Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-16
2002-07-16
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S912000
Reexamination Certificate
active
06420399
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
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 mast cell stabilizers for treating and/or preventing allergic eye diseases.
2. Description of the Related Art
Conventional antihistamine drugs are known to exhibit biphasic effects on mast cells. At lower concentrations, antihistamines promote an inhibition of histamine release from mast cells. As concentrations of antihistamines are increased there is a spontaneous release of histamine from mast cells, which is associated with an apparent loss of mast cell membrane stability. See, for example, Mota et al.,
Brit. J. Pharmacol.
15:396-404. This biphasic behavior has been demonstrated for the anti-allergy drug ketotifen (4,9-dihydro-4-(1-methyl-4-piperidinyl-idene)-10H-benzo[4,5]cyclohepta-[1,2-b]thiophen-10-one) in purified preparations of human conjunctival mast cells. Yanni et al.,
J. Ocular Pharmacol.,
12:389-400 (1996).
First generation mast cell stabilizer drugs without antihistaminic activity, such as cromolyn sodium, also exhibit biphasic behavior. Johnson et al.,
Monogr. Allergy,
14:299-306 (1979).
U.S. Pat. Nos. 4,871,865 and 4,923,892, both assigned to Burroughs Wellcome Co. (“the Burroughs Wellcome Patents”), describes 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, as mast cell stabilizers with antihistaminic action. These compounds inhibit the release of autacoids (i.e., histamine, serotonin, and the like) from mast cells and 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.
U.S. Pat. No. 5,641,805 discloses topical ophthalmic formulations for treating allergic eye diseases. The topical formulations contain acetic acid derivatives of doxepin and, in particular, Z-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid (i.e., olopatadine), which is the cis form of the compound having the formula.
Unlike other antihistamine or mast cell stabilizer anti-allergy drugs, olopatadine does not provoke a release of histamine from mast cells at concentrations higher than those for which antihistaminic activity is observed. Other topical ocular anti-allergy drugs that maintain mast cell membrane stability and prevent histamine release from mast cells over a drug concentration range of 0.01-0.5% (w/v) are desired.
SUMMARY OF THE INVENTION
The present invention provides a method for selecting anti-allergy drug concentrations that are suitable for use in the topical treatment of allergic eye diseases. According to the present method, an amphipathic anti-allergy compound's Surface Activity Rating is determined as described below. For topically administrable ophthalmic anti-allergy products, the anti-allergy drug concentration is chosen so that the drug has a Surface Activity Rating (in units of mN/m) from about 2-11.
The present invention is also directed toward topically administrable ophthalmic anti-allergy pharmaceutical drug products comprising an amphipathic anti-allergy drug at a concentration such that the drug has a Surface Activity Rating from about 2-11.
Among other factors, the present invention is based on the finding that amphipathic anti-allergy compounds formulated at concentrations at which they have a Surface Activity Rating of greater than 11 are likely to cause mast cell membrane instability and leakage of autocoids, including histamine, from human conjunctival mast cells.
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Graff Gustav
Yanni John M.
Alcon Manufacturing Ltd.
Fay Zohreh
Ryan Patrick M.
LandOfFree
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