United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,641,805
`
`Hayakawa et al.
`
`[45] Date of Patent:
`
`Jun. 24, 1997
`
`US005641805A
`
`[54] TOPICAL OPHTHALMIC FORMULATIONS
`FOR TREATING ALLERGIC EYE DISEASES
`
`Inventors: Eiji Hayakawa, Susono; Masashi
`Nakakura. Shizuoka-ken, both of
`Japan; Stella M. Robertson, Arlington;
`John Michael Yanni, Burleson, both of
`Tex.
`
`Assignees: Alcon Laboratories, Inc., Fort Worth,
`Tex.; Kyowa Hakko Kogyo Co. Ltd.,
`Tokyo, Japan
`
`Appl. No.: 469,729
`
`Filed:
`
`Jun. 6, 1995
`
`Int. Cl.5 ................................................... A61K 31/335
`US. Cl.
`............................................................ .. S14/450
`Field of Search ............................................... 514/450
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`...................... 549/354
`10/1989 Lever, Jr.et al.
`4,871,865
`.
`S14/450
`5/1990 Lever, Jr. et al.
`4,923,892
`......................... 514/450
`5/1992 Oshima et al.
`5,116,863
`FOREIGN PATENT DOCUMENTS
`
`0048(Y23A2
`02l4779Al
`0235796A2
`
`3/1982 European Pat. Olf. .
`3/1987 European Pat. Olf. .
`9/1987 European Pat. Olf. .
`OTHER PUBLICATIONS
`
`Kamei et al., “Etfccts of Certain Antiallergic Drugs on
`Experimental Conjunctivitis in Guinea Pigs,” Atarashi
`Ganka, vol. 11(4), pp. 603-605 (1994) (abstract only).
`Kamei et al., “Etfect of (Z)-11—[3-(Dimethylamino) propy-
`lidene]—6,11-dil1ydrodibenz[b,e]oxepin—2—acetic
`Acid
`Hydrochloride on Experimental Allergic Conjunctivitis and
`Rhinitis in Rats and Guinea Pigs,” Arzneirnittelforschung.
`vol. 45(9),. PP- 1005-1008 (1985).
`Ohsima et al., “Synthesis and Antiallergic Activity of
`11—(Arninoalkylidene)—6, ll ,dihydrodibenz[b,e]oxepin
`Derivatives,” J. Medicinal Chemistry, vol. 35(11), pp.
`2074-1084 (1992).
`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 Phamza-
`cology and Experimental Therapeutics, vol. 278(3), pp.
`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).
`
`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 Elfeclive Anti—al1ergic/
`Antihistamlinic Agent,” Investigative Ophthalmology &
`Visual Science, vol. 37(3), p. 1028 (1996) (abstract only).
`Zhang et al., “Optically Active Analogues of Ebastine:
`Synthesis and Elfect of Chirality on Their Antihistaminic
`and Antimuscarinic Activity," Chirality, Vol. 6(8), pp.
`631-641 (1994).
`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).
`Irani et al., “Mast Cell Heterogeneity," Clinical and Experi-
`mental Allergy, vol. 19, pp. 143-155 (1989).
`Pearce et al., “Effect Disodium Cromoglycate on Antigen
`Evoked Histamine Release in Human Skin,” Clinical Exp.
`Immunol.,vol. 17, pp. 437-440 (1974).
`Siraganian, “An Automated Continuous Flow System for the
`Extraction and Fluorometric Analysis of Histamine,” Anal.
`Biochem, vol. 57, pp. 383-394 (1974).
`‘The Lung,” Scientific Foundations, Raven Press, Ltd., New
`York, Ch. 3.4.11 (1991), Schwartz, pp. 601-615.
`Kamei et al. ‘Effect of Certain Antirallergic Drugs on
`Experimental Conjunctivitis in Guinea Pigs”, Atarashii
`Ganka 11(4) pp. 603-605 1994 (month unavailable).
`
`Primary Examiner-Jeffrey C. Mullis
`Attomey, Agent, or Firm—Patrick M. Ryan
`
`[57]
`
`ABSTRACT
`
`Topical ophthalmic formulations of the invention contain as
`an active ingredient 11-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepin—2—acetic acid or a pharmaceuti-
`cally acceptable salt thereof. The formulations are useful for
`treating allergic eye diseases such as allergic conjunctivitis,
`vernal conjunctivitis, vernalkeratoconjunctivitis, and giant
`papillary conjunctivitis.
`
`12 Claims, No Drawings
`
`APOTEX EX1008
`
`Page 1
`
`

`
`5,641,805
`
`1
`TOPICAL OPHTHALMIC FORMULATIONS
`FOR TREATING ALLERGIC EYE DISEASES
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`
`The present invention relates to topical ophthalmic for-
`mulations used for treating allergic eye diseases, such as
`allergic conjunctivitis, vernal conjunctivitis, vernal
`keratoconjunctivitis, and giant papillary conjunctivitis.
`More particularly, the present invention relates to therapeu-
`tic and prophylactic topical use of 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid for treating and/or preventing allergic
`eye diseases.
`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
`doxepin, including 11-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepine-2-carboxylic acid and 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepine-2(E)-acrylic acid, have antihistamine and
`antiasthmatic activity. These two patents classify the car-
`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
`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.
`
`Although both of the Burroughs Wellcome Patents claim
`that the variety of pharmaceutical formulations disclosed are
`etfective both for veterinary and for human medical use,
`neither patent contains an example demonstrating that the
`carboxylic acid derivatives of doxepin have activity in
`humans. Example 7 in the Burroughs Wellcome Patents
`demonstrates antihistamine activity in male guinea pigs and
`Example G demonstrates anaphylactoid activity in Wistar
`rats.
`
`It is now well established, however, that the types of mast
`cells which exist in rodents are dilferent from those in
`humans. See, for example, THE LUNG: Scientific
`Foundations, Raven Press, Ltd, New York, Ch. 3.4.11
`(1991). Moreover, mast cell populations exist within the
`same species that differ in phenotype, biochemical
`properties, functional and pharmacological responses and
`ontogeny. These recognized differences in mast cells both
`between and within species are referred to as mast cell
`heterogeneity. See for example, Irani et al., “Mast Cell
`Heterogeneity,” Clinical and Experimental Allergy, Vol. 19,
`pp. 143-155 (1989). Because different mast cells exhibit
`ditferent responses to pharmacological agents,
`it is not
`obvious that compounds claimed to be anti-allergic (“mast
`cell stabilizers”) will have clinical utility in specific mast
`cell populations. The assumption that mast cells are a
`homogeneous population and that therefore the effects of
`anti-allergic drugs observed in experiments in rat mast cells
`would be predictive of those in human cells is known to be
`incorrect. Church, “Is Inhibition of Mast Cell Mediator
`Release Relevant to the Clinical Activity of Anti-Allergic
`Drugs?,” Agents and Actions, Vol. 18, 3/4, 288-293, at 291
`(1986).
`Examples exist in the art in which mast cell stabilizing
`drugs inhibit only select populations of mast cells. Disodium
`
`10
`
`20
`
`25
`
`30
`
`45
`
`50
`
`2
`
`cromoglycate is an anti-allergic drug whose local effects are
`believed to be due to inhibition of mast cell degranulation
`(Church, Agents and Actions, at 288). This drug was shown
`to inhibit rodent mast cell degranulation. In human trials,
`100 pM of the drug inhibited mast cells obtained from
`bronchoalveolar lavage fluid. In dispersed human lung mast
`cell preparations, 1000 pM of the drug was required to
`inhibit only 25% to 33% of histamine release. Finally,
`histamine release from human skin mast cells was not
`
`inhibited at all by disodium cromoglycate. Pearce et al.,
`“Effect of Disodium Cromoglycate on Antigen Evoked
`Histamine Release in Human Skin,” Clinical Exp. Immunol,
`Vol. 17, 437-440 (1974); and Clegg et al., “Histamine
`Secretion from Human Skin Slices Induced by Anti-IgE and
`Artificial Secretagogues and the Effects of Sodium Cro-
`moglycate and Salbutanol,” Clin. Allergy, Vol. 15, 321-328
`(1985). These data clearly indicate that classification of a
`drug as an anti-allergic does not predict that the drug possess
`inhibitory eifects on all mast cell populations.
`Topical ophthalmic formulations which contain drugs
`having conjunctival mast cell activity may only need to be
`applied once every 12-24 hours instead of once every 2-4
`hours. One disadvantage to the ophthalmic use of reported
`anti-allergic drugs which in fact have no human conjunctival
`mast cell stabilizing activity is an increased dosage fre-
`quency. Because the effectiveness of ophthalmic formula-
`tions containing drugs which do not have conjunctival mast
`cell activity stems primarily from a placebo eifect, more
`frequent doses are typically required than for drugs which do
`exhibit conjunctival mast cell activity.
`U.S. Pat. No. 5,116,863, assigned to Kyowa Hakko
`Kogyo Co., Ltd., (“the Kyowa patent”), teaches that acetic
`acid derivatives of doxepin and, in particular, the cis form of
`the compound having the formula
`
`I
`
`CI-l2CHzN(Cl-I3);
`
`I
`
`O
`
`I
`
`CH-2COOH
`
`(i.e., Z-11-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepin-2-acetic acid), have anti-allergic
`and anti-inflammatory activity.
`The Kyowa patent demonstrates anti-allergic activity and
`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 flie treatment of allergic eye disease,
`such as allergic conjunctivitis, such administration methods
`require large doses of medicine.
`What is needed are topically administrable drug com-
`pounds which have demonstrated stabilizing activity on
`mast cells obtained from human conjunctiva. the target cells
`for treating allergic eye diseases. What is also needed are
`local administration methods for the treatment of allergic
`eye disease.
`
`SUMNIARY OF THE INVENTION
`
`65
`
`The present invention provides a method for treating an
`allergic eye disease characterized by administering to the
`eye a topical ophthalmic formulation which contains a
`therapeutically effective amount of 11-(3-
`
`Page 2
`
`Page 2
`
`

`
`5,641,805
`
`3
`-6,11-dihydrodibenz[b,e]
`dimethylaminopropylidene)
`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. and unless specified
`otherwise,“ 1 1-(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
`substantially free of the cis isomer. One isomer is “substan-
`tially free” of the other isomer if less than about two percent
`of the unwanted isomer is present.
`CompoundA has human conjunctival mast cell stabilizing
`activity, and may be applied as infrequently as once or twice
`a day in some cases. In addition to its mast cell stabilizing
`activity, Compound A also possesses significant antihista-
`minic activity. Thus, in addition to a prophylactic effect,
`Compound A will also have a therapeutic effect.
`
`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 suchas aluminum salt and
`zinc salt; and organic amine addition salts such as t:riethy-
`lamine addition salt (also known as tromethamine), mor-
`pholine addition salt and piperidine addition salt.
`The inhibitory effects of reported anti-allergic, mast cell
`stabilizing drugs on mast cells obtained from human con-
`junctiva (the target cells for topical ophthalmic drug prepa-
`rations claimed useful in treating allergic conjunctivitis)
`were tested according to the following experimental method.
`Human conjunctival
`tissues obtained from organltissue
`donors were weighed and transferred to pe1:ri dishes con-
`taining RPMI 1640 culture medium supplemented with heat
`inactivated fetal bovine serum (20%, v/v), Lglutamine (2
`mM). penicillin (100 units/rnl), streptomycin (100 pg/ml).
`amphotericin B (2.5 pg/ml) and HEPES (10 mM) and
`equilibrated overnight at 37° C. (5% CO2).
`Post equilibration. tissues were placed in 'I‘yrode’s buffer
`(in mM: 137 NaCl, 2.7 KC1. 0.35 Na H2PO4, 1.8 CaCl2. 0.98
`MgCl2. 11.9 Na HCO3, 5.5 glucose) containing 0.1% gelatin
`(TGCM) and incubated with 200 U each of collagenase
`(Type IV) and hyaluronidase (Type I-S) per gram of tissue
`for 30 minutes at 37° C. Following enzyme digestion. tissues
`were washed with an equal volume of TGCM over Nitex®
`filter cloth (Tetko, Briarclifi" Manor. N.Y.). Intact tissues
`were placed in TGCM for further enzymatic digestions.
`The flitrate obtained from each digestion was centrifuged
`(825 g. 7 minutes) and pelleted cells were resuspended in
`calcium/magnesium free Tyrode’s bufier ('I‘G). Pooled cells
`from all digestions were centrifuged (825 g. 30 minutes)
`
`5
`
`10
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`
`over a 1.058 g/L Percoll® cushion. Mast cell enriched cell
`pellets were resuspended and washed in TG buffer. Viability
`and number of mast cells were determined by vital dye
`exclusion and toluidine blue 0 staining of the harvested cell
`suspensions. Mast cell containing preparations were placed
`in supplemented RPMI 1640 culture medium and allowed to
`equilibrate at 37° C. prior to challenge with anti-human IgE
`(goat derived IgG antibody).
`Cell suspensions containing 5000 mast cells were added
`to TGCM containing tubes and challenged with anti-human
`IgE. The final volume of each reaction tube was 1.0 mL.
`Tubes were incubated at 37° C. for 15 minutes post chal-
`lenge. The release reaction was terminated by centrifugation
`(500 g, 7 minutes). Supernatants were collected and stored
`(—20° C.) until mediator analyses.
`Initially, supernatants were analyzed for histamine con-
`tent by both the automated fluorimetric method described by
`Siraganian. “An Automated Continuous Flow System for the
`Extraction and Fluorometric Analysis of Histamine,” Anal.
`Biochem., Vol. 57, 383-94 (1974), and a commercially
`available radioimmunoassay (RIA) system (AMAC, Inc.,
`Westbrook, Me.). Results from these assays were positively
`correlated (r-—-0.999): therefore. the remainder of histamine
`analyses were performed by RIA.
`Each experiment included an anti-human IgE (plus
`vehicle) positive release control, a spontaneous/vehicle
`release and a total histamine release control. Total histamine
`release was determined by treatment with Triton X-100®
`(0.1%). The experiments also included a non-specific goat
`IgG control. Test compounds are administered to the mast
`cell cultures either 1 or 15 minutes before stimulation with
`anti-human IgE. Inhibition of histamine release resulting
`from challenge of drug treated mast cells was determined by
`direct comparison with histamine release from vehicle
`treated, anti-IgE challenged mast cells using Dunnett’ s t-test
`(Dunnett, “A multiple comparison procedure for comparing
`treatments with a control, ” J. Amer. Stat Assac.. Vol. 50,
`1096-1121 (1955)). The results are reported in Table 1.
`below.
`
`As Table 1 clearly shows, the anti-allergic drugs disodium
`cromoglycate and nedocromil failed to significantly inhibit
`human conjunctival mast cell degranulation. In contrast,
`Compound A (cis isomer) produced concentration-
`dependent inhibition of mast cell degranulation.
`
`TABLE 1
`
`Compound Efiect on Histamine Release from Human
`Conjunctival Tissue Mast Cells upo_n anti-Hinnan Igg Challenge.
`Treatment
`Compound
`Dose (pM)
`(min)
`Inhibition (%)
`
`
`Cromolyn sodium
`
`Cromolyn sodium
`
`Nedocromil sodium
`
`1000
`300
`100
`30
`10
`1000
`300
`100
`30
`10
`1000
`300
`100
`30
`10
`3
`1
`
`15
`15
`15
`15
`15
`1
`1
`1
`1
`1
`15
`15
`15
`15
`15
`15
`15
`
`—-15.4
`—6.9
`-1.2
`1.8
`10.6
`-9.4
`-1.8
`1.2
`0.1
`-0.9
`7.2
`11.3
`28.2*
`15.2
`9.2
`13.2
`10.7
`
`Page 3
`
`Page 3
`
`

`
`Compound Efiect on Histamine Release from Human
`Conjunctival Tissue Mast Cells En anti-Hurnan IgE Challegge.
`Treatment
`(min)
`15
`15
`l
`1
`1
`1
`1
`1
`1
`1
`1
`15
`15
`15
`15
`15
`15
`
`Compound
`
`Nedocromil sod.ium
`
`Compound A
`
`Dose (pM)
`0.3
`0.1
`1000
`300
`100
`30
`10
`3
`1
`0.3
`0.1
`2000
`1000
`600
`300
`100
`30
`
`Inhibition (%)
`3.7
`8.7
`—l.1
`4.0
`6.7
`-0.9
`—6.5
`0.8
`4.8
`8.8
`17.4
`92.6*
`66.7*
`47.5*
`29.6*
`13.0
`-3.9
`
`*p < 0.05, Dunnett’s t-test
`
`Dunnett’s t-test, is a statistical test which compares mul-
`tiple treatment groups with one control group. In the assay
`described above, histamine released from drug treated mast
`cells are compared to histamine released from the anti-
`human IgE plus vehicle treated mast cells which serve as the
`positive control. Statistically significant inhibition is deter-
`mined using this procedure. The probability level of 0.05 is
`accepted as the level of significance in biomedical research.
`Data indicated as significant have a low probability (0.05) of
`occurring by chance, indicating that the inhibition observed
`is an effect of the drug treatment.
`The effects of the cis and trans isomers of Compound A
`on histamine release from human conjunctival tissue mast
`cells upon anti-human IgE challenge are compared in Table
`2. The same experimental method used in Table 1 was used
`in Table 2. The results in Table 2 indicate that there is no
`
`statistically significant ditference between the conjunctival
`mast cell activity of the two isomers at the indicated dose
`level.
`
`TABLE 2
`
`Isomeric Effect of Compound A on In-Vitro Histamine Release
`from I-Imnan Conjtmctival Tissue Mast Cells upon anti-Human
`IgE Challenge.
`Treatment
`(min)
`
`Compound
`
`Dose (nM)
`
`Inhibition (%)
`
`Compound A (cis)
`Compound A (trans)
`
`500
`500
`
`15
`15
`
`29.7*$
`262*;
`
`*p < 0.05, Dunnett’s t-test compared to anti-IgE positive control.
`$not significantly difl"erent; p > 0.05 Studentized Range comparison of
`indicated doses
`
`55
`
`The topical activity of Compound A was tested in a
`passive anaphylaxis assay performed in rat conjunctiva. This
`assay indicates whether a topically applied compound effec-
`tively prevents or decreases the local allergic response in the
`conjunctiva. This assay allows an assessment of bioavail-
`ability following topical dosing. Briefly, male Sprague Daw-
`ley rats (6/group) were passively sensitized by subconjunc—
`tival injection of a rat serum containing IgE specific for
`ovalbumin (OA). 'I‘wenty-four hours post sensitization, test
`compound prepared in saline (0.9% NaCl) or saline vehicle
`was applied topically onto the sensitized eye. Twenty (20)
`
`5,641,805
`
`5
`
`TABLE 1-continued
`
`5
`
`10
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`6
`minutes after dosing, rats were challenged intravenously via
`the lateral tail vein with 1.0 ml of a solution containing 0A
`(1.0 mg/rnl) and Evans Blue dye (2.5 mg/ml). Thirty (30)
`minutes post antigen challenge, animals were killed, skin
`was reflected, and the size of the resulting wheal and the
`intensity of the extravasated dye were determined. The
`Wheal area multiplied by the dye intensity produced the
`individual response score. Scores for each group of animals
`were compared with the scores of the saline treated group
`using Dunnett’s test and are listed in Table 3.
`
`TABLE 3
`
`In-Vivo Efliects of Compotmd A on Passive Conjunctival
`Anaphylaxis in Rats
`
`Compound
`NaCl
`Compound B
`Compound C
`Compound A
`(cis)
`Compound A
`(113115)
`
`Conc. (%, wlv)
`0.9
`0.1
`0.1
`0.1
`
`Permeability
`Score (X i S.D.)
`239 i 22
`133 i 53*
`139 i 36*
`55 i 56*@
`
`% Change
`—
`-55
`-53
`-86
`
`0.1
`
`43 i 34*@
`
`-81
`
`*p < 0.01, Dunnett’s test
`@p < 0.05, Studentized Range Comparison Procedure, significantly different
`from Compounds B and C.
`Compound B = (Z)-11-(3-Dimethylaminopropylidene)-6,ll-dihydrodibenz
`[b,e]oxepin-2-carboxylic acid
`”
`Compound C = (Z)-11-(3-Dimethylaininopropylidene)-6,11-dihydrodibenz
`[b,e]oxepin-2-acrylic acid
`
`CompoundA may be administered to the eye by means of
`conventional
`topical ophthalmic formulations, such as
`solutions, suspensions or gels. The preferred formulation for
`topical ophthalmic administration of Compound A is a
`solution. The solution is administered as eye drops. The
`preferred form of Compound A in the topical ophthalmic
`formulations of the present invention is the cis isomer. A
`general method of preparing the eye drops of the present
`invention is described below.
`
`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
`CompoundA is 0.0001 to 5 w/v %, preferably 0.001 to 0.2
`W/V %, and most preferably about 0.1 w/v %, based on the
`sterilized purified water. After dissolution, the pH is adjusted
`with a pH controller to be within a range which allows the
`use as an ophthalmologic medicine, preferably within the
`range of 4.5 to 8.
`Sodium chloride, glycerin 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 buifering 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 ophthalmologic chemicals such as
`epinephrine, naphazoline hydrochloride, berberine chloride,
`sodium azulenesulfonate, lysozyrne 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 ul.
`
`Page 4
`
`Page 4
`
`

`
`5,641,805
`
`7
`Certain embodiments of the invention are illustrated in the
`following examples.
`
`Example 1: Preferred Topical Ophthalmic Solution Formulation
`
`Ingredient
`
`Concentration (W/V %)
`
`Compound A.l-{Cl
`Dibasic Sodium Phosphate
`(Anhydrous), USP
`0.65
`Sodium Chloride, USP
`0.01
`Benzalkonium Chloride
`q.s. pH = 7.0
`Sodium Hydroxide, NF
`q.s. pH = 7.0
`Hydrochloric Acid, NF
`
`Purified Water q.s. 100
`
`0.1l1*
`0.5
`
`10
`
`*0.111% Compound Al-{Cl is equivalent to 0.1% Compotmd A
`Example 2: Topical Opthalmic Gel Formulation
`
`
`
` Ingredient Concentration (W/V %)
`
`0.11*
`Compound A.HCl
`0.8
`Carbopol 974 P
`0.01
`Disodium EDTIA
`0.05
`Polysorbate 80
`0.01 + 5 xs
`Benzalkonium Chloride, Solution
`q.s. pH 7.2
`Sodium Hydroxide
`q.s. pH 7.2
`Hydrochloric acid
`
`Water for Injection q.s. 100
`
`*0.ll% Compound ABC] is equivalent to 0.1% Compound A
`
`What is claimed is:
`1. A method for treating allergic eye diseases in humans
`comprising stabilizing conjuctival mast cells by topically
`administering to the eye a composition comprising a thera-
`peutically
`efiective
`amount
`of
`1l-(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
`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 0.001 to about 0.2%
`(w/v).
`
`20
`
`25
`
`30
`
`35
`
`40
`
`8
`4. The method of claim 3 wherein the amount of 11-(3-
`dimethylaminopropy1idene)—6.11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is about 0.1% (w/v).
`5. The method of claim 1 wherein the 11-(3-
`dimethylaminopropylidene)-6,11—dihydrodibenz[b,e]
`oxepin-2-acetic
`acid
`is
`(Z)-11-(3-
`dimethy1aminopropylidene)-6.11-dihydrodibenz[b,e]
`oxepin—2-acetic acid, substantially free of (E)-l1-(3-
`dimethylaminopropylidene)-6,11—dihydrodibenz[b.e]
`oxepin-2-acetic acid.
`6. The method of claim 5 wherein the amount of (Z)-11-
`(3-dimethylaminopropylidene)-6.11—dihyd.rodibenz[b.e]
`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 0.001 to about 0.2%
`(w/v).
`8. The method of claim 7 wherein the amount of (Z)-11-
`(3-dimethylaminopropylidene)-6,ll-dihyd.rodibenz[b,e]
`oxepin-2-acetic acid is 0.1% (w/v).
`9. The method of claim 1 wherein the l1-(3-
`dimethylaminopropylidene)-6,11—dihydrodibenz[b.e]
`oxepin-2—acetic
`acid
`is
`(E)-11-(3-
`dimethylaminopropylidene) -6,11 -dihydrodibenz[b,e]
`oxepin-2—acetic acid, substantially free of (Z)-11-(3-
`dimethylaminopropylidene)-6, 1 1-dihydrodibenz[b,e]
`oxepin-2-acetic acid.
`10. The method of claim 9 wherein the amount of
`
`(E)-11-(3-dimethylaminopropylidene)-6,ll-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-dimethylarninopropylidene)-6,11-dihydredibenz
`[b,e]oxepin-2-acetic acid is from about 0.001 to about 0.2%
`(w/v).
`12. The method of claim 11 wherein the amount of
`(E)-11-(3-dimethy1aminopropylidene)—6,11-dihydrodibenz
`[b,e]oxepin-2-acetic acid is about 0.1% (W/V).
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Page 5
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT N0.
`
`DATED
`
`lNVENTOR(S)
`
`:
`
`-'
`
`2
`
`5,641,805
`
`June 24, 1997
`
`Hayakavia et a1.
`
`It is certified that error appears in the abnve-identified patent and that said Letters Patent is hereby
`conemedasshownbdow:
`
`On the title page:
`
`[19]”, “Hayakawa et al.'’ should read “Yanni et al."
`
`under “United States Patent
`
`Item
`
`[75]
`
`Inventors:
`
`John Michael Yanni, Burleson;
`Stella M. Robertson, Arlington, both of Texas;
`Eiji Hayakawa, Susono;
`Masashi Nakakura, Shizuoka-ken, both of Japan
`
`Arrest:
`
`Signed and Sealed this
`
`Eighteenth Day of August, 1998
`
` 4 ,8
`
`I
`
`"
`
`BRUCE LEHMAN
`
`Arresting Officer
`
`Commissioner nf Paremx and Trademarks
`
`Page 6