United States Patent 15
`Glonek et al.
`
`5,578,586
`(11) Patent Number:
`[45] Date of Patent:
`*Nov. 26, 1996
`
`
`
`US005578586A
`
`[54]
`
`[75]
`
`DRY EYE TREATMENT PROCESS AND
`SOLUTION
`
`Inventors: Thomas Glonek, Oak Park,Ill.; Jack
`V. Greiner, Winchester; Donald R.
`Korb, Boston, both of Mass.
`
`[73]
`
`Assignee: Ocular Research of Boston, Inc.,
`Boston, Mass.
`
`[*]
`
`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
`
`[63]
`
`[51]
`
`[52]
`
`[58]
`
`{56]
`
`Related U.S. Application Data
`
`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.
`Tint. Cocece A61K 31/685; AGIK 31/66;
`,
`A61K 31/20
`
`TS. Che cicceccessetseeseesseesreseesee 514/76; 514/75; 514/78;
`514/558; 514/912
`Field of Search ......0......cceee 514/76, 75, 558,
`514/912
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,522,803
`4,677,099
`4,804,539
`4,818,537
`4,839,175
`4,866,049
`4,908,154
`4,914,088
`4,938,965
`
`6/1985 Lenk et al. sscsccscsessnssssnesne 424/11
`
`sesssseeseueenne 514/78
`6/1987 Shinitzky et al.
`2/1989 Guoet ab. cessecscsisnsseentueren 424/450
`
`4/1989 GUO recesses
`ve 424/427
`6/1989 GUO eeressesessssnsnee
`va 424/450
`
`9/1989 Maumeneeet al. ssssssnssseen 514/169
`3/1990 COOKet al. cssssssnssnsneeuesee 252/314
`
`4/1990 Glonek et al.
`sesssscscssnesceueee 514/76
`7/1990 Shek et Ab. ecescsscnssssseseesnesen 424/450
`
`FOREIGN PATENT DOCUMENTS
`
`1/1978 Australia .
`16149
`0241376 10/1987 European Pat. Off.
`0391369
`4/1990 European Pat. Off.
`
`.
`.
`
`OTHER PUBLICATIONS
`
`Hardberger, Hanna and Boyd,“Effects of Drug Vehicles on
`Ocular Contact Time,” Arch. Ophthaimol., 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 form of
`a meta-stable oil in water emulsion in a dosage not exceed-
`ing 100 microliters.
`
`4,421,748 12/1983 Trager et al. ow... eesseeenees 424/199
`
`22 Claims, No Drawings
`
`TEVA - EXHIBIT 1009
`
`TEVA - EXHIBIT 1009
`
`

`

`1
`DRY EYE TREATMENT PROCESS AND
`SOLUTION
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`BACKGROUND OF THE INVENTION
`
`1. Introduction
`
`This is continuation of application(s) Ser. No. 07/898,375
`filed on Jun. 9, 1992, now U.S. Pat. No. 5,294,607 which is
`a continuation-in-part of U.S. patent application Ser. No.
`07/529,657, filed May 29, 1990, now abandoned and a
`continuation-in-part of U.S. patent application Ser. No.
`07/457,086 filed Dec. 26, 1989, now abandoned and a
`continuation-in-part, ef U.S. patent application Ser. No.
`07/111,874 filed Oct. 23, 1987, now U.S. Pat. No. 4,914,088
`and a continuation-in-part of U.S. patent application Ser. No.
`07/033,185 filed Apr. 2, 1987, now abandoned.
`
`2
`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 film. For many
`subjects, contact lens intolerance is not overcomeby topical
`application of tear substitutes. Therefore, there is a need for
`improved compositions and processes for treatment ofthe
`dry eye condition and for improving tolerance to ocular
`prostheses.
`An improved composition for dry eye treatment is the
`This invention relates to wetting the surface of the eye
`subject of U.S. Pat. No. 4,914,088 incorporated herein by
`and/or an ocular prosthesis, providing mechanical lubrica-
`reference. This patent teaches the use of charged phospho-
`tion therefor, reducing the evaporation of fluid from the
`lipids for the treatment of dry eye symptoms. The addition
`surface of the eye and if desired, delivering a medicantto the
`of a charged phospholipid to the eye assists in replicating the
`ocular surface. More particularly, the invention relates to a
`tear film that would naturally occur in the eye. In accordance
`composition capable of augmenting and maintainingastable
`with the patent, the phospholipid composition, preferably in
`tear film over the ocular surface and/or delivering a medi-
`the form of an aqueous emulsion,is topically applied to the
`cant to said surface without causing substantial blurring of
`eye whereit is believed to disperse over the ocular surface
`vision. In a preferred embodiment of the invention,
`the
`and form a film that replicates a lipid layer that would be
`invention relates to an ophthalmic composition for dry eye
`formed by the spreading of a naturally occurring lipid
`treatment. The invention is especially useful for treatment of
`secreted principally from the Meibomian glands during
`individuals wearing ocular prostheses such as contact lenses,
`blinking. Because the phospholipid, when appliedto the eye,
`as the composition of the invention wets and provides
`carries a net charge, it is believed that aligned molecules
`lubrication for both the ocular surface andthe surface ofthe
`repel each other preventing complex aggregate formation
`prosthesis in contact with the ocular surfaces.
`thereby resulting in a stable phospholipid film. The patent
`2. Description of the Prior Art
`speculates that the film formed from the charged phospho-
`lipid assists in the formation of a barrier film reducing
`It is known in the art that an aqueous tear film extends
`evaporation of the aqueouslayer, thereby preserving the tear
`over the ocular surfaces and maintains the ocular surface
`film.
`moist and lubricated. It is also known that dehydration of
`moisture from the eye may result in discomfort. Further, it
`In copending U.S. patent application Ser. No. 07/529,657,
`is known that compositions are available in the market
`filed May 29, 1990, a further improvement in dry eye
`intended for dry eye treatment. These compositions are
`treatmentis disclosed. In accordance with the disclosure of
`primarily aqueous materials that supplementthe tear film.
`said application, the dry eye treatment composition of U.S.
`Pat. No. 4,914,088 is improved by the addition of an
`The feeling of discomfort resulting from a dry eye con-
`essentially non-polar oil to the eye treatment composition.
`dition may include ocular dryness, grittiness, burning, sore-
`The oil is added to improve the performance of a dry cye
`ness or scratching, dependent upon the subject and the
`treatment composition by increasing the longevity of the tear
`condition of the subject. Proposed causes for dry eye,
`film formed on the eye following addition of the dry eye
`treatment and symptomsare described in a compendium of
`treatment solution, presumably by providing and/or thick-
`papers edited by Holly, The Preocular Tear Film in Health,
`ening the dehydration barrier (the oil layer) on the outer
`Disease, and Contact Lens Wear, The Dry Eye Institute,
`surface ofthe tear film. Thus,the oil increases the efficacy
`Lubbock, Tex. 1986, incorporated herein by reference.
`of the dry eye treatment solution and reduces performance
`The most commontreatment for dry eye involves tem-
`variability from subject to subject.
`porary alleviation of dry eye symptomsbytopical applica-
`The use of the dry eye treatment of the referenced
`tion of a tear substitute that adds a large volumeofliquid to
`application assists in overcoming dry eye symptoms as
`the anterior surface of the eye and related adnexa. Typical
`reported in the application. However, when using the pro-
`tear substitute compositions comprise water soluble polymer
`cedures and composition of the application, some subjects
`solutions. Examples of such solutions include saline solu-
`experience blurring following addition of the treatment
`tions of polyvinyl alcohol, hydroxypropylmethyl cellulose
`composition containing the oil. The time required for the
`or carboxymethyl celluloses. U.S. Pat. No. 4,421,748
`blur to clear is often unpredictable. In addition,relief of dry
`teaches an artificial tear composition comprising an aqueous
`eye symptoms was found to vary somewhat from patientto
`hypotonic solution of lecithin and a viscosity adjusting agent
`such as a solution soluble cellulose.
`patient.
`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
`
`5,578,586
`
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`SUMMARYOF THE INVENTION
`
`The invention disclosed herein is a further improvement
`over the inventions disclosed in the above referenced U.S.
`
`

`

`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 meansfor appli-
`cation of a 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.
`First, it has been discovered that the total quantity of oil
`available to form a film 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 addedto the eye as a meta-stable emulsion, not as
`a finely 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 amountof oi] contained in an emulsion and enables
`rapid formation of an oil film 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 film over the eye is capable of alleviating
`dry eye symptoms. The description that follows is based
`upon belief and that reported in theliterature.
`It is reported that a naturally occurring tear film 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 film is an aqueous layer. This layer is the thickest
`portion of the tear film, is a source of moisture and lubri-
`cation for the eye and functions as an optical planarizing
`layer. The outer layer of the tear film, 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: Theoily layerof the tear film 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 ofthe tear film are thoughtto 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
`aqueous middle layer of the tear film is minimized.
`A cause of dry eye is believed to be a deficiency in the
`quantity or quality of secretions from the Meibomian glands.
`It is postulated herein that a cause of dry eye is a deficiency
`in the polar lipid layer of the tear film, the non-polar oily
`lipid layer or both. Regardless of the causeof the deficiency,
`the compromised lipid layer fails to act as an adequate
`barrier against evaporation of the aqueousportion of the tear
`film 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 film 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 film is maintained. It
`wasbelieved that the film formed from the phospholipid
`layer acted as a 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. 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
`USS. Pat. No. 4,914,088 providedrelief of dry eye symptoms
`in the majority of patients treated as stated in said patent,
`with improved testing procedures developed subsequent to
`the filing of the application leading to the grant of said
`patent, it was found that there was variance in efficacy 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 treatmentof 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 appliedto the eye, it was preferred that the two
`components be combinedin a single treatment composition,
`most preferably in the form of a finely divided stable
`oil-in-water emulsion. A stable emulsion was desired for
`long term storage in a container. Upon application of the
`phospholipid and ofl 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 film over the aqueoustear film with charged ends
`dissolved in the aqueous layer and hydrophobic ends fur-
`thest removed from the aqueouslayer 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 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 variationsin efficacy
`from patient to patient.
`Use of the treatment compositions of the copending
`application results in formation of a tear film 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 somecases overa prolongedtime. In accordance
`with the invention described herein, the dry eye composi-
`tions alleviate dry eye symptomsat least as effectively as
`those of
`the above-referenced copending application,
`enhancepatient tolerance to ocular prostheses, and provide
`
`

`

`5,578,586
`
`5
`the further advantage of essentially avoiding prolonged
`blurred vision. In addition, in accordance with the subject
`invention, the residence time of the film 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:
`(1) the total amount of oil comprising the film 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 film of the
`efficacious components of the treatment composition
`over the ocular surface. With regard to control of the
`amount of oil comprising the film over the eye,
`it
`should be recognizedthatthe oil layer is a thin film and
`the total volumeof 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 patientwill
`experience prolonged blurred vision. The problem is
`exacerabated whenthe oil is a polar oil rather than the
`preferred non-polar oil.
`The process of formation of a tear film 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 beginsto differentiate
`while the dispersed oil phase spreads overthe ocular surface.
`In addition, the amountofa fiuid additive retained by the eye
`is up to about 10 microliters (ul). It is believed that if the
`volume of a fluid additive increases above about 10 ul,
`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 excessfluid will result
`in discharge of treatment components ofthe fluid from the
`eye, making them unavailable to form and sustain the tear
`film. This problem is exacerbatedif the fluid 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
`sufficient 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 film is a dynamic process as described
`above, the total amount of oil available for formation of a
`film 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 film formation
`exceeds about 10 ul,
`the oil film 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 patientis 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 specific oil uses.
`The treatment compositionsof the invention are desirably
`formulated to permit self administration by a patient. It is
`difficult 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-
`poundsof 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 film
`without excessive discharge of treatment composition from
`the eye and to provide water to augment the aqueous portion
`of the tear film, 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 ofoil
`must be controlled, it is apparent that the concentrationof 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 ofthe oil film
`over the corneal surface is desirable. If the film does not
`form rapidly, oil
`in the treatment composition may be
`discharged from the eye before it can form a satisfactory
`film. 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 film before excessive oil is
`discharged from the eye with excess treatment composition.
`The formation of theoil film 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 presenceof 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 film.
`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 efficacious components of the treat-
`ment solution from the eye before a 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 bestable for long term storage,
`but rapidly differentiate in the eye. Thisis difficult to achieve
`with existing technology and for purposesherein it is desired
`that the emulsion be meta-stable where a meta-stable emul-
`sion is defined as a composition that is sufficiently stable to
`provide a uniform dose to the eye but is relatively unstable
`and rapidly differentiates 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 becausethe 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
`significant blurring if their volume available forfilm forma-
`tion is carefully controlled within the most preferred con-
`
`

`

`5,578,586
`
`7
`centration range of from 1 to 5 ul, more preferably 1 to 3 ul
`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 ofan artificially formed replicated tear film on the eye.
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`8
`ferred for reasons given above and becauseofthe 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 phosphatidyicholine(leci-
`thin) have a positive charge at pH 7, and, thus, at this pH,
`these two phosphoglyceridesare 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.
`The treatment compositions of the invention comprise a
`Of the phospholipids discussed above, the net negatively
`charged phospholipid and an oil. They are applied by topical
`charged phosphoglycerides are preferred. A more preferred
`application to the eye. Topical application is by application
`class of phosphoglycerides are represented by the following
`of each componentseparately or preferably by single treat-
`formula:
`ment composition containing the two componentsinasingle
`x
`liquid vehicle such as an emulsion. More preferably, the
`emulsion is an aqueous oil-in-water, meta-stable emulsion
`wherethe oil comprises the dispersed (organic) phase of the
`emulsion.
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`Phospholipids suitable for purposes of the invention are
`knownin 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
`maintenanceof a relatively thick aqueous layer. The posi-
`tively charged phospholipid will be attracted to the nega-
`tively charged ocular surface thus compressing the tear film.
`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
`groupat one end oftheir 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 knownin the art. They
`differ in size, shape and the electric charge of their polar
`head groups. Phosphoglycerides are compounds where one
`primary hydroxy! group of glycerolis esterified to phospho-
`ric acid, and the other two hydroxyl groupsare 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
`term phosphoglycerides includes stereoisomers.
`the
`All phosphoglycerides have a negative charge at
`phosphate group at pH 7, and the pK,of this groupis 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 (pK,=10)
`and, a carboxy! group (pK,=3) and therefore, the molecule
`contains two negative charges and onepositive 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-
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 maydiffer from each
`other; and they may be saturated, monounsaturated or poly-
`unsaturated. Examples offatty acid residues include laurate,
`myristate, palmitate, 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 exemplified by glycerides, cholesterol and
`cholesterol esters; phospholipids having a net charge of zero
`as exemplified 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 insufficient
`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
`
`

`

`5,578,586
`
`9
`participate in hydrogen bonding with the aqueousportion of
`the tear film thus stabilizing the film formed overthe eye for
`an extended time.
`In accordance with the invention,an oil is also applied to
`the eye as a treatment material. As is knownin 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 glyceridesor fatty acids and
`consequently, contain a significant number of acid and/or
`ester groups rendering the same polar and lesser preferred
`for purposes of the invention. Alternatively, oils derived
`from petroleum are usually aliphatic or aromatic hydrocar-
`bons that are essentially free of polar substitution and
`therefore suitable for purposes of the present invention
`providedtheoil is refined so as to be compatible with human
`tissue such as the ocular surface. Preferably, the oil is a
`hydrocarbon oil having from 10 to 50 carbon atoms and
`more preferably, the oil is a saturated n-alkane or isoalkane
`hydrocarbon having from 14 to 26 carbon atoms. Unsatur-
`ated alkene hydrocarbons may be used but are less chemi-
`cally stable as the double bonds tend to oxidize. Aromatic
`oil