Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-21
2003-11-11
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
06645994
ABSTRACT:
The present invention is directed to the treatment of dry eye disorders. In particular, the present invention is directed toward the use of inhibitors of acyl-CoA synthetase to treat 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 14549 (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 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 steroids and cytokine release inhibitors to treat dry eye patients has been disclosed: 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; and Yanni, J. M.; et. al. WO 0003705 A1. Additionally, cyclosporine A [Tauber,
J. Adv. Exp. Med. Biol
. 1998, 438 (Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2), 969] has been disclosed for treating dry eye.
U.S. Pat. No. 5,696,166 discloses the use of certain HETE derivatives, including 15-HETE, for treating drey eye and other disorders requiring the wetting of the eye. According to the '166 patent, the HETE derivatives stimulate mucin production and/or secretion in the conjunctival epithelium and goblet cells following topical ocular application. Jumblatt, et al.,
Cornea, vol.
19, suppl. 2, p. S97 (2000), have recently reported that 15(S)-HETE is an effective secretagogue for the mucin subtype MUC1 and that the inability of 15(S)-HETE to stimulate secretion of the soluble goblet cell mucins (MUC2, MUC5AC) suggests that 15(S)-HETE acts predominantly on non-goblet conjunctival epithelial cells.
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, inhibitors of acyl-CoA synthetase are administered to a patient suffering from dry eye or other disorders requiring wetting of the eye. The inhibitors of acyl-CoA synthetase are preferably administered topically to the eye.
Among other factors, the present invention is based on the finding that inhibitors of acyl-CoA synthetase stimulate production and/or secretion of the mucin subtype 5AC (MUC5AC), which is known to be derived from goblet cells in human conjunctival tissue.
DETAILED DESCRIPTION OF THE INVENTION
Acyl-CoA synthetase enzymatically converts free fatty acids into acyl-CoA esters which are then used by various acyltransferases to incorporate fatty acids into membrane glycerolipids (such as phospholipids, triglycerides). The synthetase reaction proceeds as follows:
Free fatty acid+CoA+ATP→acyl-CoA+AMP+Ppi
Modulation of the incorporation of fatty acids into membranes can influence the structure and function cells. Inhibitors of acyl-CoA synthetase have been identified by standard biochemical techniques. The triacsins A, B and C are fungal metabolites which are competitive inhibitors of acyl-CoA. All he triacsins are 11-carbon alkenyl chains with an N-hydroxytriazene moiety at the terminus. Triacsin C, 1-hydroxy-3-(E,E,E,E-2′4′6′8′-undecatetraenylidine) triazene, is the most potent of these compounds and is commercially available from Kyowa Medix. Any acyl-CoA synthetase inhibitor is suitable for use in the methods of the present invention, provided it is not toxic.
According to the methods of the present invention, a composition comprising an i
Alcon Inc.
Fay Zohreh
Ryan Patrick M.
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