CA2195094C - Topical ophthalmic formulations containing doxepin derivatives for treating allergic eye diseases - Google Patents
Topical ophthalmic formulations containing doxepin derivatives for treating allergic eye diseases Download PDFInfo
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- CA2195094C CA2195094C CA002195094A CA2195094A CA2195094C CA 2195094 C CA2195094 C CA 2195094C CA 002195094 A CA002195094 A CA 002195094A CA 2195094 A CA2195094 A CA 2195094A CA 2195094 C CA2195094 C CA 2195094C
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- oxepin
- dihydrodibenz
- acetic acid
- dimethylaminopropylidene
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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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 pharmaceutically acceptable salt thereof. The formulations are useful for treating allergic eye diseases such as allergic conjunctiviti s, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis.
Description
219~09~
TOPICAL OPHTHALMIC FORMULATIONS CONTAINING DOXEPIN DERIVATIVES FOR TREAT-ING ALLERGIC EYE DISEASES
,o 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 particularly, 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 ,5 and/or preventing allergic eye diseases.
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 ofdoxepin, 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 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 carboxylic acid derivatives of doxepin; Example 8 (I) in both of the patents discloses an ophthalmic solution formulation.
219~09~
Although both of the Burroughs Wellcome Patents claim that the variety of pharmaceutical formulations disclosed 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.
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:
,o 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 ,5 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).
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 wM of the drug inhibited mast cells obtained from bronchoalveolar lavage fluid. In dispersed human lung mast cell preparations, 1000 ~M of tho drug was required to inhibit only 25'Yo to 330 of histamine release.
Finally, histamine release from human skin mast cells was not Inhibited at all by disodium cromoglycate. Pearcc ct al., "Effect of Disodium Cromoglycate on Antigen Evoked Histamine Kelease in !-lumen Skin," Clinical Exp. Immunol., Vol. 17, (1874): and Clegg et al_, "Histamine Secretion from Human Skin Slices Induced by Anti-IgE and Artificial Secretagogues and the Effects of Sodium Cromoglycate and 6slbutanol," Clin. ANeyy. Vol. 15, 321-32r!3 (1985). These data clearly fndieete that classification of a drug as an anti-allergic does not predict that the drug possess ,o inhibitory effects on all mast cell populations.
Topical ophthalmic formulations Which contain gorge having conjunClival mast cell activity may only need tn be applied once every 12-24 hours instead of once every 2-4 hours. Once disadvantage to the ophthalmic use of reported anti-allergic ,z drugs which in fact have no hurnan conJunetival mast cell stabilizing activity is an increased dosage frequency. ~lecause the effectiveness of ophthalmic formulations containing drugs which do not have conjunctival ntab't cell activity stems primarily from a plac:Pbo effect, more frequent dose) are typically required than for drugs which du exhibit cottlunctival mast cell activity, U,6. Patent 5,116,863, assigned to Kyowa Hakko Kogyo Co., Ltd., ("the Kyowa potent"), teaches that acetic acid derivatives of dnxepin and, in particular, the cis form of the compound having the formula .~~tJ(a-~.~
I
/' ~ ~ /:~.~ .CHI
(i.e., Z-11-(3-dimethylaminopropyiidene)-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 the treatment of allergic eye disease, such as allergic conjunctivitis, such administration methods require large doses of medicine.
,o 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.
The present invention provides a method for treating an allergic eye disease characterized by administering to the eye a topical ophthalmic formulafion which contains a therapeutically effective amount of 11-(3-dimethylaminopropylidene)-e,11-dihydrodibenz[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 traps isomer of Compound A (E-11-(3-~3 dimethylaminopropylidene)-6,11-dihydrodibenz[b,ejoxepin-2-acetic acid), or a combination of both the cis and the traps isomers of Compound 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 traps isomer or a mixture of both. "Cis isomer" means the cis isomer substantially free of the traps isomer; "traps isomer' means the traps 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.
Compound A ha:~ human conjunctival mast cell stabilizing activity, and may be applied as infrequently as once or twice a day in ;;ome cases. In addition to its mast cell stabilizing activit=~~, Compound A also possesses significant antihistaminic activity. Thus, in addition to a prophylactic effect, Compound A will also have a therapeutic 1C effect.
The present invention further provides ophthalmic compositions for treating allergic eye diseases comprising a therapeutically effective amount of the active ingredient together with a pharmaceutically acceptable carrier therefor.
l~ Detailed Description of ~he Invention Compound A is <~ 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.
Examples of the=_ pharmaceutically acceptable salts of 2C Compound A include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, fumar<~~e, tartrate and citrate; alkali metal salts such as sodium sa=Lt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; metal 2~ salts such as aluminium salt and zinc salt; and organic amine addition salts such as 1=:riethylamine addition salt (also known as tromethamine), morpho:line addition salt and piperidine addition salt..
5a 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 2195094 , containing RPMI 1640 culture medium supplemented with heat inactivated fetal bovine serum (20°~, vlv), L-glutamine (2mM), penicillin (100 unitslml), streptomycin (100 wgJml), amphotericin B (2.5uglml) and HEPES (10mM) and equilibrated overnight at 37°C (5% CO~.
TOPICAL OPHTHALMIC FORMULATIONS CONTAINING DOXEPIN DERIVATIVES FOR TREAT-ING ALLERGIC EYE DISEASES
,o 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 particularly, 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 ,5 and/or preventing allergic eye diseases.
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 ofdoxepin, 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 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 carboxylic acid derivatives of doxepin; Example 8 (I) in both of the patents discloses an ophthalmic solution formulation.
219~09~
Although both of the Burroughs Wellcome Patents claim that the variety of pharmaceutical formulations disclosed 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.
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:
,o 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 ,5 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).
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 wM of the drug inhibited mast cells obtained from bronchoalveolar lavage fluid. In dispersed human lung mast cell preparations, 1000 ~M of tho drug was required to inhibit only 25'Yo to 330 of histamine release.
Finally, histamine release from human skin mast cells was not Inhibited at all by disodium cromoglycate. Pearcc ct al., "Effect of Disodium Cromoglycate on Antigen Evoked Histamine Kelease in !-lumen Skin," Clinical Exp. Immunol., Vol. 17, (1874): and Clegg et al_, "Histamine Secretion from Human Skin Slices Induced by Anti-IgE and Artificial Secretagogues and the Effects of Sodium Cromoglycate and 6slbutanol," Clin. ANeyy. Vol. 15, 321-32r!3 (1985). These data clearly fndieete that classification of a drug as an anti-allergic does not predict that the drug possess ,o inhibitory effects on all mast cell populations.
Topical ophthalmic formulations Which contain gorge having conjunClival mast cell activity may only need tn be applied once every 12-24 hours instead of once every 2-4 hours. Once disadvantage to the ophthalmic use of reported anti-allergic ,z drugs which in fact have no hurnan conJunetival mast cell stabilizing activity is an increased dosage frequency. ~lecause the effectiveness of ophthalmic formulations containing drugs which do not have conjunctival ntab't cell activity stems primarily from a plac:Pbo effect, more frequent dose) are typically required than for drugs which du exhibit cottlunctival mast cell activity, U,6. Patent 5,116,863, assigned to Kyowa Hakko Kogyo Co., Ltd., ("the Kyowa potent"), teaches that acetic acid derivatives of dnxepin and, in particular, the cis form of the compound having the formula .~~tJ(a-~.~
I
/' ~ ~ /:~.~ .CHI
(i.e., Z-11-(3-dimethylaminopropyiidene)-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 the treatment of allergic eye disease, such as allergic conjunctivitis, such administration methods require large doses of medicine.
,o 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.
The present invention provides a method for treating an allergic eye disease characterized by administering to the eye a topical ophthalmic formulafion which contains a therapeutically effective amount of 11-(3-dimethylaminopropylidene)-e,11-dihydrodibenz[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 traps isomer of Compound A (E-11-(3-~3 dimethylaminopropylidene)-6,11-dihydrodibenz[b,ejoxepin-2-acetic acid), or a combination of both the cis and the traps isomers of Compound 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 traps isomer or a mixture of both. "Cis isomer" means the cis isomer substantially free of the traps isomer; "traps isomer' means the traps 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.
Compound A ha:~ human conjunctival mast cell stabilizing activity, and may be applied as infrequently as once or twice a day in ;;ome cases. In addition to its mast cell stabilizing activit=~~, Compound A also possesses significant antihistaminic activity. Thus, in addition to a prophylactic effect, Compound A will also have a therapeutic 1C effect.
The present invention further provides ophthalmic compositions for treating allergic eye diseases comprising a therapeutically effective amount of the active ingredient together with a pharmaceutically acceptable carrier therefor.
l~ Detailed Description of ~he Invention Compound A is <~ 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.
Examples of the=_ pharmaceutically acceptable salts of 2C Compound A include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, fumar<~~e, tartrate and citrate; alkali metal salts such as sodium sa=Lt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; metal 2~ salts such as aluminium salt and zinc salt; and organic amine addition salts such as 1=:riethylamine addition salt (also known as tromethamine), morpho:line addition salt and piperidine addition salt..
5a 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 2195094 , containing RPMI 1640 culture medium supplemented with heat inactivated fetal bovine serum (20°~, vlv), L-glutamine (2mM), penicillin (100 unitslml), streptomycin (100 wgJml), amphotericin B (2.5uglml) and HEPES (10mM) and equilibrated overnight at 37°C (5% CO~.
Post equilibration, tissues were placed in Tyrode's buffer (in mM: 137 NaCI, 2.7 KCI, 0.35 Na HZP04, 1.8 CaCl2, 0.98 MgCl2, 11.9 Na HC03, 5.5 glucose) containing 0.1 % gelatin (TGCM) and incubated with 2000 each of collagenase (Type IV) and hyaluronidase (Type I-S) per gram of tissue for 30 minutes at 37°C.
,o Following enryme 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.
The filtrate obtained from each digestion was centrifuged (825 g, 7 minutes) ,3 and pelleted cells were resuspended in calciumlmagnesium 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 zo 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 zs 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).
Supernatants were collected and stored (-20°C) until mediator analyses.
Initially, supernatants were analyzed for histamine content by both the automated fluorimetric method described by Siraganian, "An Automated Continuous Flow System for the Extraction and Fluorometric Analysis of Histamine," ~.
s WO 96/39147 219 5 0 9 4 p~~S96/06289 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.
s Each experiment included an anti-human IgE (plus vehicle) positive release control, a spontaneouslvehicle 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.
,5 StatAssoc., 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 sign~cantly inhibit human conjunctival mast cell degranulation.
In contrast, Compound A (cis isomer) produced concentration-dependent inhibition of mast cell degranulation.
W096/39d47 2 T 9 5 0 9 4 p~~g96/06289 Table t Compound Eftect on Histamine Release from Human Conjunctrval Tissue Mast Ceils upon anti-Human IgE Challenge.
Compound Dose TroatmentInhibition (pM) (min) (%) Cromolyn 1000 15 -15.4 sodium 300 15 -6.9 100 15 -1.2 30 15 1.8 10 15 10.6 Cromolynsodiumt000 1 -9.4 300 1 -1.8 100 1 1.2 30 1 0.1 10 1 -0.9 Neooaomil 1000 15 7.2 sodium 300 15 11.3 10D 15 28.2' 30 15 15.2 10 15 9.2 3 15 13.2 1 t5 t0.7 0.3 15 3.7 0.1 15 8.7 Nedoaomil 1000 1 -1.1 sodium 300 1 4.0 100 7 6.7 30 1 -0.9 10 1 $.5 3 1 0.8 1 1 4.8 0.3 1 8.8 0.1 1 17.4 Compound 2000 75 92.6' A
1000 15 66.T
600 15 47.5' 300 t5 29.6' 100 15 - 13.0 3D 15 I -3.9 I
'p<0.05. Dunnett's t-test r 2195094 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.
,o The effects of the cis and trans isomers of Compound A on histamine release from human conjunctiva) 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 conjunctiva) mast cell activity of the two isomers at the ,5 indicated dose level.
Table 2 Isomeric Effect of Compound A on In-Vitro Histamine Release m from Human Conjunctiva) Tissue Mast Cells upon anti-Human IgE Challenge.
Compound Dose Treatment Inhibition (ftM) (min) (%) Compound A(cis) 500 15 29.7*_ Compound A (traps)500 15 26.2*
~p< 0.05, Dunnett's t-test comparod to anti-IgE positive control.
a _ not significantly differont; p > 0.05 Studentized Range comparison of indicated doses 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 s 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) 3 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 wheat and the intensity of the extravasated dye were determined.
,o The wheat 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 fisted in Table 3.
,3 In-Vivo Effects of Compound A on Passive Conjunctival Anaphylaxis in Rats Compound Conc. Permeability % Change (%, w/v) Score (x t S.D.) NaCI 0.9 239 t 22 -Compound B 0.1 133 t 53* -55 Compound C 0.1 139 t 36* -53 Compound A 0.1 55 t 56*@ -86 (cis) Compound A 0.1 43 t 34'@ -81 (trans) ' p <0.01, Dunnett's test an ~ p <0.05, Studentized Range Comparison Procedure, significantly different from Compounds B and C.
Compound B = (Z)-11-(3-Dimethylaminapropylidene)-6.11~ihydrodibenzlb,e]oxepin-2-catboXylic acid Compound C = (I)-11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenz(b,e]oXepin-2-aaylie acid z3 Compound A may be administered to the eye by means of conventional topical ophthalmic formulations, such as solutions, suspensions or gels. The WO 96/39147 219 5 ~ 9 4 p~~S96/06289 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 cls isomer. A general method of preparing the eye drops of the present invention is s 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 ,° Compound A is 0.0001 to 5 wlv %, preferably 0.001 to 0.2 w/v %, and most preferably about 0.1 wlv %, 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.
,5 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 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 ophthalmologic chemicals such as epinephrine, naphazoline hydrochloride, berberine chloride, sodium azulenesulfonate, lysoryme chloride, glycyrrhizate and the like may be added.
~s 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 wl.
WO 96139147 ~ ~ ~ ~ ~ ~ PCTN596/U6289 Certain embodiments of the invention are illustrated in the following examples.
Example 1: Preferred Topical Ophthalmic Solution Formulation JDaredient Concentration (WN%1 Compound AHCI 0.111*
,o Dibasic Sodium Phosphate 0.5 (Anhydrous), USP
Sodium Chloride, USP 0.65 ,5 Benzalkonium Chloride 0.01 Sodium Hydroxide, NF q.s. pH = 7.0 Hydrochloric Acid, NF q.s. pH = 7.0 m Purified Wafer q.s. 100 * 0.111 % Compound A~HCI is equivalent to 0.1 % Compound A
WO 96139147 219 5 0 9 4 P~~S96/06289 Example 2: Topical Ophthalmic Gel Formulation In radiant Concentration (V11N%) s Compound AHCI
' 0.11*
, Carbopol 974 P O,g Disodium EDTA 0.01 Polysorbate 80 0.05 ,s Benzalkonium Chloride, Solution 0.01+5 xs Sodium Hydroxide q.s. pH 7.2 m Hydrochloric acid q.s. pH 7.2 Water for Injection q.s. 100 * 0.11 % Compound A~HCI is equivalent to 0.1 % Compound A
,o Following enryme 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.
The filtrate obtained from each digestion was centrifuged (825 g, 7 minutes) ,3 and pelleted cells were resuspended in calciumlmagnesium 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 zo 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 zs 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).
Supernatants were collected and stored (-20°C) until mediator analyses.
Initially, supernatants were analyzed for histamine content by both the automated fluorimetric method described by Siraganian, "An Automated Continuous Flow System for the Extraction and Fluorometric Analysis of Histamine," ~.
s WO 96/39147 219 5 0 9 4 p~~S96/06289 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.
s Each experiment included an anti-human IgE (plus vehicle) positive release control, a spontaneouslvehicle 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.
,5 StatAssoc., 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 sign~cantly inhibit human conjunctival mast cell degranulation.
In contrast, Compound A (cis isomer) produced concentration-dependent inhibition of mast cell degranulation.
W096/39d47 2 T 9 5 0 9 4 p~~g96/06289 Table t Compound Eftect on Histamine Release from Human Conjunctrval Tissue Mast Ceils upon anti-Human IgE Challenge.
Compound Dose TroatmentInhibition (pM) (min) (%) Cromolyn 1000 15 -15.4 sodium 300 15 -6.9 100 15 -1.2 30 15 1.8 10 15 10.6 Cromolynsodiumt000 1 -9.4 300 1 -1.8 100 1 1.2 30 1 0.1 10 1 -0.9 Neooaomil 1000 15 7.2 sodium 300 15 11.3 10D 15 28.2' 30 15 15.2 10 15 9.2 3 15 13.2 1 t5 t0.7 0.3 15 3.7 0.1 15 8.7 Nedoaomil 1000 1 -1.1 sodium 300 1 4.0 100 7 6.7 30 1 -0.9 10 1 $.5 3 1 0.8 1 1 4.8 0.3 1 8.8 0.1 1 17.4 Compound 2000 75 92.6' A
1000 15 66.T
600 15 47.5' 300 t5 29.6' 100 15 - 13.0 3D 15 I -3.9 I
'p<0.05. Dunnett's t-test r 2195094 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.
,o The effects of the cis and trans isomers of Compound A on histamine release from human conjunctiva) 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 conjunctiva) mast cell activity of the two isomers at the ,5 indicated dose level.
Table 2 Isomeric Effect of Compound A on In-Vitro Histamine Release m from Human Conjunctiva) Tissue Mast Cells upon anti-Human IgE Challenge.
Compound Dose Treatment Inhibition (ftM) (min) (%) Compound A(cis) 500 15 29.7*_ Compound A (traps)500 15 26.2*
~p< 0.05, Dunnett's t-test comparod to anti-IgE positive control.
a _ not significantly differont; p > 0.05 Studentized Range comparison of indicated doses 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 s 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) 3 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 wheat and the intensity of the extravasated dye were determined.
,o The wheat 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 fisted in Table 3.
,3 In-Vivo Effects of Compound A on Passive Conjunctival Anaphylaxis in Rats Compound Conc. Permeability % Change (%, w/v) Score (x t S.D.) NaCI 0.9 239 t 22 -Compound B 0.1 133 t 53* -55 Compound C 0.1 139 t 36* -53 Compound A 0.1 55 t 56*@ -86 (cis) Compound A 0.1 43 t 34'@ -81 (trans) ' p <0.01, Dunnett's test an ~ p <0.05, Studentized Range Comparison Procedure, significantly different from Compounds B and C.
Compound B = (Z)-11-(3-Dimethylaminapropylidene)-6.11~ihydrodibenzlb,e]oxepin-2-catboXylic acid Compound C = (I)-11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenz(b,e]oXepin-2-aaylie acid z3 Compound A may be administered to the eye by means of conventional topical ophthalmic formulations, such as solutions, suspensions or gels. The WO 96/39147 219 5 ~ 9 4 p~~S96/06289 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 cls isomer. A general method of preparing the eye drops of the present invention is s 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 ,° Compound A is 0.0001 to 5 wlv %, preferably 0.001 to 0.2 w/v %, and most preferably about 0.1 wlv %, 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.
,5 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 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 ophthalmologic chemicals such as epinephrine, naphazoline hydrochloride, berberine chloride, sodium azulenesulfonate, lysoryme chloride, glycyrrhizate and the like may be added.
~s 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 wl.
WO 96139147 ~ ~ ~ ~ ~ ~ PCTN596/U6289 Certain embodiments of the invention are illustrated in the following examples.
Example 1: Preferred Topical Ophthalmic Solution Formulation JDaredient Concentration (WN%1 Compound AHCI 0.111*
,o Dibasic Sodium Phosphate 0.5 (Anhydrous), USP
Sodium Chloride, USP 0.65 ,5 Benzalkonium Chloride 0.01 Sodium Hydroxide, NF q.s. pH = 7.0 Hydrochloric Acid, NF q.s. pH = 7.0 m Purified Wafer q.s. 100 * 0.111 % Compound A~HCI is equivalent to 0.1 % Compound A
WO 96139147 219 5 0 9 4 P~~S96/06289 Example 2: Topical Ophthalmic Gel Formulation In radiant Concentration (V11N%) s Compound AHCI
' 0.11*
, Carbopol 974 P O,g Disodium EDTA 0.01 Polysorbate 80 0.05 ,s Benzalkonium Chloride, Solution 0.01+5 xs Sodium Hydroxide q.s. pH 7.2 m Hydrochloric acid q.s. pH 7.2 Water for Injection q.s. 100 * 0.11 % Compound A~HCI is equivalent to 0.1 % Compound A
Claims (25)
1. Use of a topically administrable ophthalmic composition comprising a therapeutically effective amount of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid or a phamaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor, 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% 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-acetic acid is 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-acetic acid is about 0.1% (w/v).
5. The use of Claim 1, wherein the 11-(3-dimethylamino-propylidene)-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-dimethyl-aminopropylidene)-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-dimethyl-aminopropylidene)-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-dimethyl-aminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid.
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).
13. A topically administrable ophthalmic composition for treating allergic eye diseases comprising a therapeutically effective amount of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.
14. The composition of Claim 13 wherein the amount of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid is from about 0.0001 to about 5% (w/v).
15. The composftion of Claim 14 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).
16. The composition of Claim 15 wherein the amount of 11-(3 dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid is about 0.1% (w/v).
17. The composition of Claim 13 wherein the 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid is (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzjb,e]oxepin-2-acetic acid, substantially free of (E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid.
18. The composition of Claim 17 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).
19. The composition of Claim 18 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).
20. The composition of Claim 19 wherein the amount of (Z)-11-(3-dimethytaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid is about 0.1 % (w/v).
21. The composition of Claim 13, wherein the 11-(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)-6,11-dihydrodibenz[b,e]-oxepin-2-acetic acid.
22. The composition of Claim 21, 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).
23. The composition of Claim 22, 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).
24. The composition of Claim 23, wherein the amount of (E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]-oxepin-2-acetic acid is about 0.1% (w/v).
25. Use of a composition as defined in any one of claims 13 to 24 for the preparation of a medicament for treating allergic eye diseases.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/469,729 | 1995-06-06 | ||
| US08/469,729 US5641805A (en) | 1995-06-06 | 1995-06-06 | Topical ophthalmic formulations for treating allergic eye diseases |
| PCT/US1996/006289 WO1996039147A2 (en) | 1995-06-06 | 1996-05-03 | Topical ophthalmic formulations containing doxepin derivatives for treating allergic eye diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2195094A1 CA2195094A1 (en) | 1996-12-12 |
| CA2195094C true CA2195094C (en) | 2002-02-26 |
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ID=23864859
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002195094A Expired - Lifetime CA2195094C (en) | 1995-06-06 | 1996-05-03 | Topical ophthalmic formulations containing doxepin derivatives for treating allergic eye diseases |
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|---|---|
| US (1) | US5641805A (en) |
| EP (1) | EP0799044B1 (en) |
| JP (1) | JP3068858B2 (en) |
| KR (1) | KR100202155B1 (en) |
| CN (1) | CN1082367C (en) |
| AT (1) | ATE220906T1 (en) |
| AU (1) | AU698854B2 (en) |
| CA (1) | CA2195094C (en) |
| DE (2) | DE10299034I2 (en) |
| DK (1) | DK0799044T3 (en) |
| ES (1) | ES2179198T3 (en) |
| FI (1) | FI970489L (en) |
| LU (1) | LU90969I2 (en) |
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| MY (1) | MY116651A (en) |
| NL (1) | NL300101I2 (en) |
| NO (1) | NO311637B1 (en) |
| PT (1) | PT799044E (en) |
| TW (1) | TW438588B (en) |
| WO (1) | WO1996039147A2 (en) |
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| US5859000A (en) * | 1995-06-07 | 1999-01-12 | University Of Utah Research Foundation | Method for reducing mast cell mediated allergic reactions |
| JP2002520355A (en) * | 1998-07-14 | 2002-07-09 | アルコン ラボラトリーズ， インコーポレイテッド | 11- (3-Dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid for the manufacture of a medicament for treating non-allergic ocular inflammatory disorders and preventing ocular neovascularization Use of |
| US6174914B1 (en) | 1999-06-15 | 2001-01-16 | Alcon Laboratories, Inc. | Method of inhibiting cytokine release from human ocular cells |
| ES2213001T3 (en) | 1999-06-18 | 2004-08-16 | Alcon Manufacturing Ltd. | METHOD FOR SELECTING THE CONCENTRATION OF AN ANTIHISTAMINAL ANPHIPATHIC PHARMACO BY DETERMINING THE VALUE OF SURFACE ACTIVITY OF THE FARMACO. |
| WO2001054687A1 (en) | 2000-01-25 | 2001-08-02 | Alcon Universal Ltd. | Ophthalmic anti-allergy compositions suitable for use with contact lenses |
| KR20020093982A (en) | 2000-05-19 | 2002-12-16 | 알콘, 인코퍼레이티드 | Aniline disulfide derivatives for treating allergic diseases |
| AU2001253807B2 (en) | 2000-05-19 | 2005-02-17 | Alcon, Inc. | Compositions containing a benzamide disulfide derivative for treating allergic diseases |
| ATE330938T1 (en) | 2000-05-19 | 2006-07-15 | Alcon Inc | DISULFIDE DERIVATIVES USED FOR THE TREATMENT OF ALLERGIC DISEASES |
| EP1387696A2 (en) * | 2001-05-03 | 2004-02-11 | Novartis AG | Anti-ige antibody to treat ocular allergies |
| US7977376B2 (en) | 2001-06-27 | 2011-07-12 | Novartis Ag | Olopatadine formulations for topical nasal administration |
| TWI231759B (en) * | 2001-06-27 | 2005-05-01 | Alcon Inc | Olopatadine formulations for topical administration |
| WO2003049770A1 (en) * | 2001-12-05 | 2003-06-19 | Alcon, Inc. | Use of an h1 antagonist and a safe steroid to treat rhinitis |
| US20050209312A1 (en) * | 2004-03-19 | 2005-09-22 | Bausch & Lomb Incorporated | Carboxylic acid derivatives of doxepin formulations preserved with low-irritation preservative |
| MXPA06014648A (en) * | 2004-06-28 | 2007-02-12 | Alcon Inc | Topical formulations for treating allergic diseases. |
| CA2586553C (en) * | 2004-11-24 | 2015-02-10 | Alcon, Inc. | Nasal sprayer containing a formulation with olopatadine |
| US8101654B2 (en) * | 2005-07-08 | 2012-01-24 | Senju Pharmaceutical Co., Ltd. | Percutaneously absorptive ophthalmic preparation comprising olopatadine |
| EP2004196B1 (en) | 2006-03-31 | 2016-06-29 | Vistakon Pharmaceuticals, LLC | Ocular allergy treatments |
| US20080139531A1 (en) * | 2006-12-04 | 2008-06-12 | Alcon Manufacturing Ltd. | Use of connective tissue mast cell stabilizers to facilitate ocular surface re-epithelization and wound repair |
| EP2114367B1 (en) | 2007-02-07 | 2015-11-04 | Novartis AG | Olopatadine formulations for topical nasal administration |
| US20090182035A1 (en) * | 2007-04-11 | 2009-07-16 | Alcon Research, Ltd. | Use of a combination of olopatadine and cilomilast to treat non-infectious rhinitis and allergic conjunctivitis |
| JP2010523695A (en) * | 2007-04-11 | 2010-07-15 | アルコン リサーチ， リミテッド | Use of inhibitors of TNFα and antihistamines to treat allergic rhinitis and allergic conjunctivitis |
| WO2009031682A1 (en) | 2007-09-06 | 2009-03-12 | Kyowa Hakko Kirin Co., Ltd. | EYE DROP COMPRISING DIBENZO[b,e]OXEPIN DERIVATIVE |
| US10517839B2 (en) * | 2008-06-09 | 2019-12-31 | Cornell University | Mast cell inhibition in diseases of the retina and vitreous |
| IT1397503B1 (en) | 2009-04-21 | 2013-01-16 | F S I Fabbrica Italiana Sint | PROCESS FOR THE PREPARATION OF OLOPATADIN |
| KR20120046215A (en) | 2009-07-17 | 2012-05-09 | 알콘 리서치, 리미티드 | Olopatadine Nasal Spray Therapy for Children |
| WO2011027322A1 (en) | 2009-09-03 | 2011-03-10 | Ranbaxy Laboratories Limited | Extended release dosage form containing olopatadine for oral administration |
| BR112012007091A2 (en) | 2009-10-01 | 2016-04-19 | Alcon Res Ltd | olopatadine compositions and their uses |
| TW201206936A (en) | 2010-07-19 | 2012-02-16 | Alcon Res Ltd | Methods and compositions for the treatment of allergy |
| TWI544922B (en) * | 2011-05-19 | 2016-08-11 | 愛爾康研究有限公司 | High concentration europart ingot ophthalmic composition |
| CN103202833A (en) * | 2012-12-25 | 2013-07-17 | 常州市亚邦医药研究所有限公司 | Pharmaceutical composition of olopatadine or salts of olopatadine, and preparation method thereof |
| WO2015065576A1 (en) * | 2013-10-31 | 2015-05-07 | Nephron Pharmaceuticals Corporation | Formulation of olopatadine |
| CN113985041A (en) * | 2021-09-29 | 2022-01-28 | 武汉钢铁有限公司 | Method and device for setting control limit of precision control of laboratory detection equipment |
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| US4370324A (en) * | 1980-09-17 | 1983-01-25 | Bernstein Joel E | Method and composition for treating and preventing irritation of the eyes |
| GB8520662D0 (en) * | 1985-08-17 | 1985-09-25 | Wellcome Found | Tricyclic aromatic compounds |
| US4923892A (en) * | 1985-08-17 | 1990-05-08 | Burroughs Wellcome Co. | Tricyclic aromatic compounds |
| JPS6310784A (en) * | 1986-03-03 | 1988-01-18 | Kyowa Hakko Kogyo Co Ltd | Dibenz(b,e)oxepin derivative, antiallergic agent and anti-inflammatory agent |
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1995
- 1995-06-06 US US08/469,729 patent/US5641805A/en not_active Expired - Lifetime
-
1996
- 1996-05-03 CA CA002195094A patent/CA2195094C/en not_active Expired - Lifetime
- 1996-05-03 CN CN96190605A patent/CN1082367C/en not_active Ceased
- 1996-05-03 EP EP96915500A patent/EP0799044B1/en not_active Expired - Lifetime
- 1996-05-03 WO PCT/US1996/006289 patent/WO1996039147A2/en not_active Ceased
- 1996-05-03 DE DE2002199034 patent/DE10299034I2/en active Active
- 1996-05-03 MX MX9701013A patent/MX9701013A/en unknown
- 1996-05-03 AT AT96915500T patent/ATE220906T1/en active
- 1996-05-03 FI FI970489A patent/FI970489L/en unknown
- 1996-05-03 KR KR1019970700721A patent/KR100202155B1/en not_active Ceased
- 1996-05-03 PT PT96915500T patent/PT799044E/en unknown
- 1996-05-03 JP JP9500510A patent/JP3068858B2/en not_active Expired - Lifetime
- 1996-05-03 DE DE69622527T patent/DE69622527T2/en not_active Expired - Lifetime
- 1996-05-03 DK DK96915500T patent/DK0799044T3/en active
- 1996-05-03 AU AU57261/96A patent/AU698854B2/en not_active Expired
- 1996-05-03 ES ES96915500T patent/ES2179198T3/en not_active Expired - Lifetime
- 1996-05-14 MY MYPI96001818A patent/MY116651A/en unknown
- 1996-06-04 TW TW085106668A patent/TW438588B/en not_active IP Right Cessation
-
1997
- 1997-02-05 NO NO19970517A patent/NO311637B1/en not_active IP Right Cessation
-
2002
- 2002-09-19 NL NL300101C patent/NL300101I2/en unknown
- 2002-10-02 LU LU90969C patent/LU90969I2/en unknown
Also Published As
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| AU698854B2 (en) | 1998-11-12 |
| EP0799044B1 (en) | 2002-07-24 |
| JP3068858B2 (en) | 2000-07-24 |
| CA2195094A1 (en) | 1996-12-12 |
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| US5641805A (en) | 1997-06-24 |
| KR970704452A (en) | 1997-09-06 |
| MX9701013A (en) | 1997-05-31 |
| DK0799044T3 (en) | 2002-10-14 |
| ATE220906T1 (en) | 2002-08-15 |
| MY116651A (en) | 2004-03-31 |
| FI970489A0 (en) | 1997-02-05 |
| JPH09510235A (en) | 1997-10-14 |
| FI970489A7 (en) | 1997-02-05 |
| WO1996039147A3 (en) | 1997-02-20 |
| EP0799044A2 (en) | 1997-10-08 |
| NO970517L (en) | 1997-04-03 |
| NL300101I1 (en) | 2002-12-02 |
| WO1996039147A2 (en) | 1996-12-12 |
| CN1082367C (en) | 2002-04-10 |
| TW438588B (en) | 2001-06-07 |
| NL300101I2 (en) | 2003-01-06 |
| DE10299034I2 (en) | 2005-07-07 |
| DE69622527D1 (en) | 2002-08-29 |
| KR100202155B1 (en) | 1999-06-15 |
| CN1161000A (en) | 1997-10-01 |
| FI970489L (en) | 1997-02-05 |
| ES2179198T3 (en) | 2003-01-16 |
| PT799044E (en) | 2002-11-29 |
| NO970517D0 (en) | 1997-02-05 |
| DE69622527T2 (en) | 2002-12-05 |
| AU5726196A (en) | 1996-12-24 |
| DE10299034I1 (en) | 2003-01-23 |
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