates dry eye symptoms and increases
`patient
`as described in said applica
`tolerance for ocular prostheses
`tion However
`as
`of
`treatment with the
`consequence
`solution some
`blurred vision both
`experienced
`subjects
`initially upon application of the treatment composition to the
`eye and in some cases over
`prolonged time In accordance
`with the invention described herein the dry eye composi
`tions alleviate dry eye symptoms at
`least as effectively as
`those of
`above-referenced
`copending
`the
`application
`enhance patient tolerance to ocular prostheses and provide
`
`60
`
`65
`
`FAMY CARE - EXHIBIT 1009-0003
`
`

`
`it
`
`5578586
`
`of essentially avoiding prolonged
`advantage
`the further
`blurred vision In addition in accordance with the subject
`the residence
`time of the film is increased
`invention
`
`In accordance with the invention it has been found that
`the above described improvements are realized if any one or
`more of the following is practiced
`the total amount of oil comprising the film over the
`ocular surface is controlled
`
`the treatment composition is added to the eye in the
`form of meta-stable emulsion and
`
`the treatment composition in the form of an emulsion
`that permits increase
`contains
`surfactant
`in the oil
`content of an emulsion with decreased phospholipid
`and enables
`rapid formation of
`content
`film of the
`the treatment composition
`components
`of
`efficacious
`over the ocular surface With regard to control of the
`the eye it
`amount of oil comprising the film over
`thin film and
`should be recognized that
`the oil
`layer is
`the total volume of oil required to form this thin film is
`extremely small If
`the oil component of the tear film is
`excessively thick or irregular beaded the patient will
`prolonged blurred vision The problem is
`experience
`exacerabated when the oil
`polar oil rather than the
`
`is
`
`15
`
`20
`
`is desirable to disperse the active com
`administration
`pounds of the formulation in
`suitable vehicle that permits
`administration of larger volumes by the patient To control
`the volume of oils available for formation of the tear film
`without excessive discharge of treatment composition from
`the eye and to provide water
`the aqueous portion
`to augment
`the tear film the total amount of
`liquid treatment
`of
`treatment per eye prefer
`composition added to the eye per
`ably does not exceed 100 niicroliters ul about
`drops and
`10 more preferably varies between about 25 and 50 ul Since it
`the total volume of treatment composition
`is desired to limit
`added to the eye while recognizing that excess is discharged
`the total volume of oil
`from the eye by blinking and that
`must be controlled it
`the concentration of oil
`that
`is apparent
`in the treatment solution must be adjusted to provide the
`desired small dosage of oil
`to the eye and compensate
`for
`lost due to discharge of excess treatment composition
`that
`For reasons stated above rapid formation of the oil
`film
`over
`the film does not
`the corneal
`surface is desirable If
`in the treatment composition may be
`form rapidly oil
`from the eye before it can form satisfactory
`discharged
`film When oil
`is added in the form of an emulsion the
`emulsion should differentiate rapidly on entering the eye to
`film before excessive
`provide oil for formation of
`discharged from the eye with excess treatment composition
`The formation of the oil film is desirably assisted by use of
`in the treatment composition which assists in
`surfactant
`spreading the oil over the eye The surfactant should be one
`that enables rapid phase differentiation and further should
`and physi
`be one compatible with composition components
`compatible with the eyei.e it should not be
`ologically
`toxic nor cause stinging
`From the above discussion it
`is apparent
`treatment composition in the form of an
`sirable to provide
`reasons An emul
`excessively stable emulsion for several
`sion is often optically opaque due to the presence of distinct
`the surface of
`dispersed phases Therefore an emulsion over
`the eye is expected to cause blurring The duration of blur is
`the time required for the emulsion to
`dependent
`upon
`40 differentiate and form separate layers replicating
`tear film
`the emulsion
`Consequently blurring is likely to occur until
`and as discussed above if
`In addition
`differentiates
`emulsion is too stable excess emulsion will be discharged
`of the emulsion from the eye will
`from the eye Discharge
`result in discharge of efficacious
`components of the treat
`ment solution from the eye before
`tear film can be formed
`and these components will not be available for formation of
`the tear film Therefore in accordance with this invention it
`is preferred that the emulsion be stable for long term storage
`to achieve
`but rapidly differentiate in the eye This is difficult
`with existing technology and for purposes herein it
`is desired
`the emulsion be meta-stable where meta-stable emul
`that
`
`oil
`
`is
`
`that
`
`it
`
`is unde
`
`the
`
`25
`
`35
`
`45
`
`50
`
`preferred non-polar oil
`The process of formation of
`tear film following addition
`of
`treatment composition to the eye is
`with many steps involved If
`the treatment composition is in
`the form of an emulsion several
`are simulta
`processes
`neously set in motion immediately following the addition of
`the emulsion to the eye The emulsion begins to differentiate 30
`while the dispersed oil phase spreads over the ocular surface
`In addition the amount of
`fluid additive retained by the eye
`10 microliters ul It
`is up to about
`is believed that
`the
`if
`above about
`10 ul
`volume of
`fluid additive increases
`excess fluid moves to the canthi and rapidly enters the tear
`duct or is expressed
`from the eye as tears This can occur
`within four to five blinks following addition of the treatment
`composition to the eye Discharge of excess fluid will result
`in discharge of treatment components of the fluid from the
`eye making them unavailable to form and sustain the tear
`the fluid is in the form
`film This problem is exacerbated
`of an emulsion which does not rapidly differentiate liberat
`ing treatment components Consequently the concentration
`the emulsion must be
`of
`of
`the treatment components
`to treat the eye and compensate
`lost by
`for that
`sufficient
`and
`from the eye but should not be excessive
`discharge
`cause blurring
`In accordance with the invention
`
`dynamic process
`
`if
`
`the
`
`recognizing that
`as described
`formation of
`dynamic process
`tear film is
`above the total amount of oil available for formation of
`film preferably does not exceed 25 ul more preferably varies
`between
`about
`and 10 ul and most preferably varies
`ul Of this amount only
`about
`and
`small
`between
`portion will be available to form the oil
`layer over the ocular
`surface As the amount of oil available for film formation
`about
`film formed over
`10 ul
`exceeds
`the oil
`the eye
`becomes excessively thick or alternatively oil globules may
`form on the surface of the eye and not spread evenly over the
`eye In either ease the patient is likely to experience blurring
`oil The amount of oil beyond which
`due to excessive
`to patient and is
`occur varies from patient
`blurring will
`dependent upon the specific oil uses
`The treatment compositions of the invention are desirably
`formulated to permit self administration by
`patient
`low volumes of
`to self-administer
`difficult
`for
`patient
`treatment compositioni.e amounts of from to 10 ul
`to render
`the formulations
`suitable for self-
`Therefore
`
`55
`
`60
`
`sion is defined as
`is sufficientiy stable to
`composition that
`uniform dose to the eye but
`is relatively unstable
`provide
`and rapidly differentiates upon contact with the eye pref
`erably differentiating within about
`blinks following appli
`cation of the composition to the eye more preferably in
`less than about 30 seconds Blurring may occur
`time of
`during the time required to move the bulk of
`the excess
`liquid to the canthi and discharge the same from the eye
`In accordance with the copending
`application non-polar
`oils were used for dry eye treatment because the use of polar
`oils caused substantial blurring It
`further discovery of
`this invention that though non-polar oils are preferred polar
`65 oils may be used to alleviate dry eye symptoms without
`their volume available for film forma
`significant blurring if
`tion is carefully controlled within the most preferred con-
`
`is
`
`It
`
`is
`
`FAMY CARE - EXHIBIT 1009-0004
`
`

`
`5578586
`
`to
`
`ul
`
`centration range of from to ul more preferably
`the polar oils are diluted with non-polar oils
`or if
`upon the above the invention described
`Based
`charged phos
`comprises treatment of the eye with either
`pholipid an oil preferably an essentially non-polar oil or
`and in
`treatment solution form that
`both in amounts
`reduces or eliminates blurring and prolongs the residence
`time of an artificially formed replicated tear film on the eye
`
`herein
`
`DESCRIITION OF THE PREFERRED
`EMBODIMENTS
`
`10
`
`The treatment compositions of the invention comprise
`charged phospholipid and an oil They are applied by topical
`application to the eye Topical application is by application
`of each component separately or preferably by single treat
`ment composition containing the two components
`in single
`liquid vehicle such as an emulsion More preferably
`the
`emulsion is an aqueous oil-in-water meta-stable emulsion
`where the oil comprises the dispersed organic phase of the 20
`emulsion
`
`15
`
`ferred for reasons given above and because of the high price
`and scarcity of these compounds Examples of positively
`charged complex phospholipids within the scope of
`the
`invention are those containing the basic acyl amino acid
`groups Such compounds are
`subgroup within the family
`of the o-aminoacylphosphatidylglycerols
`
`the head groups
`to the charged phospholipids
`In contrast
`of phosphatidylethanolamine and phosphatidylcholine leci
`this pH
`positive charge at pH
`and thus at
`thin have
`these two phosphoglycerides are dipolar zwitterions with no
`compounds
`net electric charge Such
`are not within the
`scope of this invention unless chemically reacted to impart
`negative charge to the material
`Of the phospholipids discussed above the net negatively
`more preferred
`charged phosphoglycerides are preferred
`
`class of phosphoglycerides are represented by the following
`formula
`
`IC
`
`oPo
`
`It
`
`Phospholipids suitable for purposes of the invention are
`known in the art to be complex and to carry
`net positive
`or negative charge under conditions of use The preferred
`net negative charge because
`materials are those carrying
`be repelled by the
`the negatively charged material will
`thereby permitting the
`negatively charged ocular surface
`relatively thick aqueous layer The posi
`maintenance of
`to the nega
`tively charged phospholipid will be attracted
`tively charged ocular surface thus compressing the tear film
`Hence the positively
`charged phospholipids operate in
`different manner than the negatively charged phospholipids
`and are lesser preferred
`is known that complex phospholipids contain
`polar
`group at one end of their molecular structure and
`non-polar
`end of
`the molecular structure
`the opposite
`group at
`can be found in Leninger
`discussion of phospholipids
`ed Worth Publishers New York pp
`Biochemistry
`279306 incorporated herein by reference
`Many complex phospholipids are known in the art They
`in size shape and the electric charge of their polar
`differ
`head groups Phosphoglycerides are compounds where one
`is esterified to phospho
`primary hydroxyl group of glycerol
`ric acid and the other two hydroxyl groups are esterified
`with fatty acids The parent compound of the series
`is
`therefore the phosphoric acid ester of glycerol This com
`pound has an asymmetric carbon atom and therefore the
`stereoisomers
`term phosphoglycerides includes
`
`the
`
`negative
`
`have
`All phosphoglycerides
`charge at
`and the pK of this group is in the
`phosphate group at pH
`The head groups of phosphatidylinositol
`to
`range of
`phosphatidylglycerol
`including
`diphosphatidylglycerols
`having the common name cardiolipins and the phosphati
`dylsugars have no electric charge and all are polar because
`of their high hydroxyl group content Because of the nega
`and the absence of
`tive charge of the phosphate
`group
`charge in the head group the net charge of each of these
`materials is negative arid these materials are within the
`scope of the invention Likewise the head group of phos
`an alphaamino group PKalO
`phatidylserine contains
`carboxyl group plç3 and therefore the molecule
`and
`contains two negative charges and one positive charge at pH
`this compound
`7.0 giving it
`net negative charge whereby
`is also within the scope of the invention
`Complex phospholipids having
`net positive charge are
`also within the scope of this invention but are lesser pre
`
`25
`
`CH2C1-ICH2
`
`where
`and
`are each fatty acid residues preferably
`having from to 24 carbon atoms
`polyol
`is hydrogen
`3-O -aminoacylphosphatidylglycerol
`is one
`and
`30 or
`are typically com
`countercation
`and
`equivalent of
`an even or odd number of
`mon natural
`fatty acids having
`carbon atoms they may be the same or may differ from each
`other and they may be saturated monounsaturated
`or poly
`35 unsaturated Examples of fatty acid residues include laurate
`stearate oleate linoleate octanoate
`myristate palmitate
`lignocerate etc
`dodecate
`Phospholipids are available from variety of sources such
`as egg yolks soy beans etc as is known in the art These
`sources typically contain mixture of components
`including
`lipids as exemplified by glycerides cholesterol and
`natural
`net charge of zero
`cholesterol esters phospholipids having
`
`40
`
`55
`
`45
`
`50
`
`phosphatidylethano
`as exemplified by phosphatidylcholine
`lanrine various unsaturated
`and saturated
`fatty acids and
`and
`such as phosphatidyiglycerol
`charged phospholipids
`The charged phospholipids are typi
`phosphatidylinositol
`cally contained
`in these naturally occurring products
`in
`minor concentration
`varying from below one
`typically
`percent up to 10 to 15 percent of the total composition
`of the charged phospho
`the concentration
`Accordingly
`lipid from such
`natural source would likely be insufficient
`for purposes of treatment in accordance with the invention
`and
`complex phospholipid having
`net charge preferably
`phospho
`charge would be added to such
`net negative
`of the com
`lipid source to increase the total concentration
`plex charged phospholipids to
`concentration
`required for
`treatment in accordance with the invention Obviously if
`phospholipid from natural source is negatively charged
`negatively charged phospholipid would be added to supple-
`60 ment
`the concentration of the same whereby the total net
`charge remains negative
`The most preferred phospholipid
`for purposes of
`this
`charge The most
`polyol with
`invention is
`net negative
`preferred polyol phospholipids are the phosphatidylglycer
`65 ols including cardiolipins and phosphatidylinositols With
`out wishing to be bound by theory it
`is believed
`that
`the
`hydroxyl groups of the head groups of these phospholipids
`
`FAMY CARE - EXHIBIT 1009-0005
`
`

`
`5578586
`
`10
`preferably does not exceed 25 ul more preferably varies
`and 10 ul and most preferably varies
`between
`about
`the amount of oil added to the
`and ul If
`between about
`eye is in excess of 25 ul the oil
`layer on the surface of the
`eye may be too thick with formation of oil globules on the
`surface of the eye This phenomena
`in
`is likely to result
`prolonged time Self-administration of small
`blurring for
`volumes of oil
`and for this reason
`to the eye is difficult
`to the eye in the form of an emulsion is
`addition of the oil
`
`preferred
`single treatment composition for both the oil and
`In
`components
`the oil component may vary
`phospholipid
`within reasonable limits provided the amount of oil retained
`on the eye is within the controlled volumes set forth above
`concentra
`in
`treatment composition containing the oil
`tion of at least 0.1 percent by weight of the total composition
`provides some benefits
`for the oil
`preferred concentration
`the treatment
`the weight of
`least
`1.0 percent
`of
`is at
`the oil content of the treatment
`composition Preferably
`2.5 and 12.5 percent
`between
`about
`by
`solution varies
`
`10
`
`is
`
`15
`
`is
`
`20
`
`35
`
`50
`
`55
`
`60
`
`65
`
`if
`
`It
`
`weight of the composition
`In the preferred embodiment of the invention where the
`treatment composition is added to the eye as an emulsion
`of emulsion added to the eye is
`the total concentration
`desirably controlled to less than 100 ul and more preferably
`maintained as low as is practical
`for self-administration
`the oil and phospholipid compo
`should be obvious that
`by volume
`nents are added as an emulsion the concentration
`of the oil
`in the emulsion should be controlled to provide the
`limited dosage of oil described above 10 ul or less while
`from the eye For
`lost by discharge
`accounting
`for that
`the amount of emulsion added to the eye is 50
`example if
`standard drop the oil content of the emulsion prefer
`ul
`ably is about 10% by volume or ul as
`large portion of
`is likely to be discharged from the eye during the first
`the oil
`several blinks following application of the emulsion to the
`eye
`The concentration of
`in the
`the charged phospholipid
`treatment composition may also vary within wide limits
`treatment composition containing the charged phospholipid
`as low as 0.01 weight percent