United States Patent
`
`[193
`
`Kaswan
`
`[11] Patent Number:
`[451 Date of Patent:
`
`4,839,342
`* Jun. 13, 1989
`
`OTHER PUBLICATIONS
`
`Kaswan et al., Am. J. Vet. Res. 46, 376-383 (1985).
`Wenger, Synthesis of Cyclosporin and Analogues, pp.
`14-25 in Cyclosporin vol. 1, Grune & Stratton, Inc.
`(New York, 1983).
`BenEzra et al., Amer. J. Ophthalmol. 101, 278-282
`(1986).
`Hunter et al., Clin. Exp. Immunol. 45, 173-177 (1981).
`Boisjoly et al., Arch. Ophthalmol. 102, 1804-1807.
`(1984).
`Mosteller et al., Investigative Ophthalmol. Supp. 25, 3,
`33 (1984).
`Nussenblat et al., Amer. J. Ophthalmol. 96, 275-282
`(1983).
`Hoffman, et al., Kin. MbL Augenheilk. 187, 92-95 (1985)-
`and certified translation thereof.
`“Aspirin Therapy in Vernal Conjunctivitis” by Abel-
`son, et al., Amer. J. Opthal. 95,502-505 (1983).
`“Cryosurgery in the Management of Vernal Keratocon-
`junctivitis” by Abiose, et al., Annals of Ophthal. 15(8),
`744-747 (1983).
`“Vemal Conjunctivitis” by Allansmith, Chapter 9, pp.
`1-8 Clinical Opthalmology, V014, (Harper & Row 1986).
`“cyclosporine Eyedrops for the Treatment of Severe
`Vernal Keratoconjunctivitis” BenEzra, et al. Amer. J.
`Opthal. 101, 278-282 (1986).
`“Diagnosis and Treatment of Tear Deficiencies” Lemp,
`Chapter 14, pp. 1-10.
`Clinical Opthalmolog vol. 4, Duane and Jaeger, Ed.
`(Harper & Row 1986).
`“Diseases of the Cornea” by Grayson at pp. 334-367
`(The CV. Mosby Co. 1983).
`
`Primary Examiner—De1bert R. Phillips
`Assistant Examiner-T. D. Wessendorf
`Attorney, Agent, or Firm—Kilpatrick & Cody
`
`[57]
`
`ABSTRACI‘
`
`The present invention provides a method of treating an
`aqueous-deficient dry eye state in a patient suffering
`therefrom, which method includes the step of adminis-
`tering cyclosporin topically to the patient’s eye. The
`cyclosporin is administered as a solution, suspension or
`ointment in a pharmaceutically acceptable excipient.
`
`18 Claims, No Drawings
`
`[54] . METHOD OF INCREASING TEAR
`PRODUCTION BY TOPICAL
`ADMINISTRATION OF CYCLOSPORIN
`
`[75]
`
`Inventor: Renee Kaswnn, Athens, Ga.
`
`[73] Assignee: University of Georgia Research
`Foundation, Inc., Athens, Ga.
`
`[ * ] Notice:
`
`The portion of the term of this patent
`subsequent to Jun. 13, 2006 has been
`disclaimed.
`
`[21] Appl. No.: 92,466
`
`[22] Filed:
`
`Sep. 3, 1987
`
`Int. Cl.‘
`[51]
`[52] U.s. C1.
`[58] Field of Search ..........
`
`........................................... A61K 37/02
`
`.......... 514/11; 514/915
`424/78; 514/11, 9, 912,
`514/914, 915, 15; 530/317
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`...................... 514/11
`8/1978 Ruegger et al.
`4,108,985
`9/1978 Harri et al.
`.. ... .....
`...... 514/11
`4,117,118
`7/1980 Ruegger et al.
`530/321
`4,210,581
`4,215,199 7/1980 Harri et al.
`... ...
`...... 435/71
`4,220,641
`9/1980 Traber et al.
`...... 514/11
`4,220,657 9/1980 Johnson et al.
`514/912
`4,288,431
`9/1981 Traber et 3.1.
`.......
`...... 514/11
`4,289,851
`9/1981 Traber et al.
`.......
`...... 435/71
`4,384,996
`5/1983 Bollinger et a1.
`530/321
`4,388,307
`6/1983 Cavanak ......
`514/11
`4,396,542 #8/1983 Wenger
`...... 530/32
`4,452,818
`6/1984 Haidt .......
`514/912
`4,554,351 11/1985 Wenger ...........
`...... 514/11
`4,639,434
`1/1987 Wenger et al.
`.
`514/11
`4,649,047 3/ 1987 Kaswan ...........
`514/11
`4,681,754 7/1987 Sicgl ........
`.. 424/10
`4,703,033 10/1987 Seebach ................................ 514/1 1
`
`
`
`FOREIGN PATENT DOCUMENTS
`19197 3/1972 Australia ............................... 424/78
`
`8404681 12/1984 PCT Int’1 Appl.
`.
`514/912
`8501875
`5/1985 PCT Int’1 Appl. .
`514/914
`8603966 7/1986 PCT Int’1 Appl. ................. 514/912
`
`ALL 2002
`ARGENTUM PHARMACEUTICALS V. ALLERGAN
`IPR2016-01232
`
`1
`
`ALL 2002
`ARGENTUM PHARMACEUTICALS V. ALLERGAN
`IPR2016-01232
`
`

`
`1
`
`4,839,342
`
`METHOD OF INCREASING TEAR PRODUCTION
`BY TOPICAL ADMINISTRATION OF
`'
`CYCLOSPORIN
`
`FIELD OF THE INVENTION
`
`The present invention relates to a method of increas-
`ing tear production in a patient suffering from deficient
`tears in the eye due to an autoimmune dysfunction of
`the lacrimal (tear) glands. More specifically, this inven-
`tion relates to a method of treating immune mediated
`keratoconjunctivitis sicca (KCS or dry eye disease) in a
`patient suffering therefrom, which method includes-
`administering a cyclosporin topically to the patient’s
`eye.
`
`2
`Histologically in KCS (as part of Sjogren’s syndrome
`or in isolation), the initial changes seen in the lacrimal
`gland are those of focal lymphocytic and plasma cell
`infiltrates associated with degeneration of glandular
`tissue. These changes resemble those seen in autoim-
`mune disease in other tissue, giving rise to the specula-
`tion that KCS has an autoimmune basis.
`Sjogren’s syndrome is recognized as an exocrine
`gland dysfunction. Characteristically,
`the lacrimal
`glands show a mononuclear-cell infiltration that ulti-
`mately leads to destruction of the glandular structure.
`Conventional treatment of KCS is symptomatic.
`Normally, aqueous-deficient dry eye states are
`treated by supplementation of the tears with artificial
`tear substitutes. However, relief is limited by the reten-
`tion 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
`The exposed part of a normal eye is covered by a thin
`forty-five minutes. The effect of such products, while
`tear film‘ The presence of a continuous tear mm is im' 20 soothing initially does not last long enough The patient
`portant for the well-being of the corneal and conjuncti-
`is inconvenienced by the necessity of repeated adminis-
`val epithelium and provides the cornea with an opti-
`tration of the artificial tear solution in the eye as needed
`cally high quality surface. In addition, the aqueous part
`to supplement the normal tears. Moreover, such treat-
`of the tear film acts as a lubricant to the eyelids during
`ment merely acts to alleviate the symptoms of the dry
`blinking of the lids. Furthermore, certain enzymes con- 25
`eye state and does not cure any underlying disorders or
`tained in the tear fluid, for example immunoglobulin A,
`causes of the dry eye state.
`lysozyme and beta lysin, are known to have bacterio-
`I-Iistologic studies of the lacrimal glands in patients
`static properties.
`suffering from Sjogren’s syndrome have shown some
`A sound lacrimal system functionsto form and main-
`evidence of lacrimal gland inflammation. Such inflam-
`tain a properly structured, continuous tear film. The 30
`mation may simply be due to the normal aging of the
`lacrimal apparatus consists of the secretory system (the
`patient. It has been suggested that the use of antiinflam-
`source), the distribution system and the excretory sys-
`matory agents might serve to decrease the glandular
`tem (the sink). In the secretory system, aqueous tears
`inflammation. The systemic use of corticosteroids has
`are supplied by the main and accessory lacrimal glands.
`been advocated in these conditions. However, the merit
`The bulk of the tear film is made of such aqueous 35
`of systemic corticosteroids in dry eye states has not
`tears. The continuous production and drainage of aque-
`been established. In most dry eye cases the hazards of
`ous tear is important in maintaining the corneal and
`long term use of antiinflammatory agents would seem to
`conjunctival epithelium in a moist state, in providing
`outweigh their potential merit.
`nutrients for epithelial respiration, in supplying bacte-
`Surgical procedures have also been suggested in the
`riostatic agents and in cleaning the ocular surface by the 40
`management of dry eye states. Where there has been
`flushing action of tear movement.
`significant conjunctival destruction, mucuous mem-
`Abnormalities of the tear film include an absolute or
`brane transplants have been advocated. It has also been
`partial deficiency in aqueous tear production (kerato-
`suggested that parotid (saliva) duct transplantation can
`conjunctivitis sicca or KCS).
`be useful in the management of dry eyes. However,
`In relatively mild cases, the main symptom of KCS is 4.5
`since surgical alterations to combat dry eye conditions
`a foreign body sensation or a mild “scratchiness”. This
`constitute such a drastic remedy and the benefit result-
`can progress to become a constant, intense burning or
`ing from these alterations is questionable, these methods
`irritative sensation (which can be debilitating to the
`are usually used in dry eye patients only as a last resort.
`patient.
`It has also been suggested to administer orally a dilute
`More severe fonns progress to the development of 50
`solution of pilocarpine to stimulate the autonomic ner-
`filamentary keratitis, a painful condition characterized
`vous system to effect increased aqueous tear produc-
`tion. This method of treatment has not met with univer-
`by the appearance of numerous strands or filaments
`attached to the corneal surface. Recent evidence sug-
`sal favor because of the unpleasant side effects of in-
`gests that these filaments represent breaks in the conti-
`gested pilocarpine.
`Animal models of Sjogren’s syndrome have been
`nuity of the normal corneal epithelial cells. The shear‘
`created by lid motion pulls these filaments, causing pain.
`instrumental in basic ophthalmic research. A Sjogren’s-
`Management of‘ this stage of KCS is very difficult.
`like disease has been found in dogs with systemic lupus
`erythematosus.
`A frequent complication of KCS is secondary infec-
`tion. Several breakdowns in the eye’s normal defense
`Canine KCS is a common, chronic progressive, and
`mechanism seem to occur, presumably attributable to a
`potentially blinding disease. A continuum of corneal
`decrease in the concentration of antibacterial lysozyme
`and conjunctival lesions ensues from the dry eye state.
`The cause of KCS in canines is often not identified.
`in the aqueous tears of a patient suffering from KCS.
`Although KCS can develop in the absence of any
`Usually, canine KCS is not an isolated ophthalmic dis-
`ease. It has been speculated in Kaswan et a.l., Am. J.
`other overt systemic abnormality, there is a frequent
`association of KCS with systemic disease. KCS can
`Vet. Res. 46, 376-383 (1985), that most cases of canine
`KCS occur via autoimmune mechanisms.
`occur as part of a larger systemic involvement known as
`Sjogren’s syndrome. This classically consists of the
`The term autoimmunity is used to indicate immuno-
`triad of dry eyes, dry mouth, and arthritis.
`logic self injury, but not a singular etiology. Autoim-
`
`BACKGROUND OF THE INVENTION
`
`10
`
`15
`
`55
`
`60
`
`65
`
`2
`
`

`
`5
`
`3
`mune disease is multifactorial, including hormonal, en-
`vironmental, and polygenetic factors. A reasonable
`concept of autoimmune pathogenesis proposes that
`autoimmunity may arise whenever there exists a state of
`immunologic imbalance in which B-cell activity is ex-
`cessive and/or suppressor T-cell activity is diminished.
`Cyclosporins are unique imrnunosuppressive agents
`derived from an extract of soil fungi. Cyclosporine
`(Cyclosporin A) and its natural and synthetic analogs
`and isomers (such as Cyclosporins B, C, D, E and H)
`are cyclic peptides composed of 11 amino acid residues.
`Wenger, Synthesis of Cyclosporine and Analogues, pp.
`14-25 in Cyclosporine vol. 1, Grune & Stratton, Inc.
`(New York 1983). Cyclosporin A was first proposed for
`use as an antifungal agent, but its immunosuppressive
`effects were found to be more marked than its antifun-
`gal potential. This drug inhibits the generation of effec-
`tor T-lymphocytes without inhibiting the expression of
`suppressor lymphocytes.
`Cyclosporine’s immunosuppressive properties have 20
`led to its use in immune system related diseases. For
`example, U.S. Pat. No. 4,649,047, the disclosure of
`which is herein incorporated by reference, describes a
`method for the treatment of phacoanaphylactic endoph-
`thalmitis and uveitis in the anterior or posterior segment
`of an eye, in which method a cyclosporin is topically
`administered to the eye. In other ophthalmic applica-
`tions, cyclosporine has been used topically only for the
`treatment of external (e.g., corneal) eye diseases.
`BenEzra et al., Amer. J. Ophthalmol. 101, 278-282
`(1986), describe the effect of 2% cyclosporine eyedrops
`on severe vernal keratoconjunctivitis. Severe vernal
`keratoconjunctivitis is a seasonal allergic disorder unre-
`lated to tear deficiency.
`~
`Hunter et al., Clin. Exp. Immunol. 45, 173-177 (1981)
`describe the topical administration of cyclosporine in a
`rabbit model of corneal graft rejection with positive
`results. These effects were found to be attributable to
`T-cell suppression within the eye or within systemic
`compartments such as blood or lymph.
`Boisjoly et al., Arch. Ophthalmol. 102, 1804-1807,
`(1984), have reported that topical application of cyclos-
`porine had a beneficial prophylactic effect towards the
`treatment of severe herpetic stromal keratitis.
`Mosteller et al., Investigative Ophthalrnol. Supp. 25,
`3, 38 (1984), propose the potential suppression of delete-
`rious ocular immune reactions such as the eye surface
`cornea allograft reaction by applying a single dose of a
`10% Cyclosporin A ointment in the lower cul-de-sac of
`rabbit eyelids.
`In other ophthalmic applications, where the disease
`being treated is not limited to the eye surface, cyclospo-
`rine has been used systemically.
`For example, Nussenblatt et al., Amer. J. Ophthal-
`mol. 96, 275-282 (1983), have reported clinical
`im-
`provement in some patients with noninfectious poste-
`rior uveitis following systemic treatment with cyclospo-
`nn.
`
`50
`
`However, systemic therapy with cyclosporine has
`serious drawbacks. There is a high risk of adverse re-
`sponses when cyclosporine is used systemically. Cy-
`closporine used systemically has been associated with a
`high incidence of renal toxicity (kidney failure), some
`cases of hepatotoxicity,
`increased incidence of lym-
`phoid tumors and increased incidence of opportunistic
`infections. Cyclosporine is only slightly less toxic than
`other immunosuppressive agents such as cytoxan or
`aziothioprine. The systemic side effects of cyclosporine
`
`4,839,342
`
`4
`are so severe and so common that they limit its use to
`life-threatening or in some cases severe sight-threatem
`ing disease. Finally, systemic application of cyclospo-
`rine is limited by its prohibitive cost.
`To date, there has been no suggestion to treat a glan-
`dula.r dysfunction, a lacrimal gland dysfunction or an
`aqueous-deficient dry eye state with a cyclosporin, ei-
`ther topically or systemically.
`It can thus be readily appreciated that provision of a
`method of increasing tear production in a patient suffer-
`ing from deficient tears in the eye due to an autoimmune
`dysfunction of the lacrimal glands, which method pro-
`vides improved treatment of KCS and eliminates the
`previously discussed problems, would be a highly desir-
`able advance over the current state of the art in KCS
`
`at
`treatment.
`OBJECTS OF THE INVENTION
`
`It is therefore an object of this invention to provide a
`method of increasing tear production for a tear-defi-
`cient eye.
`It is a second object of this invention to provide a
`method of increasing tear production in an eye of a
`patient suffering from an immune mediated dysfunction
`of the lacrimal glands.
`It is an additional object of this invention to provide
`a method of treating KCS in a patient suffering there-
`from.
`It is also an object of this invention to provide a
`method of treating a disorder caused by excessive im-
`mune activity in a lacrimal gland of a patient.
`It is a further object of this invention to provide a
`method of treating a disorder exacerbated by KCS in a
`patient suffering therefrom.
`It is another object of this invention to provide a
`cyclosporin-based treatment of the lacrimal glands
`without the accompanying adverse physiological re-
`sponses and economic difficulties associated with sys-
`temic cyclosporin treatments.
`These and other objects and advantages of the pres-'
`ent invention will become more readily apparent after
`consideration of the following.
`STATEMENT OF THE INVENTION
`
`In one aspect, the present invention is directed to a
`method of treating a dry eye state in a patient by admin-
`istering a cyclosporin topically to the patient’s eye.
`In another of its aspects, the present invention pro-
`vides a cyclosporin-based treatment of an autoimmune
`dysfunction of the lacrimal glands.
`In still another of its aspects, the present invention
`relates to a cyclosporin in a carrier adaptable to topical
`administration into a patient’s eye.
`DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`The present invention, as well as other objects and
`features thereof, will be understood more clearly and
`fully from the following description of certain preferred
`embodiments.
`The present invention provides a method of treating
`an aqueous-deficient dry eye state due to an autoim-
`mune dysfunction of the lacrimal glands in a patient
`suffering therefrom, which method includes the step of
`administering a cyclosporin topically to the patient’s
`eye. Surprisingly, this topical administration of a cy-
`closporin to the eye provides cyclosporin treatment to
`
`3
`
`

`
`4,839,342
`
`5
`the lacrimal glands, and such treatment increases tear
`production in a patient suffering from KCS.
`Conventional treatment of KCS involves alleviating
`the symptoms of the dry eye state without treating the
`underlying disorders or causes of the dry eye state.
`Symptomatic treatment of the dry eye state, such as by
`supplementation of the aqueous tears with artificial tear
`substitutes, necessarily involves continuous and re-
`peated attention as needed to alleviate the recurring
`symptoms.
`To date, there has been no suggestion to treat a glan-
`dular dysfunction, a lacrimal gland dysfunction or an
`aqueous-deficient dry eye state with a cyclosporin, ei-
`ther topically or systemically.
`Topical administration to a patient’s eye has surpris-
`ingly been found to be an excellent method for provid-
`ing a cyclosporin to the lacrimal glands of the patient to
`treat KCS. Additionally, since by its very nature topical
`administration does not require cyclosporin dispersion
`throughout the patient’s system as is the case with sys-
`temic administrations, the present invention provides a
`means for directing cyclosporin to the desired location
`without the accompanying high risk of adverse re-
`sponses and high cost associated with systemic treat-
`ments.
`Cyclosporine concentration was determined for vari-
`ous eye compartments and tissues surrounding the eye
`after bilateral topical administration of cyclosporine to
`the eyes of three rabbits. The cyclosporine was adminis-
`tered in each of the rabbits’ eyes in drops (approxi-
`mately l7 microliters) of 2% radiolabelled cyclosporine
`in an olive oil solution applied every 15 minutes for 6
`applications, followed by a period of two hours to allow
`for absorption. The rabbits were then euthanized and
`the eyes and surrounding tissue were enucleated and
`frozen. The eyes and surrounding tissue were dissected
`into their component parts. These were then digested in
`collagenase and the resulting solutions were analyzed
`by liquid scintillation counting for cyclosporine con-
`tent. The following average cyclosporine concentra-
`tions were measured:
`Accessory lacrimal gland: 2850 mg of cyclosporine/-
`gram of tissue;
`Periorbital fat: 800 ng/gram;
`Cornea: 4700 ng/gram;
`Iris: 1200 ng/gram;
`Retina: 50 ng/gram;
`Aqueous humor: 30 ng/gram;
`Vitreous humor: 30 ng/gram;
`Anterior sclera: 3150 ng/gram; and
`Posterior sclera: 1550 ng/gram.
`Thus,
`topical administration of cyclosporine to a
`patient’s eye surprisingly provides a suitable concentra-
`tion of cyclosporine to the laorimal glands of the patient
`for treatment of KCS.
`In accordance with the present invention. the cyclos-
`porin may be used in any efficacious concentration, e.g.,
`0.01 to saturation (e.g., greater than 20 weight percent).
`in a pharmaceutically acceptable excipient. From 0.01
`to 50 weight percent, preferably from 0.1 to 20 weight
`percent, of a cyclosporin in a pharmaceutically accept-
`able excipient is used. Such pharmaceutically accept-
`able excipients are, for example, animal oil, vegetable
`oil, an appropriate organic or aqueous solvent, an arti-
`ficial tear solution, a natural or synthetic _polymer or an -65
`appropriate membrane.
`Examples of these pharmaceutically acceptable ex-
`cipients are olive oil, arachis oil, castor oil, mineral oil,
`
`‘ 6
`petroleum jelly, dimethyl sulphoxide, chremophor, Mi-
`glyol 182 (commercially available from Dynarnit Nobel
`Kay-Fries Chemical Company, Mont Vale, N.J.), an
`alcohol (e.g., ethanol, n-propyl alcohol or iso-propyl
`alcohol), liposomes or liposome-like products or a sili-
`cone fluid. Preferred excipients are dimethyl sulphoxide
`and olive oil. Mixtures of at least two of any suitable
`excipients may be used.
`Examples of artificial tear excipients which can be
`advantageously used in the practice of this invention are
`isotonic sodium chloride, cellulose ethers such as hy-
`droxypropylmethylcellulose
`and hydroxyethylce1lu-
`lose, polyvinyl alcohol and other commercially avail-
`able artificial tea solutions.
`An example of useful polymeric excipient is a po1yox-
`yethylated castor oil.
`Examples of pharmaceutically acceptable membranes
`which can advantageously be used in the practice of this
`invention are: mictodone, an artificial lipid membrane,
`polyvinylalcohol, or methylcellulose.
`The cyclosporin is advantageously administered topi-
`cally as an ophthalmic drop (solution or suspension) or
`ophthalmic ointment containing a effective amount of
`the cyclosporin. Concentrations of 0.01 to 50 weight
`percent, preferably 0.1 to 20 weight percent, of a cy-
`closporin are used.
`In accordance with the method of the present inven-
`tion, a cyclosporin is administered topically in any
`quantity required to provide the degree of treatment
`needed. For example, 5 microliters to 1 milliliter of a
`solution, suspension or ointment containing an effective
`amount of a cyclosporin, such as 0.01 to 50 weight
`percent, preferably 0.1 to 20 weight percent, of cyclos-
`porin is advantageously used.
`Cyclosporins which are useful in the practice of the
`present invention are both natural or synthetic cyclos-
`porin. For example, Cyclosporin A is advantageously
`used in the practice of the present invention. Other
`forms of cyclosporins (e.g., analogs and isomers such as
`Cyclosporins B, C, D, E, and H) may also be used.
`Mixtures of at least two different cyclosporins may be
`used.
`Numerous advantages accrue with the practice of the
`present invention. The method of the present invention
`is useful in that it can locally prevent activation of a
`presystemic response. Topical administration of a cy-
`closporin into a patient’s tear deficient eye increases
`tear production in the eye. Thus, such treatment further
`serves to correct corneal and conjunctival disorders
`exacerbated by tear deficiency and KCS, such as cor-
`neal scarring, corneal ulceration, inflammation of the
`cornea or conjunctiva, filamentary keratitis, mucopuru-
`lent discharge and vascularization of the cornea. Fur-
`thermore, cyclosporin directly decreases the immune
`response of granulation and neovascularization in the
`cornea.
`
`Further objects of this invention, together with addi-
`tional features contributing thereto and advantages ac-
`cruing therefrom, will be apparent from the following
`examples of the invention.
`EXAMPLE 1
`
`A one year old standard female Poodle with conjunc-
`tivitis exhibited mild aqueous tear deficiency in both
`eyes. The dog had a Schirmer tear test value of 15
`mm/minute in the right eye and 10 mm/minute in the
`left eye.
`
`4
`
`

`
`4,839,342
`
`7
`The Schirmer tear test is a test of aqueous tear pro-
`duction. The test depends upon observing the extent of
`wetting of a strip of filter paper placed over the lower
`lid of an eye for a specified time. Standardized strips are
`commercially available. The strip is folded at a notched
`marking and is then placed over the edge of the lateral
`one-third of the eyelid. The strip is usually left in place
`for a period of time while the patient looks straight
`ahead in dim light.
`The degree of wetting of the paper is measured in mm
`from the notch. For human patients, a normal end point
`is 5 mm of wetting at five minutes. For canine patients,
`the normal tear production is 14 to 20 mm. of wetting at
`one minute.
`The dog was treated with dexamethasone by topical
`administration in both eyes four times daily.
`The same dog at approximately six years old still
`exhibited conjunctivitis in both eyes and had a Schirmer
`tear test value of 3 mm/minute in both eyes. Topical
`dexamethasone was used in both eyes twice daily for
`nine weeks without benefit.
`The dog was then treated by topical application of
`2% cyclosporine in an olive oil solution in both eyes
`once daily without any other medications. After ten
`days, the dog showed markedly increased tear produc-
`tion and had a Schirmer tear test value of 22 mm/mi-
`nute in the right eye and 8 mm/minute in the left eye.
`The treatment by topical application of 2% cyclospo-
`rine in an olive oil solution in both eyes once daily was
`continued for an additional three weeks. At this time,
`the dog exhibited plentiful aqueous tear production and
`the treatment was stopped for one week. After this
`week, the dog had a Schirmer tear test value of lo
`mm/minute in the right eye and 9 mm/minute in the left
`eye.
`At this time, the treatment by topical application of
`2% cyclosporine in an olive oil solution in both eyes
`once daily was restarted andcontinued for six days.
`After these six days, the dog had a Schirmer tear test
`value of 22 mm/minute in the right eye and 16 mm/1n.i-
`nute in the left eye.
`In this case, a dog with chronic tear deficiency in
`which prior use of corticosteroids failed to improve tear
`secretion showed a surprising increase in tear produc-
`tion with cyclosporine treatment. The increased tear
`production continued only while cyclosporine therapy
`continued. When the treatment was stopped for a week;
`recurrence of tear deficiency was found. However, tear
`production increased to normal levels after the treat-
`ment was restarted.
`
`EXAMPLE 2
`
`An eight year old male Lhasa Apso had had a four
`year prior cat scratch in his left eye and an active 4 mm
`strornal ulcer in his right eye. An ocular examination of
`the dog showed conjunctivitis in both eyes with muco-
`purulent discharge, diffuse irregular corneal surfaces,
`pigment formation and neovascularization in the cornea
`of the left eye. The Schirmer tear test values were 12
`mm/minute in the right eye and 3 mm/minute in the left
`eye.
`The dog was treated with topical administration to
`both eyes of 2% cyclosporine in an olive oil solution
`once daily, neosporin twice daily and ophthalmic petro-
`latum. After five days, the Schirmer tear test values
`were 22 mm/minute in the right eye and 23 mm/minute
`in the left eye. In addition, the ulcer in- the right eye was
`
`8
`healed to 2 mm and the left eye was assessed to have
`decreased vascularization.
`In this case, cyclosporine increased tear production
`significantly in a short period of time. Moreover, cy-
`closporine, unlike corticosteroids, did not retard cor-
`neal healing nor activate corneal collagenase. Accord-
`ingly, cyclosporine can be used in eyes having active
`corneal ulcers.
`
`20
`
`35
`
`55
`
`EXAMPLE 3
`
`A six year old male English Bulldog had had a long
`history of KCS. The Schirmer tear test values were 2
`mm/minute in the right eye and 3 mm/minute in the left
`eye.
`The right eye was neovascularized over the entire
`cornea. No intraocular detail could be visualized
`through the opaque cornea. The cornea was grossly
`thick and irregular in surface. The left eye had neovas-
`cularimtion over about half of the cornea, mostly axi-
`ally.
`The dog was treated with three drops of 2% pi1ocar-
`pine by month. After two hours, the Schirmer tear test
`values were 0 mm/minute in the right eye and 10
`mm/minute in the left eye.
`The dog was then treated with 2% cyclosporine in an
`olive oil solution administered topically to both eyes
`once daily and three drops of 2% pilocarpine adminis-
`tered by mouth twice daily. After twelve days,
`the
`Schirmer tear test values were 10 mm/minute in the
`right eye and 15 mm/minute in the left eye.
`In this case, while pilocarpine alone increased tear
`production in the left eye from a Schirmer tear test
`value of 3 mm/minute to 10 mm/minute, pilocarpine
`did not increase tear production in the right eye. Use of
`cyclosporine with pilocarpine increased tear produc-
`tion to a Schirmer tear test value of 15 mm/minute in
`the left eye and from O mm/minute to 10 mm/minute in
`the right eye. The use of cyclosporine markedly in-
`creased tear ‘production over the use of pilocarpine
`alone.
`
`EXAMPLE 4
`
`A seven year old Miniature Poodle had a history of
`severe KCS of six to seven months duration. The dog _
`was considered to be blind for two months duration.
`Treatment with artificial tears six times daily did not
`effect the apparent blindness.
`The dog showed marked mucopurulent discharge in
`both eyes. The Schirmer tear test values were 0 mm/mi-
`nute in both eyes. The dogs corneas were thickened
`and neovascularized with an irregular surface. No intra-
`ocular detail could be visualized through the opaque
`corneas.
`
`The dog was treated with one drop of 2% pilocarpine
`by mouth two times daily and ophthalmic petrolatum
`four times daily. After two weeks, the Schirmer tear
`test values were still 0 mm/minute in both eyes. The
`corneal vascularity and scarring remained dense and the
`anterior chambers of the dog’s eye were not visualiza-
`ble.
`The dog was then treated with 2% cyclosporine in an
`olive oil solution administered topically in both eyes
`once daily and two drops pilocarpine administered by
`mouth twice daily.
`After two weeks, the Schirmer tear test values were
`8 mm/minute in the right eye and 6 mm/minute in the
`left eye. Although corneal vascularization and scarring
`remained, the iris and lens could be evaluated, there was
`
`5
`
`

`
`‘ 4,839,342
`
`20
`
`.10
`tering a therapeutically effective amount of a cyclospo-
`rin topically to the patient’s eye.
`8. The method of claim 2 for treating keratoconjunc-
`tivitis sicca in a patient comprising the step of adminis-
`tering a therapeutically effective amount of a cyclospo-
`rin topically to the patient’s eye.
`9. The method of claim 1 for treating a disorder
`caused by immune activity in a lacrimal gland of a pa-
`tient comprising the step of topically administering to
`the patient’s eye a therapeutically effective amount of a
`cyclosporin to enhance or restore tearing.
`10. The method of claim 9 wherein said cyclosporin is
`administered as a solution, suspension or ointment com-
`prising 0.01 to 50 weight percent of cyclosporin in a
`pharmaceutically acceptable excipient.
`11. The method of claim 10 wherein said cyclosporin
`is administered in an amount of 0.1 to 20 weight percent.
`12. The method of claim 10 wherein the pharmaceuti-
`cally acceptable excipient is olive oil, arachis oil, castor
`oil, polyoxyethylated castor oil, mineral oil, petroleum
`jelly, dimethyl sulphoxide, an alcohol, liposome, sili-
`cone fluid or a mixture thereof.
`13. The method of claim 9, wherein said cyclosporin
`is Cyclosporin A.
`14. The method of claim 1 for treating a disorder
`exacerbated by deficient tear production in a patient
`comprising topically administering a therapeutically
`effective amount of a cyclosporin to the patient’s eye to
`enhance or restore tearing.
`15. The method of claim 14 wherein said cyclosporin
`is administered as a solution, suspension or ointment
`, comprising 0.01 to 50 weight percent of cyclosporin in
`a pharrnaceutically acceptable excipient.
`16. The method of claim 15 wherein said cyclosporin
`is administered in an amount of 0.1 to 20 weight percent.
`17. The method of claim 15 wherein the pharmaceuti-
`cally acceptable excipient is olive oil, arachis oil, castor
`oil, polyoxyethylated castor oil, mineral oil, petroleum
`jelly, dimethyl sulphoxide, an alcohol, liposome, sili-
`0 cone fluid or a mixture thereof.
`18. The method of claim 14, wherein said cyclosporin
`is Cyclosporin A.
`II
`=l=
`II
`*
`t
`
`9
`no mucoid discharge in either eye as previously and the
`KCS was assessed as medically improved.
`After similar treatment for another two months, the
`Schirmer tear test values were ll mm/minute in the
`right eye and 17 mm/minute in the left eye. The dog’s
`eyes had minimal corneal vascularization and minimal
`scarring.
`In this case, although the dog was treated initially
`with pilocarpine, pilocarpine alone is not known to
`cause such a drastic improvement in tear production.
`After treatment with cyclosporine, the dog improved
`from no tear flow in either eye to normal tear produc-
`tion in both eyes. The dog improved from blinding
`corneal inflammation to very mild corneal pigmentation
`in both eyes. Treatment with cyclosporine markedly
`increased tear production and allowed the dog to return
`to normal vision