United States Patent [19J
`Ding et al.
`
`[54] EMULSION EYE DROP FOR ALLEVIATION
`OF DRY EYE RELATED SYMPTOMS IN 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
`
`[22] Filed:
`
`Jan. 20, 1998
`
`[51]
`
`Int. Cl.6
`
`.......................... A61K 47/12; A61K 47/14;
`A61K 47/34
`[52] U.S. Cl. .......................... 514/785; 514/786; 514/912;
`514/915; 514/941; 514/943; 514/975
`[58] Field of Search .................................. 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
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US005981607A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,981,607
`Nov. 9,1999
`
`5/1995 Kaswan ..................................... 514/11
`5,411,952
`5,474,979 12/1995 Ding eta!. ................................ 514/11
`
`FOREIGN PATENT DOCUMENTS
`
`8/1990 United Kingdom .
`2228198
`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 Kaswan ..................................... 514/11
`
`4 Claims, 7 Drawing Sheets
`
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`APOTEX 1002, pg. 1
`
`

`

`U.S. Patent
`
`Nov. 9,1999
`
`Sheet 1 of 7
`
`5,981,607
`
`PIIRT I: C/15TOR
`01 L
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`Pill( T II: 1/QUEOUS
`STOCK 51JLLJTION
`(tONT/i/NING WI/TEI(,
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`APOTEX 1002, pg. 2
`
`

`

`U.S. Patent
`
`Nov. 9,1999
`
`Sheet 2 of 7
`
`5,981,607
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`APOTEX 1002, pg. 3
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`

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`U.S. Patent
`
`Nov. 9,1999
`
`Sheet 3 of 7
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`5,981,607
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`

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`U.S. Patent
`
`Nov. 9,1999
`
`Sheet 4 of 7
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`APOTEX 1002, pg. 5
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`

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`U.S. Patent
`
`Nov. 9,1999
`
`Sheet 5 of 7
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`5,981,607
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`APOTEX 1002, pg. 6
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`

`

`U.S. Patent
`
`Nov. 9,1999
`
`Sheet 6 of 7
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`5,981,607
`
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`APOTEX 1002, pg. 7
`
`

`

`U.S. Patent
`
`Nov. 9,1999
`
`Sheet 7 of 7
`
`5,981,607
`
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`
`APOTEX 1002, pg. 8
`
`

`

`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(cid:173)
`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 U.S. Pat. No. 5,474,
`979. The referenced applications/patent are to be incorpo(cid:173)
`rated herein by this specific reference thereto.
`The present invention relates to a pharmaceutical com(cid:173)
`position for alleviating dry eye related symptoms, for
`example, as in patients having immune mediated keratocon(cid:173)
`junctivitis sicca (KCS) or dry eye disease or other autoim(cid:173)
`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(cid:173)
`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(cid:173)
`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 produce reflex tearing and the misleading com(cid:173)
`plaint of excess tears. Typically, symptoms of tear deficiency
`are worse late in the day, with prolonged use of the eyes (as 35
`when the patient reads or watches television), and in con(cid:173)
`ditions of heat, wind, and low humidity (as on the beach or
`ski slopes). Symptoms that are worse in the morning suggest
`an associated chronic blepharitis, recurrent corneal epithelial
`erosion, or exposure keratopathy. Further, symptoms include 40
`superficial punctate erosions, corneal filaments, coarse
`mucus plaques, and epithelial defects.
`As hereinabove noted, most of these symptoms result
`from the unstable tear film and abnormal ocular surface that
`diminish the ability of the ocular surface to respond to
`environmental challenges. Dry eye syndrome, if left
`untreated, can cause progressive pathological changes in the
`conjunctival and corneal epithelium.
`The etiologies of dry eye are varied. The disease gener(cid:173)
`ally referred to as "dry eye" may be the result of age-related
`decreases in systemic androgen support to the lacrimal gland
`or systemic autoimmune diseases such as Sjogrens Syn(cid:173)
`drome. A growing body of research suggests that dry eye is
`the result of an underlying cytokine and receptor-mediated
`inflammatory process.
`Palliative agents, such as tear replacement, tear
`preservation, and autonomic tear stimulation, may provide
`complete or partial relief of symptoms. However, therapeu-
`tic treatments directed at the underlying inflammatory pro(cid:173)
`cess may prove beneficial in correcting the underlying
`disorder.
`The tear film in a normal eye consists of a thin (about
`6-45 urn in thickness) film composed of a mucous layer
`lying over the corneal epithelium and an aqueous layer
`covering the mucous layer and epithelium, which is in turn 65
`covered by an extremely thin (0.01-0.22 urn) layer of lipid
`molecules.
`
`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 aqueous part of the tear film acts as
`5 a lubricant to the eyelids during blinking of the lids.
`Furthermore, certain enzymes contained in the tear fluid, for
`example, immunoglobulin A, lysozyme and beta lysin, are
`known to have bacteriostatic properties.
`It is believed that the lipid layer is responsible for
`10 retarding evaporation of water from the eye. If the lipid layer
`of the tear film is disturbed by, for example, trauma, disease,
`irritation of the eye or contact lens wear, excessive evapo(cid:173)
`ration of water from the eye may occur, leaving the surface
`of the eye "dry" (see e.g., Cedarstaff and Tomlinson, Am. 1.
`15 Optometry & Physiol. Optics, 60:167-174, 1983 [tear film
`disruption in patients with keratoconjunctivitis sicca, or "dry
`eye"]).
`A normal lacrimal system functions to form and maintain
`a properly structured, continuous tear film. The lacrimal
`20 system consists of the secretory system (the source), the
`distribution system and the excretory system (the sink). In
`the secretory system, aqueous tears are supplied by the main
`and accessory lacrimal glands.
`Excessive evaporation of water from the tear film results
`25 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(cid:173)
`ological and pathological changes in the tissue of the eye,
`especially in the cornea. For contact lens wearers, such
`30 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 account this 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
`45 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
`50 the appearance of numerous strands or 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. Management of this stage of
`55 KCS is very difficult.
`A frequent complication of KCS is secondary infection.
`Several breakdowns in the eye's normal defense mechanism
`seem to occur, presumably attributable to a decrease in the
`concentration of antibacterial lysozyme in the aqueous tears
`60 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-
`
`APOTEX 1002, pg. 9
`
`

`

`5,981,607
`
`5
`
`15
`
`20
`
`3
`ing initially, does not last long enough. The patient is
`inconvenienced by the necessity of repeated administration
`of the artificial tear solution in the eye as needed to supple(cid:173)
`ment the normal tears.
`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 10
`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,
`methyl or ethyl cellulose, polyvinyl alcohol and/or glycerin.
`Recently, several lecithin and phospholipid-based solu(cid:173)
`tions have been proposed as treatments to reduce evapora(cid:173)
`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 25
`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 30
`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(cid:173)
`tion with polysorbate 80 which results in an emulsion with
`a high comfort level and low irritation potential suitable for 35
`delivery of medications to sensitive areas such as ocular
`tissues as well as being suitable itself for alleviating dry eye
`symptoms.
`
`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(cid:173)
`tion of the emulsion in accordance with the present inven(cid:173)
`tion;
`
`FIG. 4 is a bar graph showing change in superficial
`punctate Keratitis, as measured with fluorescein, as a func(cid:173)
`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(cid:173)
`lation of the emulsion in accordance with the present inven(cid:173)
`tion;
`
`SUMMARY OF THE INVENTION
`
`FIG. 6 is a bar graph of subjective reports of Ocular
`dryness as a function of time following instillation of the
`40 emulsion in accordance with the present 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(cid:173)
`sifying amount of a higher fatty acid glycerol and polysor- 45
`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 50
`composition may comprise an active agent such as, for
`example, cyclosporine.
`Preferably, the weight ratio of the castor oil to the
`polysorbate 80 is between about 0.3 to about 30 and a weight 55
`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 weight ratio
`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(cid:173)
`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
`
`FIG. 7 is a bar graph of mean ocular residue time, in
`hours, as a function of the amount of 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
`60 mineral oil and an emulsifier and dispersing agent, polysor(cid:173)
`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
`65 sorbitol anhydrides, consisting predominantly of the
`monoester, condensed with approximately 20 moles of eth(cid:173)
`ylene oxide. It conforms generally to the formula:
`
`APOTEX 1002, pg. 10
`
`

`

`5
`
`5,981,607
`
`6
`EXAMPLE 1
`
`5
`
`10
`
`Castor oil
`Polysorbate 80
`Pemulen ®
`Glycerine
`NaOH
`Purified water
`pH
`
`A
`
`B
`
`5.00%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`2.50%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`c
`
`1.25%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`D
`
`0.625%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`15
`
`20
`
`EXAMPLE 2
`
`Castor oil
`Polysorbate 80
`Carbomer 1382
`Glycerine
`NaOH
`Purified water
`pH
`
`A
`
`2.50%
`0.75%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`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
`30 range of the fatty acid glyceride, which may be castor oil,
`corn oil, sunflower oil 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
`35 between about 0.05 and about 2 percent, by weight.
`The following clinical tests were performed in a double
`marked randomized study to measure aqueous deficiency in
`keratoconjunctivitis sicca. These clinical tests include the
`Schirmer, Rose Bengal Staining and Fluorescein used to
`40 determine punctate Keratitis. In addition, subject tests here(cid:173)
`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.
`
`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 which utilizes
`a higher fatty acid glyceride, such as castor oil, by itself or
`in combination with an active agent.
`Other than U.S. Pat. No. 5,474,979 hereinabove refer(cid:173)
`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 25
`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(cid:173)
`electrolytes if more than one, from the family of cross-linked
`polyacrylates, such as carbomers and Pemulen®.
`Pemulen® is a polymeric emulsifier having a CTFAname
`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(cid:173)
`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(cid:173)
`boxylic acid (-COOH) groups. The viscosity of a neutral(cid:173)
`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 45
`molecular weight copolymer of acrylic acid and a long chain
`alkyl methacrylate cross-linked with allyl ethers of pen(cid:173)
`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(cid:173)
`tion may include cyclosporine, other chemicals which are
`poorly soluble in water such as indomethacin and steroids
`such as androgens, prednisolone, prednisolone acetate, 60
`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 65
`weight. Emulsions were prepared according to the manu(cid:173)
`facturer's schematic shown in FIG. 1.
`
`CLINICAL TESTS
`
`Schirmer
`
`Clinical measures of tear film volume and tear flow rates
`50 help quantitate the severity of aqueous deficiency in kera(cid:173)
`toconjunctivitis sicca.
`The Schirmer test measures the volume of tears produced
`during a fixed time period. It is performed by placing the
`folded 5-mm. end of a standard size number 41 Whatman
`55 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
`following instillation of the emulsion of Example 1B into an
`eye of a patient, is shown in FIG. 2, the number of patients
`being indicated on the bar graph by the character "n". As
`shown, the instillation of the emulsion increases the mea(cid:173)
`sured tear volume.
`
`Rose Bengal Staining
`
`As hereinabove discussed, patients with tear film dys(cid:173)
`function may become symptomatic because of dry spots on
`
`APOTEX 1002, pg. 11
`
`

`

`5,981,607
`
`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
`5 where O=no discomfort, +l=mild, +2=moderate, +3=severe,
`and +4=very severe. Duration of recorded symptoms will
`also be recorded in seconds only immediately after instilla(cid:173)
`tion of masked medication.
`The grading of the symptoms of discomfort for either eye
`10 will be defined as follows:
`
`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(cid:173)
`able corneal surface pathology present a more difficult
`diagnostic problem. The two commonly used dyes are rose
`bengal and fluorescein.
`Rose bengal 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 end of 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 15
`staining, and is not uncomfortable to the patient. Using the
`green filter, a score is given to each medial and lateral
`interpalpebral zones.
`As shown in FIG. 3, a mean charge in score is shown as
`a function of time using Temporal Rose Bengal Staining 20
`following instillation of the emulsion of Example lB. These
`changes represent significant reduction in conjunctival dry
`areas.
`
`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 lB.
`
`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:
`
`Superficial Punctuate Keratitis
`
`25
`
`Fluorescein is used to determine punctate Keratitis. Fluo(cid:173)
`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 30
`anesthetic. One drop of 2% fluorescein provides an exces(cid:173)
`sive amount of fluorescein. 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.
`
`35
`
`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 40
`for each eye and in a weekly diary, subjects recorded how
`both eyes felt on average for symptoms of ocular discomfort.
`Subjective assessment on several indices: stinging/
`burning, tearing, discharge (not associated with infection),
`itching, foreign body sensation, blurred vision, dryness, 45
`photophobia, pain and other. Assessment employed a 5 point
`Liukert Scale where O=no discomfort, +l=mild,
`+2=moderate, +3=severe, and +4=very severe.
`The grading of symptoms of discomfort for either eye will
`be defined as follows:
`
`55
`
`None
`Mild
`
`Moderate
`
`Severe
`
`Very Severe
`
`Other
`
`(0) ~ No discomfort
`( + 1) ~ Awareness, but no discomfort
`and no intervention
`required.
`( +2) ~ Discomfort that causes
`intermittent awareness and
`requires intervention.
`( +3) ~ Discomfort that causes
`continuous awareness and
`requires intervention.
`( +4) ~ Discomfort that interferes
`with normal daily activity
`and requires intervention.
`(9) ~ 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,
`
`General Method
`After a baseline examination of the tear film is docu(cid:173)
`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 (T0-3 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 recording the tear fringes
`the tearscope is the most important component, as it is a
`50 highly specialized light source.
`A semi -quantitative determination (Guill on Technique) of
`the thickness of the lipid/oil component of the pre-ocular
`tear film (POTF) was carried 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-
`60 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-
`65 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.
`
`APOTEX 1002, pg. 12
`
`

`

`5,981,607
`
`9
`
`What is claimed is:
`1. A method for 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
`5 present in the emulsion in an amount of between about
`0.625%, by weight, and about 5.0%, by weight, the polysor(cid:173)
`bate 80 is present in an amount of about 1.0%, by weight, the
`Pemulen is present in an amount of about 0.05%, by weight,
`and the glycerine is present in an amount of about 2.2%, by
`weight.
`
`* * * * *
`
`APOTEX 1002, pg. 13
`
`