`5,981,607
`[11] Patent Number:
`United States Patent 55
`Dinget al.
`[45] Date of Patent:
`Nov. 9, 1999
`
`
`[54] EMULSION EYE DROP FOR ALLEVIATION
`OF DRY EYE RELATED SYMPTOMSIN DRY
`EYE PATIENTS AND/OR CONTACT LENS
`WEARERS
`
`[75]
`
`:
`Inventors: Shulin Ding, Irvine; Orest Olejnik,
`Trabuco Canyon; Brenda L. Reis,
`Costa Mesa, all of Calif.
`
`[73] Assignee: Allergan,Irvine, Calif.
`
`[21] Appl. No.: 09/008,924
`:
`Filed:
`
`Jan. 20, 1998
`
`[22]
`
`[51]
`Int. C18 A61K 47/12; A61K 47/14;
`A61K 47/34
`514/785; 514/786; 514/912:
`[52] US. Cl
`514/915; 514/941; 514/943; 514/975
`[58] Field of Search 0eee 514/9, 11, 178,
`514/179, 180, 181, 420, 625, 627, 784,
`785, 786, 912, 913, 914, 915, 941, 943,
`975
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`5,411,952
`5,474,979
`
`5/1995 Kaswatt ou... eesccssseecenecensne conse 514/11
`12/1995 Ding et abe oe eceeeeseeeeeeeees 514/11
`
`FOREIGN PATENT DOCUMENTS
`2228198
`8/1990 United Kingdom .
`95/31211
`11/1995 WIPO.
`
`OTHER PUBLICATIONS
`
`Diagnosis and Management of Tear Film Dysfunction;
`Stultng & Waring, pp. 445-468 (not dated).
`Diagnosis and Management of Dry Eye and Ucular Surface
`Disorders: OPH Clinic of N.A.vol. 3, No. 4, pp. 575-594,
`Dec. 1990.
`
`.
`.
`Primary Examiner—Jeffrey E. Russel
`Attorney, Agent, or Firm—Walter A. Hackler
`[57]
`ABSTRACT
`
`An eye drop composition for alleviation of dry eye related
`symptoms in dry eye patients and contact
`lens wearers
`includes an emulsion of a higher fatty acid glyceride,
`polysorbate 80 and an emulsion stabilizing amount of
`Pemulen® in water suitable for topical application to ocular
`tissue.
`
`4,839,342
`
`6/1989 Kaswanr .o..ccccesseeeceseecseeeeeees 514/11
`
`4 Claims, 7 Drawing Sheets
`
`WEEK 4
`
`WEEK 8
`
`WEEK £2
`
`NOFW
`IM7290EW0OYSFONCH?
`
`
`POST-TX WR 2
`
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`TEVA - EXHIBIT 1010
`
`TEVA - EXHIBIT 1010
`
`
`
`U.S. Patent
`
`Nov. 9, 1999
`
`Sheet 1 of 7
`
`5,981,607
`
`PART[IT: AQUEOLS
`
`PART I: CASTOR
`Ole
`
`|
`
` STOCK SOLUTION
`
`(CONTAINING WATER,
`POLYSORBATE 80,
`AND GLYCERIN)
`
`STERILE
`FILTRATION
`
`STERILE
`FILTRATION
`
`STERILE FILTRATE
`OF PART I
`
`STERILE FILTRATE
`OF PART If
`
`ASEPTIC
`HOMOGENIZATION
`(60°C-65°C)
`
`mere
`BULK HEAT\PEMULEN TR-2
`STERILE|STERILIZATION|STOCK DISPERSION
`PARTI
`
`(CONTAINING
`
`PEMULEN TR-2
`AND WATER)
`
`ASEPTIC MIKING
`STAGE I
`STERILE
`(60° -70°C)
`STERILE LYLTRATION|PARTI DILUTE
`ASEPTIC MIXING
`neMerl
`NaOH5OLLTION
`
`
`
`LfPARTIV
`
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`BULK EML/LS/ON
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`COOL TO ROOM
`TEMPERATURE
`
`CLARIFICATION
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`
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`
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`U.S.PatentNov.9,1999Sheet4of75,981,607
`
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`U.S.PatentNov.9,1999Sheet5of75,981,607
`
`
`
`
`
`5,981,607
`
`
`
`U.S. Patent
`
`Nov. 9, 1999
`
`Sheet 7 of 7
`
`5,981,607
`
`~L
`
`g
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`
`CASTOR OL CONCENTRATION IN VEHICLE (%ow/w)
`
`_kte- 7
`
`
`
`5,981,607
`
`1
`EMULSION EYE DROP FOR ALLEVIATION
`OF DRY EYE RELATED SYMPTOMS IN DRY
`EYE PATIENTS AND/OR CONTACT LENS
`WEARERS
`
`The present application is related to pending Interna-
`tional Patent Application Ser. No. PCT/US95/06302 filed
`May 17, 1995, designating the United States, which is a
`continuation-in-part of U.S. patent application Ser. No.
`08/243,279 filed May 17, 1994, now USS. Pat. No. 5,474,
`979. The referenced applications/patent are to be incorpo-
`rated herein by this specific reference thereto.
`The present invention relates to a pharmaceutical com-
`position for alleviating dry eye related symptoms,
`for
`example, as in patients having immune mediated keratocon-
`junctivitis sicca (KCS) or dry eye disease or other autoim-
`mune dysfunction of the lacrimal gland, as well as dry eye
`symptoms of contact lens wearers.
`Dry eye generally refers to any tear film abnormality,
`usually with epithelial abnormalities. A specific deficiency
`of the aqueous component of the tear film is known as
`keratoconjunctivitis sicca (KCS), which affects about 30
`million people worldwide. It is usually included as part of
`Sjogren’s syndrome. Literally the term denotes inflamma-
`tion of the cornea and conjunctiva secondary to drying.
`When the tear film fails to perform its functions of
`lubrication, oxygenation, and removal of debris, symptoms
`of foreign body sensation (grittiness, scratchiness,
`sandiness), fatigue, and dryness result. A patient may expe-
`rience severe pain, especially in the presence of filamentary
`keratopathy. Loss of the smooth refractive surface of the tear
`film causes blurred vision, which can vary from blink to
`blink, accounting for a variable manifest refraction and for
`complaints of variable vision throughout the day. Surface
`drying may producereflex tearing and the misleading com-
`plaint of excesstears. Typically, symptomsoftear deficiency
`are worselate in the day, with prolonged use of the eyes (as
`whenthe patient reads or watches television), and in con-
`ditions of heat, wind, and low humidity (as on the beach or
`ski slopes). Symptomsthat are worse in the morning suggest
`an associated chronic blepharitis, recurrent coreal epithelial
`erosion, or exposure keratopathy. Further, symptomsinclude
`superficial punctate erosions, corneal
`filaments, coarse
`mucus plaques, and epithelial defects.
`As hereinabove noted, most of these symptomsresult
`from the unstable tear film and abnormalocular surface that
`diminish the ability of the ocular surface to respond to
`environmental challenges. Dry eye syndrome,
`if left
`untreated, can cause progressive pathological changesin the
`conjunctival and corneal epithelium.
`The etiologies of dry eye are varied. The disease gener-
`ally referred to as “dry eye” maybe the result of age-related
`decreases in systemic androgen support to the lacrimal gland
`or systemic autoimmune diseases such as Sjogrens Syn-
`drome. A growing body of research suggests that dry eye is
`the result of an underlying cytokine and receptor-mediated
`inflammatory process.
`tear
`Palliative agents, such as tear replacement,
`preservation, and autonomic tear stimulation, may provide
`complete or partial relief of symptoms. However, therapeu-
`tic treatments directed at the underlying inflammatory pro-
`cess may prove beneficial
`in correcting the underlying
`disorder.
`The tear film in a normal eye consists of a thin (about
`6-45 um in thickness) film composed of a mucous layer
`lying over the corneal epithelium and an aqueous layer
`covering the mucous layer and epithelium, whichis in turn
`covered by an extremely thin (0.01-0.22 um) layer of lipid
`molecules.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
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`
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`
`2
`The presence of a continuous tear film is important for
`the well-being of the corneal and conjunctival epithelium
`and provides the cornea with an optically high quality
`surface. In addition, the aqueouspart of the tear film acts as
`a lubricant
`to the eyelids during blinking of the lids.
`Furthermore, certain enzymes containedin thetear fluid, for
`example, immunoglobulin A, lysozyme and beta lysin, are
`knownto have bacteriostatic properties.
`It
`is believed that
`the lipid layer is responsible for
`retarding evaporation of water from the eye. If the lipid layer
`of the tearfilm is disturbed by, for example, trauma,disease,
`irritation of the eye or contact lens wear, excessive evapo-
`ration of water from the eye may occur, leaving the surface
`of the eye “dry” (see e.g., Cedarstaff and Tomlinson, Am. J.
`Optometry & Physiol. Optics, 60:167—-174, 1983 [tear film
`disruption in patients with keratoconjunctivitis sicca, or “dry
`eye”]).
`Anormallacrimal system functions to form and maintain
`a properly structured, continuous tear film. The lacrimal
`system consists of the secretory system (the source), the
`distribution system and the excretory system (the sink). In
`the secretory system, aqueoustears are supplied by the main
`and accessory lacrimal glands.
`Excessive evaporation of water from the tear film results
`in ocular discomfort (frequently experienced by the person
`as dryness or tired eyes or other less frequently reported
`discomfort symptoms) and may eventually lead to physi-
`ological and pathological changes in the tissue of the eye,
`especially in the cornea. For contact lens wearers, such
`discomfort is particularly acute because the loss of water
`from the tear film occurs at the interface between the tear
`film and the lens. Further, if the lens is a hydrogel “soft”
`lens, excessive evaporation of water from the tear film can
`also result in excessive evaporation of water from the lens.
`Thus taking into accountthis evaporation, the continuous
`production and drainage of aqueous tear is important to
`maintaining the corneal and conjunctival epithelium in a
`moist state, in providing nutrients for epithelian respiration,
`in supplying bacteriostatic agents and in cleaning the ocular
`surface by the flushing action of tear movement.
`Abnormalities of the tear film include an absolute or
`partial deficiency in aqueous tear production
`(keratoconjunctivitis sicca or KCS).
`In relatively mild cases, the main symptom of KCS is a
`foreign body sensation or a mild “scratchiness”. This can
`progress to become a constant, intense burning irritative
`sensation which can be debilitating to the patient.
`More severe forms of KCS progress to the development
`of filamentary keratitis, a painful condition characterized by
`the appearance of numerousstrandsor filaments attached to
`the corneal surface. Recent evidence suggests that these
`filaments represent breaks in the continuity of the normal
`corneal epithelial cells. The shear created by lid motion pulls
`these filaments, causing pain. Managementof this stage of
`KCSis very difficult.
`A frequent complication of KCS is secondary infection.
`Several breakdownsin the eye’s normal defense mechanism
`seem to occur, presumably attributable to a decrease in the
`concentration of antibacterial lysozyme in the aqueoustears
`of a patient suffering from KCS.
`Normally, aqueous-deficient dry eye states, such as, for
`example, KCS, are treated by supplementation of the tears
`with artificial tear substitutes. However,relief is limited by
`the retention time of the administered artificial tear solution
`
`in the eye. Typically, the effect of an artificial tear solution
`administered to the eye dissipates within about thirty to
`forty-five minutes. The effect of such products, while sooth-
`
`
`
`5,981,607
`
`3
`is
`long enough. The patient
`last
`ing initially, does not
`inconvenienced by the necessity of repeated administration
`of the artificial tear solution in the eye as needed to supple-
`ment the normaltears.
`Presently, artificial tear preparations, lens rewetting solu-
`tions and ophthalmic lubricants and ointments utilizing
`active components other than monolayer forming long chain
`fatty alcohols are extant in the art. Such available artificial
`tear solutions commonly include carboxymethyl, methyl or
`ethyl cellulose or polyvinyl alcohol as the principal active
`ingredient. Lubricants and ointments tend more toward
`replacement of oil in the lipid layer of the tear film and
`commonly include petrolatum, lanolin and/or mineral oil.
`Contact lens rewetting products vary in composition to a
`greater extent; however, the solutions are typically aqueous,
`buffered solutions which frequently contain carboxymethyl,
`methylor ethyl cellulose, polyvinyl alcohol and/or glycerin.
`Recently, several lecithin and phospholipid-based solu-
`tions have been proposed as treatments to reduce evapora-
`tion of water from the tear film. U.S. Pat. No. 4,421,748, to
`Trager,
`issued Dec. 20, 1983, discloses an artificial tear
`composition comprising an aqueous hypotonic solution of
`lecithin and a viscosity adjusting agent for the alleviation of
`dry eye conditions.
`U.S. Pat. No. 5,474,979, hereinabove referenced and
`incorporated herein by reference thereto,
`teaches novel
`pharmaceutical compositions incorporating chemicals
`which are poorly soluble in water and is more particularly
`related to a novel ophthalmic emulsion including
`cyclosporin in admixture with castor oil and polysorbate 80
`with high comfort level and low irritation potential.
`The present invention is directed to an emulsion system
`which utilizes higher fatty acid glycerides but in combina-
`tion with polysorbate 80 which results in an emulsion with
`a high comfort level and low irritation potential suitable for
`delivery of medications to sensitive areas such as ocular
`tissues as well as being suitable itself for alleviating dry eye
`symptoms.
`
`SUMMARYOF THE INVENTION
`
`In accordance with the present invention, a non-irritating
`pharmaceutical composition with high comfort level and
`low irritation potential suitable for delivery to sensitive areas
`such as ocular tissues comprises an admixture of an emul-
`sifying amount of a higher fatty acid glycerol and polysor-
`bate 80. The higher fatty acid glyceride may comprise, for
`example, castor oil, corn oil, sunflower oil or light mineral
`oil. The emulsion may also be used to advantage for
`introducing an active agent such as cyclosporine as set forth
`in parent U.S. Pat. No. 5,474,979. In one embodiment, the
`composition may comprise an active agent such as, for
`example, cyclosporine.
`to the
`ratio of the castor oil
`Preferably,
`the weight
`polysorbate 80 is between about 0.3 to about 30 and a weight
`ratio of the active agent to the fatty acid glyceride is below
`0.16. More preferably,
`the weight ratio of castor oil
`to
`polysorbate 80 is between 0.5 and 12.5, and the weightratio
`of active agent to castor oil is between about 0.001 to about
`0.7.
`
`When an active agent is dissolved in the oil phase in
`accordance with the present invention, the emulsion is found
`to be physically stable upon long term storage. No demul-
`sification or crystallization of active agent was noticed after
`up to one year at room temperature.
`Most importantly, the emulsion of the present invention
`provides for long retention of the higher fatty acid glyceride
`
`10
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`25
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`30
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`35
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`40
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`45
`
`50
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`55
`
`60
`
`65
`
`4
`when the emulsion is instilled into an eye. This in turn can
`retard water evaporation from the eye which alleviates dry
`eye symptoms.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The advantages and features of the present invention will
`be better understood by the following description when
`considered in conjunction with the accompanying drawings,
`in which:
`
`FIG. 1 is a manufacturing schematic for production of
`sterile emulsion in accordance with the present invention;
`
`FIG. 2 is a bar graph showing mean change from baseline
`as a function of time as clinically diagnosed using the
`Schirmer test following the instillation of the emulsion in
`accordance with the present invention;
`
`FIG. 3 is a bar graph showing mean change from baseline
`as a function of time as clinically diagnosed using the
`Temporal Rose Bengal Staining test following the instilla-
`tion of the emulsion in accordance with the present inven-
`tion;
`
`FIG. 4 is a bar graph showing change in superficial
`punctate Keratitis, as measured with fluorescein, as a func-
`tion of time following the instillation of the emulsion in
`accordance with the present invention;
`
`FIG. 5 is a bar graph of subjective reports of Burning and
`Stinging by patients as a function of time following instil-
`lation of the emulsion in accordance with the present inven-
`tion;
`
`FIG. 6 is a bar graph of subjective reports of Ocular
`dryness as a function of time following instillation of the
`emulsion in accordance with the present invention.
`
`FIG. 7 is a bar graph of mean ocular residue time, in
`hours, as a function of the amountof fatty acid glyceride in
`an emulsion in accordance with the present invention.
`
`DETAILED DESCRIPTION
`
`An ocular monolayer with significant efficiency of water
`evaporation retardation should spread effectively and form a
`compressed film after spreading has occurred. Furthermore,
`the compressed film should be sufficiently flexible so that
`when broken by wind, the eye lids or a contact lens, it will
`re-form promptly, and, therefore, reduce the tear film local
`dryup and breakup.
`
`The discovery on which the present invention is founded
`relates to an emulsion of a higher fatty acid glyceride such
`as, for example, castor oil, corn oil, sunflower oil or light
`mineral oil and an emulsifier and dispersing agent, polysor-
`bate 80. The selection of these components could not have
`been anticipated on the basis of conventional thinking.
`
`Polysorbate 80 is a mixture of oleate esters of sorbitol and
`sorbitol anhydrides, consisting predominantly of the
`monoester, condensed with approximately 20 moles of eth-
`ylene oxide. It conforms generally to the formula:
`
`
`
`5,981,607
`
`(OCH;CH),OH
`
`O
`
`
`CH
`
`
`
`(OCH,CH3),OH
`
`(OCH2CH2),OH 9
`
`CH
`
`(OCH)CH),0 — C(CH3)7CH
`
`CH3(CH));CH
`
`where w+x+y+z has an average value of 20. Polysorbate 80
`is available from ICI Americas, Inc., Wilmington, Del.
`For example, it is well known that castor oil is irritating
`to sensitive tissues such as the eye. Thus, conventional
`teaching in the art is away from a formulation whichutilizes
`a higher fatty acid glyceride, such as castoroil, by itself or
`in combination with an active agent.
`Other than U.S. Pat. No. 5,474,979 hereinabove refer-
`enced and incorporated herein by reference thereto, there are
`no examples of polysorbate 80 in combination with castor
`oil which produces an emulsion with a high comfort level
`and low irritation potential suitable for the delivery of
`medication to sensitive areas such as ocular tissues.
`
`In accordance with the present invention, the emulsions
`can be further stabilized using a polyelectrolyte, or poly-
`electrolytes if more than one, from the family of cross-linked
`polyacrylates, such as carbomers and Pemulen®.
`Pemulen® is a polymeric emulsifier having a CTFA name
`of Acrylates/C10-30 Alkyl Acrylate Cross-Polymer and is
`described in the “Carbomer 1342” monograph in the
`USPXXII/NFXVII.
`
`Carbomer 1342 is a high molecular weight copolymer of
`acrylic acid and a long chain alkyl methacrylate cross-linked
`with allyl ethers of pentaerythritol. Carbomer 1342, previ-
`ously dried in vacuum at 80° for 1 hour, contains not less
`than 52.0 percent and not more than 62.0 percent of car-
`boxylic acid (—COOH) groups. The viscosity of a neutral-
`ized 1.0 percent aqueous dispersion of Carbomer 1342 is
`between 9,500 and 26,500 centipoises.
`Carbomer 1342 is available from B. F. Goodrich. Car-
`
`bomer 1382 is also available from B. F. Goodrich in a high
`molecular weight copolymerof acrylic acid and a long chain
`alkyl methacrylate cross-linked with allyl ethers of pen-
`taerythritol.
`In addition, the tonicity of the emulsions can be further
`adjusted using glycerine, mannitol, or sorbitol if desired.
`The pH of the emulsions can be adjusted in a conventional
`manner using sodium hydroxide to a near physiological pH
`level and while buffering agents are not required, suitable
`buffers may include phosphates, citrates, acetates and
`borates.
`
`While a medication in accordance with the present inven-
`tion may include cyclosporine, other chemicals which are
`poorly soluble in water such as indomethacin and steroids
`such as androgens, prednisolone, prednisolone acetate,
`fluorometholone, and dexamethasones, may be emulsified
`with castor oil and polysorbate 80 resulting in a composition
`with similar low irritation potential.
`The invention is further illustrated by the following
`examples with all parts and percentages expressed by
`weight. Emulsions were prepared according to the manu-
`facturer’s schematic shown in FIG. 1.
`
`Castor oil
`Polysorbate 80
`Pemulen ®
`Glycerine
`NaOH
`Purified water
`pH
`
`EXAMPLE1
`
`A
`
`5.00%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-1.6
`
`B
`
`2.50%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`EXAMPLE2
`
`Castor oil
`Polysorbate 80
`Carbomer 1382
`Glycerine
`NaOH
`Purified water
`pH
`
`D
`
`0.625%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-1.6
`
`c
`
`1.25%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-1.6
`
`A
`
`2.50%
`0.75%
`0.05%
`2.20%
`qs
`qs
`7.2-1.6
`
`The formulations set forth in Examples 1—2 were used for
`treatment of keratoconjunctivitis sicca (dry eye) syndrome
`with Example 2, Carbomer 1382 replacing the Pemulen®.
`It should be appreciated that while specific examples
`hereinabove are presented for illustration purposes,
`the
`range of the fatty acid glyceride, which may becastoroil,
`corn oil, sunfloweroil or light mineral oil, may vary between
`about 0.5 and about 10 percent by weight. The range of
`Polysorbate 80 may be between about 0.2 and about 5
`percent, by weight, and the range of Pemulen® may be
`between about 0.05 and about 2 percent, by weight.
`The following clinical tests were performed in a double
`marked randomized study to measure aqueousdeficiency in
`keratoconjunctivitis sicca. These clinical tests include the
`Schirmer, Rose Bengal Staining and Fluorescein used to
`determine punctate Keratitis. In addition, subject tests here-
`inafter presented show a relative assessment based on
`patient reports of stinging/burning,
`tearing, discharge,
`itching, foreign body sensation, blurred vision, dryness,
`photophobia, and pain.
`
`CLINICAL TESTS
`
`Schirmer
`
`Clinical measures of tear film volumeandtear flow rates
`help quantitate the severity of aqueous deficiency in kera-
`toconjunctivitis sicca.
`The Schirmer test measures the volumeof tears produced
`during a fixed time period. It is performed by placing the
`folded 5-mm. end of a standard size number 41 Whatman
`filter paper strip over the lower lid, between its middle third
`and lateral third. After 5 minutes the strip is removed, and
`the amount of wetting is measured from the fold.
`The relative amount of wetting as a function of time
`followinginstillation of the emulsion of Example 1B into an
`eye of a patient, is shown in FIG. 2, the numberof patients
`being indicated on the bar graph by the character “n’”. As
`shown,the instillation of the emulsion increases the mea-
`sured tear volume.
`
`Rose Bengal Staining
`
`As hereinabove discussed, patients with tear film dys-
`function may become symptomatic because of dry spots on
`
`10
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`15
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`20
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`5,981,607
`
`7
`the cornea. Identification of dry areas with topically applied
`stains substantiates the diagnosis. Patients who complain of
`nonspecific itching, burning, and stinging without identifi-
`able corneal surface pathology present a more difficult
`diagnostic problem. The two commonly used dyes are rose
`bengal and fluorescein.
`Rosebengal is a red aniline dye related to fluorescein that
`stains devitalized and degenerating corneal and conjunctival
`cells, mucus,and filaments. A full drop of a 1% solution may
`elicit pain. Placing a drop on the wooden endof a cotton tip
`applicator and then touching it to the eye will reduce the
`volume delivered to approximately one third of a drop. A
`micropipette (Pipetteman, Ranin, Woburn, Mass.) may be
`used to deliver 2.5 uL to 5.0 uL into the inferior fornix. This
`standardizes the amount,
`is sufficient
`to obtain adequate
`staining, and is not uncomfortable to the patient. Using the
`green filter, a score is given to each medial and lateral
`interpalpebral zones.
`As shownin FIG. 3, a mean charge in score is shown as
`a function of time using Temporal Rose Bengal Staining
`followinginstillation of the emulsion of Example 1B. These
`changesrepresent significant reduction in conjunctival dry
`areas.
`
`Superficial Punctuate Keratitis
`
`Fluorescein is used to determine punctate Keratitis. Fluo-
`rescein is also an aniline dye that differs from rose bengal in
`that it stains areas of epithelial cell loss and not devitalized
`epithelium. Fluorescein is available in sterile filter paper
`strips or as a 2% solution, alone or in combination with topic
`anesthetic. One drop of 2% fluorescein provides an exces-
`sive amountoffluorescein. A sterile fluorescein strip touches
`to the inferior tear lake is preferred. Patterns of conjunctival
`and corneal staining similar in distribution to rose bengal
`staining are shown in FIG. 4.
`
`SUBJECTIVE TESTS
`
`Subjective Tests on patients reporting ocular burning/
`stinging and ocular dryness are shown in FIGS. 5-6.
`Subjects responded about symptoms of ocular discomfort
`for each eye and in a weekly diary, subjects recorded how
`both eyes felt on average for symptomsof ocular discomfort.
`Subjective assessment on several
`indices: stinging/
`burning, tearing, discharge (not associated with infection),
`itching, foreign body sensation, blurred vision, dryness,
`photophobia, pain and other. Assessment employed a 5 point
`Liukert Scale where O=no discomfort, +1=mild,
`+2=moderate, +3=severe, and +4=very severe.
`The grading of symptomsof discomfort for either eye will
`be defined as follows:
`
`None
`Mild
`
`Moderate
`
`Severe
`
`Very Severe
`
`Other
`
`O)=
`1) =
`
`(+2) =
`
`(+3) =
`
`(+4) =
`
`OQ) =
`
`No discomfort
`Awareness, but no discomfort
`and no intervention
`required.
`Discomfort that causes
`intermittent awareness and
`requires intervention.
`Discomfort that causes
`continuous awareness and
`requires intervention.
`Discomfort that interferes
`with normal daily activity
`and requires intervention.
`I do not remember (used only
`in Subject Diary).
`
`Tolerability of the emulsion by the subject was evaluated
`immediately after instillation of masked study medication,
`
`8
`then at 15 and 30 minutes post-instillation. Subjective
`assessment on several
`indices: stinging/burning,
`itching,
`foreign body sensation, blurred vision photophobia, pain
`and other. Assessment employed a 5 point Likert Scale
`where O=no discomfort, +1=mild, +2=moderate, +3=severe,
`and +4=very severe. Duration of recorded symptoms will
`also be recorded in seconds only immediately after instilla-
`tion of masked medication.
`
`10
`
`The grading of the symptomsof discomfort for either eye
`will be defined as follows:
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`None
`Mild
`
`Moderate
`
`Severe
`
`Very Severe
`
`(0) = No discomfort.
`(+1) = Awareness, but no
`discomfort.
`(+2) = Discomfort that causes
`intermittent awareness.
`(+3) = Discomfort that causes
`continuous awareness.
`(+4) = Discomfort that interferes
`with normal daily activity.
`
`The results shown in FIGS. 5-6 reveal that reduction in
`subject ocular burning/stinging and dryness occur follows
`instillation of the emulsions of Example 1B.
`Retention Time
`
`As can be appreciated, retention of the emulsion in the
`subject’s eye is also important in achieving the objectives of
`the present invention. In that regard, emulsion in accordance
`with the present invention can provide a mean ocular residue
`time of castor oil in ocular tissue for up to about three hours.
`This has been established by an interferometric study in
`Beagle dog eyes, as follows:
`General Method
`After a baseline examination of the tear film is docu-
`mented (VHS recorder), one drop of formulation B.C. D.
`shown in Example 1 and a further formulation having
`0.125% w/w of castor oil was instilled superiorly onto the
`corneal surface of a Beagle dog eye, and a three minute
`observation time point was carried out (TO-3 min.) . Addi-
`tional observation points are made at 20, 60, 120, and 240
`minutes post instillation. The results are shown in FIG. 7.
`The results shown in FIG. 7 are based on the Guillon
`Technique. The primary components for carrying out the
`tear evaluations are: a Keeler Tearscope, CCD camera and
`remote, color monitor, VDR and cassettes, and a slit lamp
`bio-microscope. For observing and recordingthe tear fringes
`the tearscope is the most important component, as it is a
`highly specialized light source.
`Asemi-quantitative determination (Guillon Technique) of
`the thickness of the lipid/oil component of the pre-ocular
`tear film (POTF) wascarried out with review of the video
`film footage of the experiments.
`It should be appreciated that castor oil itself will abolish
`the lipid layer completely. Accordingly,it is unexpected that
`the emulsions in accordance with the present invention can
`provide substantial residence time for castor oil in the eye.
`Although there has been hereinabove described a particu-
`lar pharmaceutical composition in the form of a nonirritating
`emulsion for the purpose of illustrating the manner in which
`the invention may be used to advantage,
`it should be
`appreciated that
`the invention is not
`limited thereto.
`Accordingly, any and al modifications, variations or equiva-
`lent arrangements, which may occur to those skilled in the
`art, should be considered to be within the scope of the
`present invention as defined in the appended claims.
`
`
`
`5,981,607
`
`Whatis claimedis:
`
`9
`
`1. A methodfor alleviation of dry eye related symptoms
`in dry eye patients and contact lens wearers, said method
`comprising topically applying to ocular tissue an emulsion
`of a higher fatty acid glyceride, polysorbate 80 and an
`emulsion stabilizing amount of Pemulen in water, said
`emulsion being characterized by an absence of cyclosporin.
`2. The method according to claim 1 wherein the weight
`ratio of the higher fatty acid glyceride to the polysorbate 80
`in the emulsion is between about 0.3 and about 30,
`
`10
`3. The method according to claim 2 wherein the higher
`fatty acid glyceride in the emulsion is selected from the
`group consisting of castor oil and corn oil.
`4. The method according to claim 3 wherein castor oil is
`present in the emulsion in an amount of between about
`0.625%, by weight, and about 5.0%, by weight, the polysor-
`bate 80 is present in an amountof about 1.0%, by weight, the
`Pemulenis present in an amount of about 0.05%, by weight,
`and the glycerine is present in an amountof about 2.2%, by
`weight.
`*
`*
`*
`*
`
`