(12) United States Patent
`Yanni et al.
`
`(54) METHOD OF INHIBITING CYTOKINE
`RELEASE FROM HUMAN OCULAR CELLS
`
`(75)
`
`Inventors: John M. Yanni, Burleson; Daniel A.
`Gamache; Lori K. Weimer, both of
`Arlington, all of TX (US)
`
`(73) Assignee: Alcon Laboratories, Inc., Fort Worth,
`TX (US)
`
`(*) Notice:
`
`Under 35 U.S.C. 154(b), the term of this
`patent shall be extended for 0 days.
`
`(21) Appl. No.: 09/333,454
`
`(22) Filed: (cid:9)
`
`Jun. 15, 1999
`
`Related U.S. Application Data
`(60) Provisional application No. 60/092,762, filed on Jul. 14,
`1998.
`Int. C1.7 (cid:9)
`(51)
`(52) U.S. Cl. (cid:9)
`(58) Field of Search
`
`A61K 31/335
`514/450
`514/450
`
`
`
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,871,865 (cid:9)
`4,923,892 (cid:9)
`5,116,863 (cid:9)
`5,641,805 (cid:9)
`
`10/1989 Lever, Jr. et al. (cid:9)
`5/1990 Lever, Jr. et al. (cid:9)
`5/1992 Oshima et al. (cid:9)
`6/1997 Yanni et al. (cid:9)
`
`
`
`
`
`
`549/354
`514/450
`514/450
`514/450
`
`FOREIGN PATENT DOCUMENTS
`
`0 048 023 A2
`0 214 779 Al
`0 235 796 A2
`
`3/1982 (EP) .
`3/1987 (EP) .
`9/1987 (EP) .
`
`OTHER PUBLICATIONS
`
`Yanni et al. (1), Ocul. Pharmacol. Ther., vol. 12, No. 4, pp.
`389-400, 1996.*
`Kamei et al, Biol. Pharm. Bull., vol. 18, No. 11, pp.
`1518-1521, Nov. 1995.*
`Kamei et al, Arzneimittelforschung, vol. 45, No. 9, pp.
`1008-1008, Sep. 1995.*
`Miki et al., "Histamine Enhanced the TNF—a—Induced
`Expression of E—Selectin and ICAM-1 on Vascular Endot-
`helial Cells," Cellular Immunology, vol. 171, pp. 285-288
`(1996).
`Church, "Is Inhibition of Mast Cell Mediator Release Rel-
`evant to the Clinical Activity of Anti—allergic Drugs?,"
`Agents and Actions, vol. 18, 3/4, pp. 288-293 (1986).
`Clegg et al., "Histamine Secretion from Human Skin Slices
`Induced by Anti—IgE and Artificial Secretagogues and the
`Effects of Sodium Cromoglycate and Salbutanol," Clin.
`Allergy, vol. 15, pp. 321-328 (1985).
`Hamilton et al., "Comparison of a New Antihistaminic and
`Antiallergic Compound KW 4679 with Terfenadine and
`Placebo on Skin and Nasal Provocation in Atopic Individu-
`als," Clinical and Experimental Allergy, vol. 24, pp.
`955-959 (1994).
`Ikeda et al., "Effects of Oxatomide and KW-4679 on
`Acetylcholine—Induced Responses in the Isolated Acini of
`Guinea Pig Nasal Glands," Int. Arch. Allergy Immunol., vol.
`106, pp. 157-162 (1995.
`
`1111111111111111111111111110I191111111111111111111111111
`
`(to) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`US 6,174,914 B1
`Jan. 16, 2001
`
`Irani et al., "Mast Cell Heterogeneity," Clinical and Experi-
`mental Allergy, vol. 19, pp. 143-155 (1989).
`Kamei et al., "Effects of Certain Antiallergic Drugs on
`Experimental Conjunctivitis in Guinea Pigs," Atarashii
`Ganka, vol. 11(4), p. 603-605 (1994) (abstract only).
`Kamei et al., "Effect of (Z)-11—[3—(Dimethylamino) propy-
`lidene]-6,11—clihydrodibenz[b,e]oxepin-2—acetic (cid:9)
`Acid
`Hydrochloride on Experimental Allergic Conjunctivitis and
`Rhinitis in Rats and Guinea Pigs," Arzneimittelforschung,
`vol. 45 (9), p. 1005-1008 (1995).
`Ohshima et al., "Synthesis and Antiallergic Activity of
`11—(Aminoalkylidene)-6,11,dihydrodibenz[b,e] (cid:9)
`oxepin
`Derivatives," J. (cid:9) Medicinal (cid:9) Chemistry, (cid:9) vol. (cid:9) 35(11), (cid:9) p.
`2074-2084 (1992).
`Pearce et al., "Effect of Disodium Cromoglycate on Antigen
`Evoked Histamine Release in Human Skin," Clinical Exp.
`Immunol., vol. 17, pp. 437-440 (1974).
`Sharif et al., "Characterization of the Ocular Antiallergic and
`Antihistaminic Effects of Olopatadine (AL-4943A), a Novel
`Drug for Treating Ocular Allergic Diseases," J. of Pharma-
`cology and Experimental Therapeutics, vol. 278(3), p.
`1252-1261 (1996).
`Sharif et al., "Olopatadine (AL-4943A): Pharmacological
`Profile of a Novel Anti—histaminic/Anti—allergic Drug for
`Use in Allergic Conjunctivitis," Investigative Ophthalmol-
`ogy & Visual Science, vol. 37(3), p. 1027 (1996) (abstract
`only).
`Siraganian, "An Automated Continuous Flow System for the
`Extraction and Fluorometric Analysis of Histamine," Anal.
`Biochem., vol. 57, pp. 383-394 (1974).
`Spitalny et al., "Olopatadine Ophthalmic Solution Decreases
`Itching and Redness Associated with Allergic Conjunctivi-
`tis," Investigative Ophthalmology & Visual Science, vol.
`37(3), p. 593 (1996) (abstract only).
`Yanni et al., "The In Vitro and In Vivo Ocular Pharmacology
`of Olopatadine (AL-4943A), An Effective Anti—allergic/
`Anti—histaminic Agent," Investigative Ophthalmology &
`Visual Science, vol. 37(3), p. 1028 (1996) (abstract only).
`Yoshida et al., "Role of NF—kB—Mediated Interleukin-8
`Expression in Intraocular Neovascularization," Investigative
`Ophthalmology & Visual Science, vol. 39(7), pp. 1097-1106
`(1998).
`Zhang et al., "Optically Active Analogues of Ebastine:
`Synthesis and Effect of Chirality on Their Antihistaminic
`and Antimuscarinic Activity," Chirality, vol. 6(8), p.
`631-641 (1994).
`
`(List continued on next page.)
`
`Primary Examiner—James H. Reamer
`(74) Attorney, Agent, or Firm—Patrick M. Ryan
`
`(57) (cid:9)
`
`ABSTRACT
`
`Ophthalmic formulations containing as an active ingredient
`11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid or a pharmaceutically acceptable salt
`thereof are useful for inhibiting cytokine release (e.g., IL-6
`and IL-8) from human ocular cells. Such formulations can
`be used to treat or prevent ocular neovascularization and
`non-allergic inflammatory disorders such as dry-eye,
`keratitis, blepharitis, uveitis and inflammation related to
`infection.
`
`14 Claims, No Drawings
`
`MYLAN Ex. 1004, Page 1
`
`

`
`US 6,174,914 B1
`Page 2
`
`OTHER PUBLICATIONS
`
`"The Lung," Scientific Foundations, Raven Press, Ltd., New
`York, Ch. 3.4.11 (1991).
`Cutarelli et al., "The Painful Eye External and Anteiror
`Segment Causes," Clinics in Geriatric Medicine, vol. 15 (1),
`pp. 103-112 (1999).
`
`Yanni et al., "Inhibition of Histamine—Induced Human Con-
`junctival Epithelial Cell Responses by Ocular Allergy
`Drugs," Arch. Ophthalmology, vol. 117, pp. 643-647
`(1999).
`
`* cited by examiner
`
`MYLAN Ex. 1004, Page 2
`
`

`
`1
`METHOD OF INHIBITING CYTOKINE
`RELEASE FROM HUMAN OCULAR CELLS
`
`US 6,174,914 B1
`
`This application claims priority from co-pending U.S.
`Provisional Patent Application Ser. No. 60/092,762, filed 5
`Jul. 14, 1998.
`
`15
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`The present invention relates to ophthalmic pharmaceu-
`10
`tical formulations. More particularly, the present invention
`relates to therapeutic and prophylactic use of 11-(3-
`dimethylamino-propylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid for treating and/or preventing cytokine
`release from human ocular cells and resulting ocular neovas-
`cularization or non-allergic inflammatory conditions.
`2. Description of the Related Art
`As taught in U.S. Pat. Nos. 4,871,865 and 4,923,892, both
`assigned to Burroughs Wellcome Co. ("the Burroughs
`Wellcome Patents"), certain carboxylic acid derivatives of 20
`doxepin, including 11-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepine-2-carboxylic acid and 11-(3-
`dimethylamino-propylidene)-6,11-dihydrodibenz[b,e]
`oxepine-2(E)-acrylic acid, have antihistaminic and
`antiasthmatic activity. These two patents classify the car-
`25
`boxylic acid derivatives of doxepin as mast cell stabilizers
`with antihistaminic action because they are believed to
`inhibit the release of autacoids (i.e., histamine, serotonin,
`and the like) from mast cells and to inhibit directly hista-
`mine's effects on target tissues. The Burroughs Wellcome 30
`Patents teach various pharmaceutical formulations contain-
`ing the carboxylic acid derivatives of doxepin; Example 8 (I)
`in both of the patents discloses an ophthalmic solution
`formulation.
`U.S. Pat. No. 5,116,863, assigned to Kyowa Hakko 35
`Kogyo Co., Ltd., ("the Kyowa patent"), teaches that acetic
`acid derivatives of doxepin, including Z-11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid, have anti-allergic and anti-
`inflammatory activity. The anti-inflammatory activity is 40
`attributable to prostaglandin biosynthesis inhibiting activity
`(see Col. 28, lines 51-57). The doxepin derivatives disclosed
`by the Kyowa patent are represented by Compound (I):
`
`X— (CH2) Z
`
`(I) (cid:9)
`
`45
`
`50
`
`Compounds where X represents =N—, =CH— or
`—CH2— are described as having strong antiallergic activity,
`whereas compounds where X represents =N— are 55
`described as having strong antiinflammatory activity (see
`Col. 24, lines 20-57). Thus, for anti-inflammatory
`applications, the Kyowa patent suggests doxepin derivatives
`of Compound (I) where X is =N—.
`The Kyowa patent demonstrates anti-allergic activity and 60
`anti-inflammatory activity in Wistar male rats. Medicament
`forms taught by the Kyowa patent for the acetic acid
`derivatives of doxepin include a wide range of acceptable
`carriers; however, only oral and injection administration
`forms are mentioned. In the treatment of allergic eye disease, 65
`such as allergic conjunctivitis, such administration methods
`require large doses of medicine.
`
`2
`U.S. Pat. No. 5,641,805 discloses topical ophthalmic
`formulations containing 11-(3-dimethylamino-
`propylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid
`for treating allergic eye diseases.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides a method for treating or
`preventing ophthalmic neovascularization and non-allergic
`inflammatory disorders involving cytokine release from
`human ocular cells. The method comprises inhibiting cytok-
`ine release from human ocular cells by administering to the
`eye an ophthalmic formulation which contains a therapeu-
`tically (cid:9)
`effective (cid:9)
`amount (cid:9)
`of (cid:9)
`1 1 - ( 3 -
`dim e thyl am inop r op ylide ne) -6 ,11 - dihy dr o dib enz[b ,e ]
`oxepin-2-acetic acid (referred to as "Compound A"
`hereinafter) or a pharmaceutically acceptable salt thereof.
`The formulation may contain the cis isomer of Compound A
`(Z-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz-
`[b,e]oxepin-2-acetic acid), the trans isomer of Compound A
`(E -11 -(3 -dimethylaminopropylidene)-6,11-dihydrodibenz
`[b,e]oxepin-2-acetic acid), or a combination of both the cis
`and the trans isomers of Compound A. Unless specified
`otherwise, "11-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz-[b,e]oxepin-2-acetic acid" or "Compound A"
`means the cis isomer, the trans isomer or a mixture of both.
`"Cis isomer" means the cis isomer substantially free of the
`trans isomer; "trans isomer" means the trans isomer sub-
`stantially free of the cis isomer. One isomer is "substantially
`free" of the other isomer if less than about two percent of the
`unwanted isomer is present.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Compound A is a known compound and both the cis and
`the trans isomers of Compound A can be obtained by the
`methods disclosed in U.S. Pat. No. 5,116,863, the entire
`contents of which are hereby incorporated by reference in
`the present specification.
`Examples of the pharmaceutically acceptable salts of
`Compound A include inorganic acid salts such as
`hydrochloride, hydrobromide, sulfate and phosphate;
`organic acid salts such as acetate, maleate, fumarate, tartrate
`and citrate; alkali metal salts such as sodium salt and
`potassium salt; alkaline earth metal salts such as magnesium
`salt and calcium salt; metal salts such as aluminum salt and
`zinc salt; and organic amine addition salts such as triethy-
`lamine addition salt (also known as tromethamine), mor-
`pholine addition salt and piperidine addition salt.
`Compound A may be administered to the eye in a variety
`of ways. The most preferred way is by means of conven-
`tional topical ophthalmic formulations, such as solutions,
`suspensions or gels. Alternatively, Compound A may be
`administered to the eye via injection or implant. Depending
`upon the type of formulation, conventional ingredients will
`be combined with Compound A. The preferred formulation
`for topical ophthalmic administration of Compound A is a
`solution administered as eye drops. The preferred form of
`Compound A in the ophthalmic formulations of the present
`invention is the cis isomer. A general method of preparing an
`eye drop formulation of the present invention is described
`below as a nonlimiting example.
`Compound A and an isotonic agent are added to sterilized
`purified water, and if required, a preservative, a buffering
`agent, a stabilizer, a viscous vehicle and the like are added
`to the solution and dissolved therein. The concentration of
`Compound A is 0.0001 to 5 w/v %, preferably 0.0001 to
`
`MYLAN Ex. 1004, Page 3
`
`

`
`US 6,174,914 B1
`
`3
`0.001 w/v %, and most preferably about 0.0005 w/v %,
`based on the sterilized purified water. After dissolution, the
`pH is adjusted with a pH controller to be within a range
`suitable for use as an ophthalmic medicine, preferably
`within the range of 4.5 to 8.
`Sodium chloride, glycerin, mannitol or the like may be
`used as the isotonic agent; p-hydroxybenzoic acid ester,
`benzalkonium chloride or the like as the preservative;
`sodium hydrogenphosphate, sodium dihydrogenphosphate,
`boric acid or the like as the buffering agent; sodium edetate
`or the like as the stabilizer; polyvinyl alcohol, polyvinyl
`pyrrolidone, polyacrylic acid or the like as the viscous
`vehicle; and sodium hydroxide, hydrochloric acid or the like
`as the pH controller.
`If required, other ophthalmic drugs such as epinephrine,
`naphazoline hydrochloride, berberine chloride, sodium
`azulenesulfonate, lysozyme chloride, glycyrrhizate and the
`like may be added.
`The eye drops produced by the above method typically
`need only be applied to the eyes a few times a day in an
`amount of one to several drops at a time, though in more
`severe cases the drops may be applied several times a day.
`A typical drop is about 30 /A.
`According to the method of the present invention, oph-
`thalmic formulations containing Compound A are used to
`inhibit pro-inflammatory cytokine secretion from human
`ocular cells, such as human conjunctival epithelial cells.
`This type of cytokine secretion (e.g., IL-6 and IL-8) can
`stimulate ocular neovascularization (see, for example,
`Yoshida et al., IOVS, 39:1097 (1998)) and other non-allergic
`inflammatory conditions, such as dry eye, keratitits,
`blepharitis, uveitis and inflammation related to infection, for
`example.
`Certain embodiments of the invention are illustrated in the
`following examples.
`
`EXAMPLE 1
`
`Preferred Topical Ophthalmic Solution Formulation
`
`Ingredient (cid:9)
`
`Concentration (W/V
`
`Compound A•HC1
`Dibasic Sodium Phosphate
`(Anhydrous), USP
`Sodium Chloride, USP
`Benzalkonium Chloride
`Sodium Hydroxide, NF
`Hydrochloric Acid, NF
`Purified Water (cid:9)
`
`0.111*
`0.5
`
`0.65
`0.01
`q.s. pH = 7.0
`q.s. pH = 7.0
`q.s. 100
`
`*0.111% Compound A•HC1 is equivalent to 0.1% Compound A
`
`EXAMPLE 2
`
`Topical Ophthalmic Gel Formulation
`
`Ingredient
`
`Concentration (W/V
`
`Compound A•HC1
`Carbopol 974 P
`Disodium EDTA
`Polysorbate 80
`Benzalkonium Chloride, Solution
`Sodium Hydroxide
`
`0.11*
`0.8
`0.01
`0.05
`0.01 + 5 xs
`q.s. pH 7.2
`
`4
`
`-continued
`
`Ingredient (cid:9)
`
`Hydrochloric acid (cid:9)
`Water for Injection (cid:9)
`
`Concentration (W/V
`
`q.s. pH 7.2
`q.s. 100
`
`*0.11% Compound A•HC1 is equivalent to 0.1% Compound A
`
`EXAMPLE 3
`
`5
`
`10
`
`30 (cid:9)
`
`Inhibition of Cytokine Release
`A. Human Conjunctival Epithelial Cell (HCE) Cultures.
`Methods detailing the preparation of primary epithelial
`15 cell cultures and cytokine release studies using these cells
`have been described. See Gamache, et al., "Secretion of
`proinflammatory cytokines by human conjunctival epithelial
`cells," Ocul Immunol Inflamm., 5:117-128 (1997). Briefly,
`cultures of human conjunctival epithelial cells were initiated
`20 from donor tissues obtained within eight hours post mortem
`by various eye banks. The tissues were enzymatically
`digested overnight. Epithelial cells were gently scraped from
`the tissue surface, dissociated into a single cell suspension,
`and cultured in keratinocyte growth medium (Clonetics®,
`25 San Diego, Calif.). Cells were used only through passage 6.
`Cultures were maintained in a preconfluent state to prevent
`differentiation. Cells were identified as epithelial by positive
`keratin staining.
`B. Cytokine Assays.
`Several compounds with histamine H1 antagonist activity
`were evaluated for their ability to inhibit secretion of cytok-
`ines (IL-6 and IL-8) from cultured human conjunctival
`epithelial cells in response to histamine stimulation. Cells
`were plated at 2x104 cells/well and cultured overnight at 5%
`35 CO2/37° C. The following day, fresh medium containing test
`compound was added directly to wells and the cells were
`incubated for 30 minutes prior to 24-hour stimulation with
`histamine (30 tiM). Three separate culture wells were used
`for each treatment group. At harvest, supernatants were
`40 collected, centrifuged at 200x g, and stored at —20° C.
`Samples were analyzed for IL-6 and IL-8 by ELISA (R&D
`Systems, Minneapolis, Minn.) as directed by the manufac-
`turer. The sensitivities of each ELISA are as follows: IL-6
`0.7 pg/ml and IL-8 3.0 pg/ml.
`45 C. Data Analysis
`The antagonist potency (IC„) was defined as the concen-
`tration of the drug required to produce 50% inhibition of the
`agonist-stimulated functional response. Data derived from
`the cytokine assays were calculated as mean and standard
`50 error (SEM) values which represent the variability among
`identically treated culture wells. The dose-dependent effect
`of pharmacological agents and IC„'s were determined by
`linear regression. Data are expressed as mean ±S.E.M. from
`3-5 independent experiments.
`55 D. Results.
`Exposure of HCE to 30 iM of histamine increased IL-6
`and IL-8 secretion 1.59±0.19 and 1.80±0.28 fold above
`basal levels, respectively. (Basal levels of the cytokines were
`153±42 pg/ml, n=4, for IL-6 and 197±48 pg/ml, n=6, for
`60 IL-8.)
`Treatment of HCE with drugs possessing anti-histaminic
`activity and available for topical ocular administration prior
`to histamine exposure resulted in concentration-dependent
`inhibition of IL-6 secretion and IL-8 secretion. The results
`65 are shown below in Table 1.
`The potency of emedastine in intact cells is consistent
`with its activity determined in receptor binding assays using
`
`MYLAN Ex. 1004, Page 4
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`US 6,174,914 B1
`
`5
`tissue homogenates. Levocabastine also inhibited the IL-6,
`and IL-8 secretion at a level consistent with its H1-receptor
`binding affinity Antazoline and pheniramine, two first gen-
`eration topical ocular anti-histamine compounds, were dra-
`matically less potent inhibitors of IL-6 and IL-8 secretion
`than predicted from their histamine H1-receptor binding
`affinities (20-140-fold). Olopatadine, however, was more
`potent than predicted from its published histamine
`H1-receptor binding affinity (36 nM). Olopatadine, antazo-
`line and pheniramine exhibit similar H1 binding affinities
`(32-39 nM). Yet, olopatadine was approximately 10-fold
`more potent as an inhibitor of cytokine secretion (IC„'s of
`5.5 nM and 1.7 nM for IL-6 and IL-8 secretion, respectively)
`than predicted from binding data. These results indicate that,
`unlike the other compounds tested, olopatadine's ability to
`inhibit cytokine secretion is attributable to something more
`than H1-receptor binding affinity.
`
`TABLE 1
`
`Histamine H1 Antagonists: Inhibition of IL-6 and IL-8 Secretion in
`Human Conjunctival Epithelial Cells and H, Receptor Binding Affinities
`
`H1 Antagonist
`
`Emedastinea
`Olopatadineb
`Levocabastinec
`Antazolined
`Pheniraminee
`
`IL-6
`IC, (nM)
`
`IL-8
`IC50 (nM)
`
`H1 Binding
`(nM)
`
`2.5
`5.5
`25.1
`1014
`4826
`
`4.0
`1.7
`11.9
`652
`1216
`
`1.22*
`36.0 §
`52.6 *
`38.4 *
`33.9 (cid:9) *
`
`a1H-Benzimidazole,1-(2-ethoxyethy0-2-(hexahydro-4-methy1-1H-1,4-
`diazepin-l-y1),(E)-2-butenedioate (1:2).
`bZ-11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenz
`e( ) trans 1 [cis 4 Cyano 4 (p fluorophenyOcyclohexyll-3-methyl-4-
`phenylisonipecotic acid monohydrochloride.
`d4,5-Dihydro-N-phenyl-N-(phenylmethy0-1H-imidazole-2-methanamine.
`eN,N-Dimethyl-y-phenyl-2-pyridine-propanamine.
`* Sharif et al., J Ocul Pharmacol., 10:653-664 (1994)
`§ Yanni et al., Ann Allergy Asthma Immunol., 79:541-545 (1997)
`
`6
`4. The method of claim 3 wherein the amount of 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is about 0.0005% (w/v).
`5. The method of claim 1 wherein the 11-(3-
`5 dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic (cid:9)
`acid (cid:9)
`is (cid:9)
`(Z)-11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid, substantially free of (E)-11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid.
`6. The method of claim 5 wherein the composition is a
`topically administrable solution and the amount of (Z)-11-
`(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`15 oxepin-2-acetic acid is from about 0.0001 to about 5%
`(w/v).
`7. The method of claim 6 wherein the amount of (Z)-11-
`(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is from about 0.0001 to about 0.001%
`
`10
`
`20
`
`30
`
`35
`
`(w/v ). 8.The method of claim 7 wherein the amount of (Z)-11-
`(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is 0.0005% (w/v).
`9. The method of claim 1 wherein the 11-(3-
`25 dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic (cid:9)
`acid
`is (cid:9)
`(E)-11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid, substantially free of (Z)-11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid.
`10. The method of claim 9 wherein the composition is a
`topically administrable composition and the amount of (E)-
`11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is from about 0.0001 to about 5%
`(w/v).
`11. The method of claim 10 wherein the amount of
`(E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz
`[b,e]oxepin-2-acetic acid is from about 0.0001 to about
`0.001% (w/v).
`12. The method of claim 11 wherein the amount of
`(E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz
`[b,e]oxepin-2-acetic acid is about 0.0005% (w/v).
`13. The method of claim 1 wherein the non-allergic
`ophthalmic inflammatory disorder is selected from the group
`consisting of dry eye, keratitits, blepharitis, uveitis and
`inflammation related to infection.
`14. The method of claim 1 wherein the ocular neovascu-
`larization and non-allergic ophthalmic inflammatory disor-
`ders involve cytokine release from human conjunctival
`epithelial cells.
`
`What is claimed is:
`1. A method of treating or preventing ocular neovascu-
`larization and non-allergic ophthalmic inflammatory disor-
`ders involving cytokine release from human ocular cells 40
`comprising the step of administering to the eye a composi-
`tion comprising a therapeutically-effective amount of 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid or a pharmaceutically acceptable salt
`thereof.
`2. The method of claim 1 wherein the composition is a
`topically administrable solution and the amount of 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is from about 0.0001 w/v.% to about
`5% (w/v).
`3. The method of claim 2 wherein the amount of 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is from about 0.0001 to about 0.001%
`(w/v).
`
`45
`
`50
`
`MYLAN Ex. 1004, Page 5