United States Patent [191
`Glonek et al.
`
`illllllllllllllllllllllllllllllllllllllllllllll1||||llllllllllllillllllllll
`5,578,586
`*Nov. 26, 1996
`
`[11] Patent Number:
`[45] Date of Patent:
`
`USOO5578586A
`
`[54] DRY EYE TREATMENT PROCESS AND
`SOLUTION
`
`[75] Inventors: Thomas Glonek, Oak Park, 111.; Jack
`V. Greiner, Winchester; Donald R.
`Korb, Boston, both of Mass.
`
`[73] Assignee: Ocular Research of Boston, Inc.,
`Boston, Mass.
`
`[*1 Notice:
`
`The term of this patent shall not extend
`beyond the expiration date of Pat. No.
`5,294,607.
`
`[21] Appl. No.: 192,051
`[22] Filed:
`Feb. 4, 1994
`
`Related US. Application Data
`
`[63] Continuation of Ser. No. 898,375, Jun. 9, 1992, Pat. No.
`5,294,607, which is a continuation—in-part of Ser. No. 529,
`657, May 29, 1990, abandoned, Ser. No. 457,086, Dec. 26,
`1989, abandoned, Ser. No. 111,874, Oct. 23, 1987, Pat. No.
`4,914,088, and Ser. No. 33,185, Apr. 2, 1987, abandoned.
`
`[51]
`
`Int. Cl.6 ...................... .. A61K 31/685; A61K 31/66;
`A61K 31/20
`[52] US. Cl. ............................... .. 514/76; 514/75; 514/78;
`514/558; 514/912
`[58] Field of Search .............................. .. 514/76, 75, 558,
`514/912
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,522,803
`
`6/1985 Lenk etal. . . . . . . . . . . . . .
`
`. . . . .. 424/1.1
`
`4,677,099
`
`6/1987 Shinitzky et al.
`
`..... .. 514/78
`
`4,804,539
`
`2/1989 Guo et a1. . . , . . . . . . .
`
`. . . .. 424/450
`
`4,818,537
`
`4/1989 Guo . . . . . . . .
`
`. . . .. 424/427
`
`4,839,175
`
`6/1989 Guo . . . . . . . . . . . . . . . . . . . .
`
`. . . .. 424/450
`
`4,866,049
`
`9/1989 Maumenee et al.
`
`514/169
`
`4,908,154
`
`3/1990 Cook etal. . . . . . . . . . . . .
`
`. . . .. 252/314
`
`4,914,088
`4,938,965
`
`4/1990 Glonek et al. . . . . .
`. . . . . .. 514/76
`7/1990 Shek et a1. ............................ .. 424/450
`
`FOREIGN PATENT DOCUMENTS
`
`1/1978 Australia .
`16149
`0241376 10/1987 European Pat. O?’. .
`0391369 4/1990 European Pat. O?. .
`
`OTHER PUBLICATIONS
`
`Hardberger, Hanna and Boyd, “Effects of Drug Vehicles on
`Ocular Contact Time,” Arch. Ophthalmol., vol. 93, Jan.
`1975.
`
`Primary Examiner~Zohreh Fay
`Attorney, Agent, or Firm—Robert L. Goldberg
`
`[57]
`
`ABSTRACT
`
`A method and composition for reducing evaporation of an
`aqueous layer from the surface of the eye. The method
`comprises applying an admixture of a charged phospholipid
`and a non-polar oil over the eye, preferably in the fonn of
`a meta-stable oil in water emulsion in a dosage not exceed
`ing 100 microliters.
`
`4,421,748 12/1983 Trager et al. ......................... .. 424/199
`
`22 Claims, N0 Drawings
`
`APOTEX 1031, pg. 1
`
`

`

`5,578,586
`
`1
`DRY EYE TREATMENT PROCESS AND
`SOLUTION
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This is continuation of application(s) Ser. No. 07/898,375
`?led on Jun. 9, 1992, now US. Pat. No. 5,294,607 which is
`a continuation-in-part of US. patent application Ser. No.
`07/529,657, ?led May 29, 1990, now abandoned and a
`continuation-impart of US. patent application Ser. No.
`07/457,086 ?led Dec. 26, 1989, now abandoned and a
`continuation-in-part, of US. patent application Ser. No.
`07/111,874 ?led Oct. 23, 1987, now US. Pat. No. 4,914,088
`and a continuation-in-part of US patent application Ser. No.
`07/033,185 ?led Apr. 2, 1987, now abandoned.
`
`10
`
`BACKGROUND OF THE INVENTION
`
`1. Introduction
`This invention relates to wetting the surface of the eye
`and/or an ocular prosthesis, providing mechanical lubrica
`tion therefor, reducing the evaporation of ?uid from the
`surface of the eye and if desired, delivering a medicant to the
`ocular surface. More particularly, the invention relates to a
`composition capable of augmenting and maintaining a stable
`tear ?lm over the ocular surface and/or delivering a medi
`cant to said surface without causing substantial blurring of
`vision. In a preferred embodiment of the invention, the
`invention relates to an ophthalmic composition for dry eye
`treatment. The invention is especially useful for treatment of
`individuals wearing ocular prostheses such as contact lenses,
`as the composition of the invention wets and provides
`lubrication for both the ocular surface and the surface of the
`prosthesis in contact with the ocular surfaces.
`2. Description of the Prior Art
`It is known in the art that an aqueous tear ?lm extends
`over the ocular surfaces and maintains the ocular surface
`moist and lubricated. It is also known that dehydration of
`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 ?lm.
`The feeling of discomfort resulting from a dry eye con
`dition may include ocular dryness, grittiness, burning, sore
`ness or scratching, dependent upon the subject and the
`condition of the subject. Proposed causes for dry eye,
`treatment and symptoms are described in a compendium of
`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.
`The most common treatment for dry eye involves tem
`porary alleviation of dry eye symptoms by topical applica
`tion of a tear substitute that adds a large volume of liquid to
`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
`or carboxymethyl celluloses. US. Pat. No. 4,421,748
`teaches an arti?cial tear composition comprising an aqueous
`hypotonic solution of lecithin and a viscosity adjusting agent
`such as a solution soluble cellulose.
`Methods used to quantify the effectiveness of tear sub
`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
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`inaccurate. For this reason, it is known that reported relief of
`dry eye symptoms using known tear substitutes varies
`considerably from subject to subject, and regardless of the
`method used to quantify relief using a tear substitute, relief
`often does not exceed several minutes.
`The symptoms associated with dry eye are often exacer
`bated with subjects using ocular prostheses such as contact
`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
`accelerated by the nature of the contact lens surface and the
`physical presence of the contact lens results in meniscii
`formation with additional physical and evaporative effects,
`even with subjects having an adequate tear ?lm. For many
`subjects, contact lens intolerance is not overcome by topical
`application of tear substitutes. Therefore, there is a need for
`improved compositions and processes for treatment of the
`dry eye condition and for improving tolerance to ocular
`prostheses.
`An improved composition for dry eye treatment is the
`subject of US. Pat. No. 4,914,088 incorporated herein by
`reference. This patent teaches the use of charged phospho
`lipids for the treatment of dry eye symptoms. The addition
`of a charged phospholipid to the eye assists in replicating the
`tear ?lm 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
`eye where it is believed to disperse over the ocular surface
`and form a ?lm that replicates a lipid layer that would be
`formed by the spreading of a naturally occurring lipid
`secreted principally from the Meibornian glands during
`blinking. Because the phospholipid, when applied to the eye,
`carries a net charge, it is believed that aligned molecules
`repel each other preventing complex aggregate formation
`thereby resulting in a stable phospholipid ?lm. The patent
`speculates that the ?lm formed from the charged phospho
`lipid assists in the fonnation of a barrier ?lm reducing
`evaporation of the aqueous layer, thereby preserving the tear
`?lm.
`In copending US. patent application Ser. No. 07/529,657,
`?led May 29, 1990, a further improvement in dry eye
`treatment is disclosed. In accordance with the disclosure of
`said application, the dry eye treatment composition of US.
`Pat. No. 4,914,088 is improved by the addition of an
`essentially non-polar oil to the eye treatment composition.
`The oil is added to improve the performance of a dry eye
`treatment composition by increasing the longevity of the tear
`?lm formed on the eye following addition of the dry eye
`treatment solution, presumably by providing and/or thick
`ening the dehydration barrier (the oil layer) on the outer
`surface of the tear ?lm. Thus, the oil increases the e?icacy
`of the dry eye treatment solution and reduces performance
`variability from subject to subject.
`The use of the dry eye treatment of the referenced
`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
`experience blurring following addition of the treatment
`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
`patient.
`
`SUMMARY OF THE INVENTION
`
`The invention disclosed herein is a further improvement
`over the inventions disclosed in the above referenced U.S.
`
`APOTEX 1031, pg. 2
`
`

`

`5,578,586
`
`3
`Pat. No. 4,914,088 and copending application Ser. No.
`07/529,657. In accordance with the invention disclosed
`herein, dry eye treatment compositions and processes are
`further improved by providing a controlled means for appli
`cation of a dry eye treatment composition to the eye whereby
`blurred vision is reduced or eliminated and the residence
`time of tear ?lm on the eye is prolonged.
`The invention herein is the result of several discoveries.
`First, it has been discovered that the total quantity of oil
`available to form a ?lm over the ocular surface should be
`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 a meta-stable emulsion, not as
`a ?nely divided, stable emulsion. Finally, it has been dis
`covered that the surfactant used in the preparations of the
`preferred treatment composition be one that enables control
`of the amount of oil contained in an emulsion and enables
`rapid formation of an oil ?lm over the ocular surface.
`To understand how the treatment compositions of the
`invention function and the basis for the improvements
`described herein, it is desirable to understand the mechanism
`by which a barrier ?lm over the eye is capable of alleviating
`dry eye symptoms. The description that follows is based
`upon belief and that reported in the literature.
`It is reported that a naturally occuning tear ?lm comprises
`a 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 ?lm is an aqueous layer. This layer is the thickest
`portion of the tear ?lm, is a source of moisture and lubri
`cation for the eye and functions as an optical planarizing
`layer. The outer layer of the tear ?lm, at the interface with
`the atmosphere, is a non-polar oily, naturally occurring lipid
`layer. This oily lipid layer is reported to act as a barrier that
`prevents evaporation of the aqueous layer (Mishima and
`Maurice: The oily layer of the tear ?lm and evaporation from
`the corneal surface, Exp. Eye Res. 1961; 1:39-45). Finally,
`the oily layer is bound to the aqueous layer through a polar
`interfacial phospholipid layer.
`The polar phospholipid and non-polar oily lipid compo
`nents of the tear ?lm are thought to originate primarily from
`secretions of the Meibomian glands. The oily layer of the
`tear ?lm is formed from these secretions and is constantly
`replenished during blinking by expression of the secretions
`from the Meibonrian 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 ?lm is maintained and evaporation of the
`aqueous middle layer of the tear ?lm is minirrrized.
`A cause of dry eye is believed to be a de?ciency in the
`quantity or quality of secretions from the Meibomian glands.
`It is postulated herein that a cause of dry eye is a de?ciency
`in the polar lipid layer of the tear ?lm, the non-polar oily
`lipid layer or both. Regardless of the cause of the de?ciency,
`the compromised lipid layer fails to act as an adequate
`barrier against evaporation of the aqueous portion of the tear
`?lm resulting in one form of the dry eye condition.
`In accordance with the invention of U.S. Pat. No. 4,914,
`088, a 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 a ?lm replicating the lipid
`layer formed by spreading a naturally occurring lipid
`secreted from the Meibomian glands during blinking. Where
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`the phospholipid applied to the eye preferably carries a net
`charge, it is believed that the aligned molecules repel each
`other such that complex aggregate formation is prevented
`and the integrity of the phospholipid ?lm is maintained. It
`was believed that the ?lm formed from the phospholipid
`layer acted as a barrier, reducing evaporation of the aqueous
`layer, thereby preserving the tear ?lm.
`In practice, it was found that treatment of dry eye symp
`toms with the phospholipid compositions claimed in U.S.
`Pat. No. 4,914,088 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. 4,914,088 provided relief of dry eye symptoms
`in the majority of patients treated as stated in said patent,
`with improved testing procedures developed subsequent to
`the ?ling of the application leading to the grant of said
`patent, it was found that there was variance in ef?cacy from
`patient to patient.
`In copending U.S. patent application Ser. No. 07/529,657,
`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
`essentially non-polar oil to the eye. In a preferred embodi
`ment of the invention, dry eye treatment involved adding a
`combination of a charged phospholipid and an essentially
`non-polar oil to the eye. In accordance with said application,
`though the charged phospholipid and the non-polar oil could
`be separately applied to the eye, it was preferred that the two
`components be combined in a single treatment composition,
`most preferably in the form of a ?nely divided stable
`oil-in-water emulsion. A stable emulsion was desired for
`long term storage in a container. Upon application of the
`phospholipid and oil to the eye, whether as separate addi
`tions or as a single treatment composition, it was postulated
`that the negatively charged phospholipid layer formed an
`aligned ?lm over the aqueous tear ?lm with charged ends
`dissolved in the aqueous layer and hydrophobic ends fur
`thest removed from the aqueous layer available to bond with
`the non-polar oil layer. This caused the oil layer to disperse
`over the top surface of the eye as a thin, continuous and
`stable layer that functioned as an evaporation barrier. Rec
`ognizing that the tear ?lm naturally occurring in the eye may
`be de?cient 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 ?lm, thereby reducing variations in ef?cacy
`from patient to patient.
`Use of the treatment compositions of the copending
`application results in formation of a tear ?lm over the eye
`that alleviates dry eye symptoms and increases patient
`tolerance for ocular prostheses as described in said applica
`tion. However, as a consequence of treatment with the
`solution, some subjects experienced blurred vision both
`initially upon application of the treatment composition to the
`eye, and in some cases over a prolonged time. In accordance
`with the invention described herein, the dry eye composi
`tions alleviate dry eye symptoms at least as elfectively as
`those of the above-referenced copending application,
`enhance patient tolerance to ocular prostheses, and provide
`
`APOTEX 1031, pg. 3
`
`

`

`5,578,586
`
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`5
`the ?irther advantage of essentially avoiding prolonged
`blurred vision. In addition, in accordance with the subject
`invention, the residence time of the ?lm is increased.
`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:
`(l) the total amount of oil comprising the ?lm over the
`ocular surface is controlled;
`(2) the treatment composition is added to the eye in the
`form of a meta-stable emulsion; and
`(3) the treatment composition, in the form of an emulsion,
`contains a surfactant that permits increase in the oil
`content of an emulsion with decreased phospholipid
`content and enables rapid formation of a ?lm of the
`e?icacious components of the treatment composition
`over the ocular surface. With regard to control of the
`amount of oil comprising the ?lm over the eye, it
`should be recognized that the oil layer is a thin ?lm and
`the total volume of oil required to form this thin ?lm is
`extremely small. If the oil component of the tear ?lm is
`excessively thick or irregular (beaded), the patient will
`experience prolonged blurred vision. The problem is
`exacerabated when the oil is a polar oil rather than the
`preferred non-polar oil.
`The process of formation of a tear ?lm following addition
`of a treatment composition to the eye is a dynamic process
`with many steps involved. If the treatment composition is in
`the form of an emulsion, several processes are simulta
`neously set in motion immediately following the addition of
`the emulsion to the eye. The emulsion begins to differentiate
`while the dispersed oil phase spreads over the ocular surface.
`In addition, the amount of a ?uid additive retained by the eye
`is up to about 10 rnicroliters (ul). It is believed that if the
`volume of a ?uid additive increases above about 10 ul,
`excess ?uid moves to the canthi and rapidly enters the tear
`duct or is expressed from the eye as tears. This can occur
`within four to ?ve blinks following addition of the treatment
`composition to the eye. Discharge of excess ?uid will result
`in discharge of treatment components of the ?uid from the
`v40
`eye, making them unavailable to form and sustain the tear
`?lm. This problem is exacerbated if the ?uid is in the form
`of an emulsion which does not rapidly differentiate liberat
`ing treatment components. Consequently, the concentration
`of the treatment components of the emulsion must be
`su?icient to treat the eye and compensate for that lost by
`discharge from the eye but should not be excessive and
`cause blurring.
`In accordance with the invention, recognizing that the
`formation of a tear ?lm is a dynamic process as described
`above, the total amount of oil available for formation of a
`?lm preferably does not exceed 25 ul, more preferably varies
`between about 1 and 10 ul and most preferably varies
`between about 1 and 5 ul. Of this amount, only a small
`portion will be available to form the oil layer over the ocular
`surface. As the amount of oil available for ?lm formation
`exceeds about 10 ul, the oil ?lm formed over 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 case, the patient is likely to experience blurring
`due to excessive oil. The amount of oil beyond which
`blurring will occur varies from patient to patient and is
`dependent upon the speci?c oil uses.
`The treatment compositions of the invention are desirably
`formulated to permit self administration by a patient. It is
`di?icult for a patient to self-administer low volumes of
`treatment composition—i.e., amounts of from 1 to 10 ul.
`Therefore, to render the formulations suitable for self
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`administration, it is desirable to disperse the active com
`pounds of the formulation in a suitable vehicle that permits
`administration of larger volumes by the patient. To control
`the volume of oils available for formation of the tear ?lm
`without excessive discharge of treatment composition from
`the eye and to provide water to augment the aqueous portion
`of the tear ?lm, the total amount of a liquid treatment
`composition added to the eye per treatment per eye prefer
`ably does not exceed 100 microliters (ul) (about 2 drops) and
`more preferably varies between about 25 and 50 ul. Since it
`is desired to limit the total volume of treatment composition
`added to the eye while recognizing that excess is discharged
`from the eye by blinking, and that the total volume of oil
`must be controlled, it is apparent that the concentration of oil
`in the treatment solution must be adjusted to provide the
`desired small dosage of oil to the eye and compensate for
`that lost due to discharge of excess treatment composition.
`For reasons stated above, rapid formation of the oil ?lm
`over the corneal surface is desirable. If the ?lm does not
`form rapidly, oil in the treatment composition may be
`discharged from the eye before it can form a satisfactory
`?lm. When oil is added in the form of an emulsion, the
`emulsion should differentiate rapidly on entering the eye to
`provide oil for formation of a ?lm before excessive oil is
`discharged from the eye with excess treatment composition.
`The formation of the oil ?lm is desirably assisted by use of
`a surfactant in the treatment composition which assists in
`spreading the oil over the eye. The surfactant should be one
`that enables rapid phase differentiation and further, should
`be one compatible with composition components and physi
`ologically compatible with the eye—i.e., it should not be
`toxic nor cause stinging.
`From the above discussion, it is apparent that it is unde~
`sirable to provide a treatment composition in the form of an
`excessively stable emulsion for several reasons. An emul
`sion is often optically opaque due to the presence of distinct
`dispersed phases. Therefore, an emulsion over the surface of
`the eye is expected to cause blurring. The duration of blur is
`dependent upon the time required for the emulsion to
`differentiate and form separate layers replicating a tear ?lm.
`Consequently, blurring is likely to occur until the emulsion
`differentiates. In addition, and as discussed above, if the
`emulsion is too stable, excess emulsion will be discharged
`from the eye. Discharge of the emulsion from the eye will
`result in discharge of e?icacious components of the treat
`ment solution from the eye before a tear ?lm can be formed
`and these components will not be available for formation of
`the tear ?lm. Therefore, in accordance with this invention, it
`is preferred that the emulsion be stable for long term storage,
`but rapidly differentiate in the eye. This is difficult to achieve
`with existing technology and for purposes herein it is desired
`that the emulsion be meta-stable where a meta-stable emul
`sion is de?ned as a composition that is sufficiently stable to
`provide a uniform dose to the eye but is relatively unstable
`and rapidly diiferentiates upon contact with the eye, pref
`erably differentiating within about 5 blinks following appli
`cation of the composition to the eye, more preferably in a
`time of less than about 30 seconds. Blurring may occur
`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 is a further discovery of
`this invention that though non-polar oils are preferred, polar
`oils may be used to alleviate dry eye symptoms without
`signi?cant blurring if their volume available for ?lm forma
`tion is carefully controlled within the most preferred con
`
`APOTEX 1031, pg. 4
`
`

`

`5,578,586
`
`7
`centration range of from 1 to 5 ul, more preferably 1 to 3 111
`or if the polar oils are diluted with non-polar oils.
`Based upon the above, the invention described herein
`comprises treatment of the eye with either a charged phos
`pholipid, an oil, preferably an essentially non-polar oil, or
`both, in amounts and in a treatment solution form that
`reduces or eliminates blurring and prolongs the residence
`time of an arti?cially formed replicated tear ?lm on the eye.
`
`5
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`8
`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 a subgroup within the family
`of the o-aminoacylphosphatidylglycerols.
`In contrast to the charged phospholipids, the head groups
`of phosphatidylethanolamine and phosphatidylcholine (leci
`thin) have a positive charge at pH 7, and, thus, at this pH,
`these two phosphoglycerides are dipolar zwitterions with no
`net electric charge. Such compounds are not within the
`scope of this invention unless chemically reacted to impart
`a negative charge to the material.
`Of the phospholipids discussed above, the net negatively
`charged phosphoglycerides are preferred. A more preferred
`class of phosphoglycerides are represented by the following
`formula:
`
`where R‘ and R are each fatty acid residues preferably
`having from 8 to 24 carbon atoms; X is hydrogen, a polyol
`or a 3'-O -aminoacylphosphatidylglycerol; and M is one
`equivalent of a countercation. R and R‘ are typically com
`mon natural fatty acids having an even or odd number of
`carbon atoms; they may be the same or may di?er from each
`other; and they may be saturated, monounsaturated or poly
`unsaturated. Examples of fatty acid residues include laurate,
`myristate, palrnitate, stearate, oleate, linoleate, octanoate,
`dodecate, lignocerate, etc.
`Phospholipids are available from a variety of sources such
`as egg yolks, soy beans, etc. as is known in the art. These
`sources typically contain a mixture of components including
`natural lipids as exempli?ed by glycerides, cholesterol and
`cholesterol esters; phospholipids having a net charge of zero
`as exempli?ed by phosphatidylcholine, phosphatidylethano
`lamine; various unsaturated and saturated fatty acids; and
`charged phospholipids such as phosphatidylglycerol and
`phosphatidylinositol. The charged phospholipids are typi
`cally contained in these naturally occurring products in
`minor concentration, typically varying from below one
`percent up to 10 to 15 percent of the total composition.
`Accordingly, the concentration of the charged phospho
`lipid from such a natural source would likely be insu?icient
`for purposes of treatment in accordance with the invention,
`and a complex phospholipid having a net charge, preferably
`a net negative charge, would be added to such a phospho
`lipid source to increase the total concentration of the com
`plex charged phospholipids to a concentration required for
`treatment in accordance with the invention. Obviously, if a
`phospholipid from a natural source is negatively charged, a
`negatively charged phospholipid would be added to supple
`ment the concentration of the same whereby the total net
`charge remains negative.
`The most preferred phospholipid for purposes of this
`invention is a polyol with a net negative charge. The most
`preferred polyol phospholipids are the phosphatidylglycer
`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
`
`20
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`25
`
`30
`
`40
`
`The treatment compositions of the invention comprise a
`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 a 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
`emulsion.
`Phospholipids suitable for purposes of the invention are
`known in the art to be complex and to carry a net positive
`or negative charge under conditions of use. The preferred
`materials are those carrying a net negative charge because
`the negatively charged material will be repelled by the
`negatively charged ocular surface thereby permitting the
`maintenance of a relatively thick aqueous layer. The posi
`tively charged phospholipid will be attracted to the nega
`tively charged ocular surface thus compressing the tear ?lm.
`Hence the positively charged phospholipids operate in a
`different manner than the negatively charged phospholipids
`and are lesser preferred.
`It is known that complex phospholipids contain a polar
`35
`group at one end of their molecular structure and a non-polar
`group at the opposite end of the molecular structure. A
`discussion of phospholipids can be found in Leninger,
`Biochemistry, 2 ed., Worth Publishers, New York, pp.
`279-306, incorporated herein by reference.
`Many complex phospholipids are known in the art. They
`differ in size, shape and the electric charge of their polar
`head groups. Phosphoglycerides are compounds where one
`primary hydroxyl group of glycerol is esteri?ed to phospho
`ric acid, and the other two hydroxyl groups are esteri?ed
`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
`term phosphoglycerides includes stereoisomers.
`All phosphoglycerides have a negative charge at the
`phosphate group at pH 7, and the pK,, of this group is in the
`range of 1 to 2. The head groups of phosphatidylinositol,
`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
`tive charge of the phosphate group and the absence of a
`charge in the head group, the net charge of each of these
`materials is negative, and these materials are within the
`scope of the invention. Likewise, the head group of phos
`phatidylserine contains an alpha—amino group (pKa=10)
`and, a carboxyl group (pK,,=3) and therefore, the molecule
`contains two negative charges and one positive charge at pH
`7.0, giving it a net negative charge whereby this compound
`is also within the scope of the invention.
`Complex phospholipids having a net positive charge are
`also within the scope of this invention but are lesser pre—
`
`50
`
`55
`
`60
`
`65
`
`APOTEX 1031, pg. 5
`
`

`

`10
`
`25
`
`9
`participate in hydrogen bonding with the aqueous portion of
`the tear ?lm thus stabilizing the ?lm formed over the eye for
`an extended time.
`In accordance with the invention, an oil is also applied to
`the eye as a treatment material. As is known in the art, oils
`may be derived from animals, plants, nuts, petroleum, etc.
`Those derived from animals, plant seeds, and nuts are
`similar to fats and are primarily glycerides o