Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-17
2004-02-24
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
06696453
ABSTRACT:
The present invention is directed to the treatment of dry eye disorders. In particular, the present invention is directed to the use of NF-&kgr;B inhibitors in the treatment of dry eye and other disorders requiring the wetting of the eye in mammals.
BACKGROUND OF THE INVENTION
Dry eye, also known generically as
keratoconjunctivitis sicca
, is a common ophthalmological disorder affecting millions of Americans each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren's disease and
cicatricial pemphigoid
manifest dry eye complications.
Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the complication share a common effect, that is the breakdown of the pre-ocular tear film, which results in dehydration of the exposed outer surface and many of the symptoms outlined above (Lemp,
Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAO Journal
, volume 21, number 4, pages 221-231 (1995)).
Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day. Other approaches include the use of ocular inserts that provide a tear substitute or stimulation of endogenous tear production.
Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Phospholipid compositions have been shown to be useful in treating dry eye; see, e.g., McCulley and Shine, Tear film structure and dry eye,
Contactologia
, volume 20(4), pages 145-49 (1998); and Shine and McCulley,
Keratoconjunctivitis sicca
associated with meibomian secretion polar lipid abnormality,
Archives of Ophthalmology
, volume 116(7), pages 849-52 (1998). Examples of phospholipid compositions for the treatment of dry eye are disclosed in U.S. Pat. No. 4,131,651 (Shah et al.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S. Pat. No. 4,744,980 and U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat. No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.), U.S. Pat. No. 5,371,108 (Korb et al.) and U.S. Pat. No. 5,578,586 (Glonek et al.). U.S. Pat. No. 5,174,988 (Mautone et al.) discloses phospholipid drug delivery systems involving phospholipids, propellants and an active substance.
Another approach involves the provision of lubricating substances in lieu of artificial tears. For example, U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating, liposome-based composition, and U.S. Pat. No. 5,800,807 (Hu et al.) discloses compositions containing glycerin and propylene glycol for treating dry eye.
Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient's waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is not only cumbersome and time consuming, but is also potentially very expensive. Transient symptoms of dry eye associated with refractive surgery have been reported to last in some cases from six weeks to six months or more following surgery.
Aside from efforts directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the dry eye condition have also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye conditions in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate pre-ocular tear film production; and U.S. Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
Some recent literature reports suggest that patients suffering from dry eye syndrome disproportionately exhibit the hallmarks of excessive inflammation in relevant ocular tissues, such as the lacrimal and meibomian glands. The use of various compounds to treat dry eye patients, such as steroids [e.g. U.S. Pat. No. 5,958,912; Marsh, et al., Topical nonpreserved methylprednisolone therapy for
keratoconjunctivitis sicca
in Sjogren syndrome,
Ophthalmology
, 106(4): 811-816 (1999); Pflugfelder, et. al U.S. Pat. No. 6,153,607], cytokine release inhibitors (Yanni, J. M.; et. al WO 0003705 A1), cyclosporine A [Tauber, J.
Adv. Exp. Med. Biol
. 1998, 438 (Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2), 969], and 15-HETE (Yanni et. al., U.S. Pat. No. 5,696,166), has been disclosed.
Inflammatory processes are known to involve the upregulation of several gene products by the nuclear transcription factor, NF-&kgr;B. In its quiescent state NF-&kgr;B exists as a heterodimer with the protein I&kgr;-B&agr;, which masks the nuclear localization signals and DNA binding domain of the former protein. Under inflammatory conditions I&kgr;-B&agr; is phosphorylated, causing a conformational change which results in its tagging with multiple copies of the ubiquitin protein. Ubiquinated I&kgr;-B&agr; is recognized and degraded by the proteasome, which liberates NF-&kgr;B. The free protein is translocated to the nucleus, where it binds to the appropriate DNA sequence and upregulates the production of several inflammatory mediators, such as COX-2, iNOS, IL-1, and TNF-&agr;. Therefore, inhibitors of the synthesis, activation, translocation or DNA binding activity of NF-&kgr;B could reduce inflammation and provide therapeutic benefit to dry eye patients.
SUMMARY OF THE INVENTION
The present invention is directed to methods for the treatment of dry eye and other disorders requiring the wetting of the eye, including symptoms of dry eye associated with refractive surgery such as LASIK surgery. According to the methods of the present invention, NF-&kgr;B inhibitors are administered to a patient suffering from dry eye or other disorders requiring wetting of the eye. The NF-&kgr;B inhibitors are preferably administered topically to the eye.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, “NF-&kgr;B inhibitors” means compounds that prevent the synthesis, activation, translocation and/or DNA binding activity of NF-&kgr;B. Although some steroids act as NF-&kgr;B inhibitors, for purposes of the present invention “NF-&kgr;B inhibitor” does not include any steroids.
NF-&kgr;B inhibitors are known. Examples of NF-&kgr;B inhibitors useful in the methods of the present invention include 2-chloro-N-[3,5-di(trifluoromethyl)phenyl]-4-(trifluoromethyl)pyrimidine-5-carboxamide (also known as SP-100030); 3,4-dihydro-4,4-dimethyl-2H-1,2-benzoselenazine (also known as BXT-51072); declopramide (also known as Oxi-104); and dexlipotam.
According to the methods of the present invention, a composition comprising one or more NF-&kgr;B inhibitors and a pharmaceutically acceptable carrier for topical ophthalmic administration or implantation into the conjunctival sac or anterior chamber of the eye is administered to a mammal in need thereof. The compositions are formulated in accordance with methods known in the art for the particular route of adm
Gamache Daniel A.
Yanni John M.
Alcon Inc.
Fay Zohreh
Ryan Patrick M.
LandOfFree
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