(19)
`
`(12)
`
`Europäisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`*EP000799044B1*
`EP 0 799 044 B1
`
`(11)
`
`EUROPEAN PATENT SPECIFICATION
`
`(45) Date of publication and mention
`of the grant of the patent:
`24.07.2002 Bulletin 2002/30
`
`(21) Application number: 96915500.1
`
`(22) Date of filing: 03.05.1996
`
`(51)
`
`Int Cl.7: A61K 31/45, A61P 27/14
`
`(86)
`
`International application number:
`PCT/US96/06289
`
`(87)
`
`International publication number:
`WO 96/39147 (12.12.1996 Gazette 1996/54)
`
`(54) TOPICAL OPHTHALMIC FORMULATIONS CONTAINING OLOPATADINE FOR TREATING
`ALLERGIC EYE DISEASES
`
`FORMULIERUNG ZUR TOPISCHEN ANWENDUNG AM AUGE, DIE OLOPATADINE ENTHALTEN,
`ZUR BEHANDLUNG VON ALLERGISCHEN AUGENERKRANKUNGEN
`
`COMPOSITIONS OPHTALMIQUES TOPIQUES CONTENANT OLOPATADINE DESTINEES AU
`TRAITEMENT D’AFFECTIONS ALLERGIQUES DES YEUX
`
`(84) Designated Contracting States:
`AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC
`NL PT SE
`
`(30) Priority: 06.06.1995 US 469729
`
`(43) Date of publication of application:
`08.10.1997 Bulletin 1997/41
`
`(73) Proprietors:
`• ALCON LABORATORIES, INC.
`Fort Worth Texas 76134-2099 (US)
`• KYOWA HAKKO KOGYO CO., Ltd.
`Chiyoda-ku, Tokyo 100 (JP)
`
`Inventors:
`(72)
`• YANNI, John, Michael
`Burleson, TX 76028 (US)
`• ROBERTSON, Stella, M.
`Arlington, TX 76016 (US)
`• HAYAKAWA, Eiji
`Susono-shi, Shizuoka-ken (JP)
`• NAKAKURA, Masashi
`Sunto gun, Shizuoka-ken (JP)
`
`(74) Representative: Keller, Günter, Dr. et al
`Lederer & Keller
`Patentanwälte
`Prinzregentenstrasse 16
`80538 München (DE)
`
`(56) References cited:
`EP-A- 0 048 023
`EP-A- 0 235 796
`
`EP-A- 0 214 779
`
`• JOURNAL OF PHARMACOLOGY AND
`EXPERIMENTAL THERAPEUTICS, 278 (3). 1996.
`1252-1261., XP000613049 SHARIF N A ET AL:
`"Characterization of the ocular antiallergic and
`antihistaminic effects of olopatadine
`(AL-4943A), a novel drug for treating ocular
`allergic diseases"
`• ARZNEIMITTELFORSCHUNG, SEP 1995, 45 (9)
`P1005-8, GERMANY, XP000615221 KAMEI C ET
`AL: "Effect of (Z)-11-[3-(dimethylamino)
`propylidene]-6,11-dihydrodibenz[b,e
`]oxepin-2-acetic acid hydrochloride on
`experimental allergic conjunctivitis and rhinitis
`in rats and guinea pigs."
`• INVESTIGATIVE OPHTHALMOLOGY & VISUAL
`SCIENCE, 37 (3). 1996. S1027., XP000613434
`SHARIF N A ET AL: "Olopatadine (AL-4943A):
`Pharmacological profile of a novel
`anti-histamine-anti-allergic drug for use in
`allergic conjunctivitis"
`• INVESTIGATIVE OPHTHALMOLOGY & VISUAL
`SCIENCE, 37 (3). 1996. S1028., XP000613432
`YANNI J M ET AL: "The in vitro and in vivo ocular
`pharmacology of olopatadine (AL-4943A), an
`effective anti-allergic-antihistaminic agent"
`• INVESTIGATIVE OPHTHALMOLOGY & VISUAL
`SCIENCE, 37 (3). 1996. S593., XP000613433
`SPITALNY L ET AL: "Olopatadine ophthalmic
`solution decreases itching and redness
`associated with allergic conjunctivitis"
`
`Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give
`notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in
`a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art.
`99(1) European Patent Convention).
`
`Printed by Jouve, 75001 PARIS (FR)
`
`EP0 799 044B1
`
`APOTEX EX1020
`
`Page 1
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`

`
`EP 0 799 044 B1
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`• DATABASE CHEMABS CHEMICAL ABSTRACTS
`SERVICE, COLUMBUS, OHIO, US KAMEI,
`CHIAKI ET AL: "Effects of certain anti-allergic
`drugs on experimental conjunctivitis in guinea
`pigs" XP002021562 & ATARASHII GANKA, vol.
`11, no. 4, 1994, pages 603-5,
`• J. MED. CHEM., 1992, 2074-84, XP000615220
`OHSHIMA, ETSUO ET AL: "Synthesis and
`antiallergic activity of
`11-(aminoalkylidene)-6,11-dihydrodibenz(b,
`e)oxepin derivatives"
`
`• CHIRALITY, 1994, 6/8 (631-641), USA,
`XP000613077 ZHANG M.-Q. ET AL: "Optically
`active analogues of ebastine: Synthesis and
`effect of chirality on their antihistaminic and
`antimuscarinic activity"
`• BROCKMAN ET AL: ’A comparison of the effects
`of olopatadine and ketotifen on model
`membranes’ ACTA OPHTALMOL vol. 78, 2000,
`pages 10 - 15
`
`Remarks:
`The file contains technical information submitted
`after the application was filed and not included in this
`specification
`
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`EP 0 799 044 B1
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`Description
`
`BACKGROUND OF THE INVENTION
`
`5
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`Field of the Invention
`
`[0001] The present invention relates to topical ophthalmic formulations used for treating allergic eye diseases, such
`as allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. More par-
`ticularly, the present invention relates to therapeutic 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.
`
`Description of the Related Art
`
`[0002] As taught in U.S. Patent 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-dimethylaminopropyli-
`dene)-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 carboxylic
`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 histamine's effects
`on target tissues. The Burroughs Wellcome Patents teach various pharmaceutical formulations containing the carbox-
`ylic acid derivatives of doxepin; Example 8 (I) in both of the patents discloses an ophthalmic solution formulation.
`[0003] Although both of the Burroughs Wellcome Patents claim that the variety of pharmaceutical formulations dis-
`closed are effective 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.
`[0004]
`It is now well established, however, that the types of mast cells which exist in rodents are different 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, func-
`tional 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 different 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).
`[0005] Examples exist in the art in which mast cell stabilizing drugs inhibit only select populations of mast cells.
`Disodium 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 µM of the drug inhibited mast cells obtained from bronchoalveolar lavage fluid. In dispersed human
`lung mast cell preparations, 1000 µM 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 Cromoglycate 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
`effects on all mast cell populations.
`[0006] 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 formulations containing drugs which do not have conjunctival mast
`cell activity stems primarily from a placebo effect, more frequent doses are typically required than for drugs which do
`exhibit conjunctival mast cell activity.
`[0007] U.S. Patent 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
`
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`(i.e., Z-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid), have anti-allergic and anti-in-
`flammatory activity.
`[0008] The Kyowa patent demonstrates anti-allergic activity and anti-inflammatory activity in Wistar male rats. Med-
`icament 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,
`such as allergic conjunctivitis, such administration methods require large doses of medicine.
`[0009] What is needed are topically administrable drug compounds 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.
`
`Summary of the Invention
`
`[0010] The present invention provides the use of a therapeutically effective amount of 11-(3-dimethylaminopropyli-
`dene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid (referred to as "Compound A" hereinafter) or of a pharmaceutically
`acceptable salt thereof for the preparation of a topical ophthalmic formulation for administering to the eye for treating
`an allergic eye disease. The formulation may contain the cis isomer of Compound A (Z-11-(3-dimethylaminopropyli-
`dene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid), the trans isomer of Compound A (E-11-(3-dimethylaminopropyli-
`dene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid), or a combination of both the cis and the trans isomers of Com-
`pound A, and 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 substantially 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.
`[0011] Compound A 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
`antihistaminic activity. Thus, in addition to a prophylactic effect, Compound A will also have a therapeutic effect.
`
`Detailed Description of the Invention
`
`[0012] 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. Patent No. 5,116,863, the entire contents of which are hereby incorporated by ref-
`erence in the present specification.
`[0013] Examples of the pharmaceutically acceptable salts of Compound A include inorganic acid salts such as hy-
`drochloride, 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 triethylamine
`addition salt (also known as tromethamine), morpholine addition salt and piperidine addition salt.
`[0014] The inhibitory effects of reported anti-allergic, mast cell stabilizing drugs on mast cells obtained from human
`conjunctiva (the target cells for topical ophthalmic drug preparations claimed useful in treating allergic conjunctivitis)
`were tested according to the following experimental method. Human conjunctival tissues obtained from organ/tissue
`donors were weighed and transferred to petri dishes containing RPMI 1640 culture medium supplemented with heat
`inactivated fetal bovine serum (20%, v/v), L-glutamine (2mM), penicillin (100 units/ml), streptomycin (100 µg/ml), am-
`photericin B (2.5µg/ml) and HEPES (10mM) and equilibrated overnight at 37°C (5% CO2).
`[0015] Post equilibration, tissues were placed in Tyrode's buffer (in mM: 137 NaCI, 2.7 KCI, 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 200U 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, Briarcliff Manor, NY).
`Intact tissues were placed in TGCM for further enzymatic digestions.
`[0016] The filtrate obtained from each digestion was centrifuged (825 g, 7 minutes) and pelleted cells were resus-
`
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`EP 0 799 044 B1
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`pended in calcium/magnesium free Tyrode's buffer (TG). Pooled cells from all digestions were centrifuged (825 g, 30
`minutes) 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).
`[0017] 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
`challenge. The release reaction was terminated by centrifugation (500 g, 7 minutes). Supematants were collected and
`stored (-20°C) until mediator analyses.
`[0018]
`Initially, supernatants were analyzed for histamine content by both the automated fluorimetric method de-
`scribed by Siraganian, "An Automated Continuous Flow System for the Extraction and Fluorometric Analysis of Hista-
`mine," 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.
`[0019] 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 Assoc., Vol. 50, 1096-1121 (1955)). The results are reported in Table 1, below.
`[0020] 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.
`
`Compound Effect on Histamine Release from Human Conjunctival Tissue Mast Cells upon anti-Human IgE
`Challenge.
`
`Tablet 1
`
`Compound
`
`Cromolyn sodium
`
`Cromolyn sodium
`
`Nedocromil sodium
`
`*p<0.05, Dunnett's t-test
`
`Dose (µM)
`
`Treatment (min)
`
`Inhibition (%)
`
`-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
`
`15
`
`15
`
`15
`
`15
`
`15
`
`1
`
`1
`
`1
`
`1
`
`1
`
`15
`
`15
`
`15
`
`15
`
`15
`
`15
`
`1000
`
`300
`
`100
`
`30
`
`10
`
`1000
`
`300
`
`100
`
`30
`
`10
`
`1000
`
`300
`
`100
`
`30
`
`10
`
`3
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`EP 0 799 044 B1
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`Tablet 1 (continued)
`
`Compound Effect on Histamine Release from Human Conjunctival Tissue Mast Cells upon anti-Human IgE
`Challenge.
`
`Compound
`
`Dose (µM)
`
`Treatment (min)
`
`Inhibition (%)
`
`1
`
`0.3
`
`0.1
`
`1000
`
`300
`
`100
`
`30
`
`10
`
`3
`
`1
`
`0.3
`
`0.1
`
`2000
`
`1000
`
`600
`
`300
`
`100
`
`30
`
`Nedocromil sodium
`
`Compound A
`
`*p<0.05, Dunnett's t-test
`
`15
`
`15
`
`15
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`15
`
`15
`
`15
`
`15
`
`15
`
`15
`
`10.7
`
`3.7
`
`8.7
`
`-1.1
`
`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
`
`[0021] Dunnett's t-test, is a statistical test which compares multiple 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
`determined 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.
`[0022] 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 difference between the
`conjunctival mast cell activity of the two isomers at the indicated dose level.
`
`Table 2
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`Compound
`
`Isomeric Effect of Compound A on In-Vitro Histamine Release from Human Conjunctival Tissue Mast Cells upon
`anti-Human IgE Challenge.
`Dose (µM)
`
`Treatment (min)
`
`Inhibition (%)
`
`Compound A(cis)
`
`55
`
`Compound A (trans)
`
`500
`
`500
`
`15
`
`15
`
`29.7*_
`
`26.2*_
`
`*p< 0.05. Dunnett's t-test compared to anti-IgE positive control.
`_ not significantly different: p > 0.05 Studentized Range comparison of indicated doses
`
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`[0023] 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 effectively prevents or decreases the local allergic response
`in the conjunctiva. This assay allows an assessment of bioavailability following topical dosing. Briefly, male Sprague
`Dawley rats (6/group) were passively sensitized by subconjunctival injection of a rat serum containing IgE specific for
`ovalbumin (OA). Twenty-four hours post sensitization, test compound prepared in saline (0.9% NaCI) or saline vehicle
`was applied topically onto the sensitized eye. Twenty (20) minutes after dosing, rats were challenged intravenously
`via the lateral tail vein with 1.0 ml of a solution containing OA (1.0 mg/ml) 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 indi-
`vidual 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.
`
`Compound
`
`Conc. (%, w/v)
`
`TABLE 3
`In-Vivo Effects of Compound A on Passive Conjunctival Anaphylaxis in Rats
`Permeability Score (x ± S.D.) % Change
`239 ± 22
`133 ± 53*
`139 ± 36*
`55±56*@
`43±34*@
`
`NaCI
`
`Compound B
`
`Compound C
`
`Compound A (cis)
`
`Compound A (trans)
`
`0.9
`
`0.1
`
`0.1
`
`0.1
`
`0.1
`
`---
`
`-55
`
`-53
`
`-86
`
`-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)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid
`Compound C = (Z)-11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acrylic acid
`
`[0024] Compound A 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.
`[0025] 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 con-
`centration of Compound A 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.
`[0026] Sodium chloride, glycerin or the like may be used as the isotonic agent; p-hydroxybenzoic acid ester, benza-
`lkonium 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.
`[0027]
`If required, other ophthalmologic chemicals such as epinephrine, naphazoline hydrochloride, berberine chlo-
`ride, sodium azulenesulfonate, lysozyme chloride, glycyrrhizate and the like may be added.
`[0028] 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 µl.
`[0029] Certain embodiments of the invention are illustrated in the following examples.
`
`Example 1: Preferred Topical Ophthalmic Solution Formulation
`
`[0030]
`
`Ingredient
`
`Compound A•HCl
`
`Concentration (W/V%)
`
`0.111*
`
`* 0.111% Compound A•HCl is equivalent to 0.1% Compound A
`
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`EP 0 799 044 B1
`
`(continued)
`
`Ingredient
`Dibasic Sodium Phosphate (Anhydrous), USP
`Sodium Chloride, USP
`Benzalkonium Chloride
`Sodium Hydroxide, NF
`Hydrochloric Acid, NF
`Purified Water
`
`Concentration (W/V%)
`0.5
`0.65
`0.01
`q.s. pH = 7.0
`q.s. pH = 7.0
`q.s. 100
`
`Example 2: Topical Ophthalmic Gel Formulation
`
`[0031]
`
`Ingredient
`
`Concentration (WN%)
`
`Compound A•HCl
`Carbopol 974 P
`Disodium EDTA
`Polysorbate 80
`Benzalkonium Chloride, Solution
`Sodium Hydroxide
`Hydrochloric acid
`Water for Injection
`
`0.11*
`0.8
`0.01
`0.05
`0.01+5 xs
`q.s. pH 7.2
`q.s. pH 7.2
`q.s. 100
`
`*0.11% Compound A•HCl is equivalent to 0.1% Compound A
`
`Claims
`
`1. The use of a therapeutically effective amount of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-
`2-acetic acid or a pharmaceutically acceptable salt thereof for the preparation of a topically administrable medi-
`cament for treating allergic eye diseases.
`
`2. The use 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 use of Claim 2 wherein the amount of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-ace-
`tic acid is from about 0.001 to about 0.2% (w/v).
`
`4. The use of claim 3 wherein the amount of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-ace-
`tic acid is about 0.1% (w/v).
`
`5. The use of Claim 1 wherein the 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid is
`(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 use of Claim 5 wherein the amount of (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-
`2-acetic acid is from about 0.0001 to about 5% (w/v).
`
`7. The use 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 use of Claim 7 wherein the amount of (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-
`2-acetic acid is 0.1% (w/v).
`
`9. The use of claim 1 wherein the 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid is
`
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`EP 0 799 044 B1
`
`(E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, substantially free of
`11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid.
`
`(Z)-
`
`10. The use of Claim 9 wherein 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 use of claim 10 wherein the amount of (E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-
`2-acetic acid is from about 0.001 to about 0.2% (w/v).
`
`12. The use of claim 11 wherein the amount of (E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-
`2-acetic acid is about 0.1% (w/v).
`
`Patentansprüche
`
`1. Verwendung einer therapeutisch wirksamen Menge von 11-(3-Dimethylaminopropyliden) -6,11-dihydrodibenz[b,
`e]oxepin-2-essigsäure oder einem pharmazeutisch annehmbaren Salz davon zur Herstellung eines topisch ver-
`abreichbaren Arzneimittels zur Behandlung von allergischen Augenkrankheiten.
`
`2. Verwendung nach Anspruch 1, wobei die Zusammensetzung eine Lösung ist und die Menge an 11-(3-Dimethyl-
`aminopropyliden)-6,11-dihydrodibenz[b,e]oxepin-2-essigsäure 0,0001% G/V bis 5% (G/V) ist.
`
`3. Verwendung nach Anspruch 2, wobei die Menge an 11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,e]oxe-
`pin-2-essigsäure 0,001 bis 0,2% (G/V) ist.
`
`4. Verwendung nach Anspruch 3, wobei die Menge an 11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,e]oxe-
`pin-2-essigsäure 0,1% (G/V) ist.
`
`5. Verwendung nach Anspruch 1, wobei die 11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,e]oxepin-2-essig-
`säure (Z)-11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,e]oxepin-2-essigsäure ist, die im Wesentlichen
`frei von (E)-11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,e]oxepin-2-essigsäure ist.
`
`6. Verwendung nach Anspruch 5, wobei die Menge an (Z)-11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,e]
`oxepin-2-essigsäure 0,0001 bis 5% (G/V) ist.
`
`7. Verwendung nach Anspruch 6, wobei die Menge an (Z)-11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz [b,e]
`oxepin-2-essigsäure 0,001 bis 0,2% (G/V) ist.
`
`8. Verwendung nach Anspruch 7, wobei die Menge an (Z)-11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,e]
`oxepin-2-essigsäure 0,1% (G/V) ist.
`
`9. Verwendung nach Anspruch 1, wobei die 11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,e] oxepin-2-es-
`sigsäure (E)-11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz [b,e] oxepin-2-essigsäure ist, die im Wesentli-
`chen frei ist von (Z)-11-(3-Dimethylaminopropyliden)6,11-dihydrodibenz[b,e]oxepin-2-essigsäure.
`
`10. Verwendung nach Anspruch 9, wobei die Menge an (E)-11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz [b,e]
`oxepin-2-essigsäure 0,0001 bis 5% (G/V) ist.
`
`11. Verwendung nach Anspruch 10, wobei die Menge an (E)-11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,
`e]oxepin-2-essigsäure 0,001 bis 0,2% (G/V) ist.
`
`12. Verwendung nach Anspruch 11, wobei die Menge an (E)-11-(3-Dimethylaminopropyliden)-6,11-dihydrodibenz[b,
`e] oxepin-2-essigsäure 0,1% (G/V) ist.
`
`Revendications
`
`1. Utilisation d'une quantité thérapeutiquement efficace d'acide 11-(3-diméthylaminopropylidène)-6,11-dihydrodibenz
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`EP 0 799 044 B1
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`[b,e]oxépine-2-acétique ou d'un sel pharmaceutiquement acceptable de celui-ci pour la préparation d'un médica-
`ment administrable topiquement pour le traitement de maladies oculaires allergiques.
`
`2. Utilisation suivant la revendication 1, dans laquelle la composition est une solution et la quantité d'acide 11-(3-di-
`méthylaminopropylidène)-6,11-dihydrodibenz[b,e]oxépine-2-acétique est de 0,0001 % en poids/volume à 5 %
`(poids/volume).
`
`3. Utilisation suivant la revendication 2, dans laquelle la quantité d'acide 11-(3-diméthylaminopropylidène)-6,11-di-
`hydrodibenz[b,e]oxépine-2-acétique est de 0,001 à 0,2 % (poids/volume).
`
`4. Utilisation suivant la revendication 3, dans laquelle la quantité d'acide 11-(3-diméthylaminopropylidène)-6,11-di-
`hydrodibenz[b,e]oxépine-2-acétique est de 0,1 % (poids/volume).
`
`5. Utilisation suivant la revendication 1, dans laquelle l'acide 11-(3-diméthylaminopropylidène)-6,11-dihydrodibenz
`[b,e]oxépine-2-acétique est de l'acide (Z)-11-(3-diméthylaminopropylidène)-6,11-dihydrodibenz[b,e]oxépine-
`2-acétique, essentiellement exempt d'acide (E)-11-(3-diméthylaminopropylidène)-6,11-dihydrodibenz[b,e]oxépi-
`ne-2-acétique.
`
`6. Utilisation suivant la revendication 5, dans laquelle la quantité d'acide (Z)-11-(3-diméthylaminopropylidène)-
`6,11-dihydrodibenz[b,e]oxépine-2-acétique est de 0,0001 à 5 % (poids/volume).
`
`7. Utilisation suivant la revendication 6, dans laquelle la quantité d'acide (Z)-11 -(3-diméthylaminopropylidène)-
`6,11-dihydrodibenz[b,e]oxépine-2-acétique est de 0,001 à 0,2 % (poids/volume).
`
`8. Utilisation suivant la revendication 7, dans laquelle la quantité d'acide (Z)-11-(3-diméthylaminopropylidène)-
`6,11-dihydrodibenz[b,e]oxépine-2-acétique est de 0,1 % (poids/volume).
`
`9. Utilisation suivant la revendication 1, dans laquelle l'acide 11-(3-diméthylaminopropylidène)-6,11-dihydrodibenz
`[b,e]oxépine-2-acétique est de l'acide (E)-11-(3-diméthylaminopropylidène)-6,11-dihydrodibenz[b,e]oxépine-
`2-acétique, essentiellement exempt d'acide (Z)-11-(3-diméthylaminopropylidène)-6,11 -dihydrodibenz[b,e]oxépi-
`ne-2-acétique.
`
`10. Utilisation suivant la revendication 9, dans laquelle la quantité d'acide (E)-11-(3-diméthylaminopropylidène)-
`6,11-dihydrodibenz[b,e]oxépine-2-acétique est de 0,0001 à 5 % (poids/volume).
`
`11. Utilisation suivant la revendication 10, dans laquelle la quantité d'acide (E)-11-(3-diméthylaminopropylidène)-
`6,11-dihydrodibenz[b,e]oxépine-2-acétique est de 0,001 à 0,2 % (poids/volume).
`
`12. Utilisation suivant la revendication 10, dans laquelle la quantité d'acide (E)-11-(3-diméthylaminopropylidène)-
`6,11-dihydrodibenz[b,e]oxépine-2-acétique est de 0,1 % (poids/volume).
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