Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-12
2004-06-15
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S561000, C549S563000
Reexamination Certificate
active
06750250
ABSTRACT:
The present invention is directed to the treatment of dry eye disorders. In particular, the present invention is directed toward certain novel 11,12-oxidoarachidonic acid derivatives and their use in the treatment of dry eye.
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. Nos. 4,131,651 (Shah et al.), 4,370,325 (Packman), 4,409,205 (Shively), 4,744,980 and 4,883,658 (Holly), 4,914,088 (Glonek), 5,075,104 (Gressel et al.), 5,278,151 (Korb et al.), 5,294,607 (Glonek et al.), 5,371,108 (Korb et al.) and 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.
U.S. Pat. No. 3,991,759 (Urquhart) discloses the use of ocular inserts in the treatment of dry eye. Other semi-solid therapy has included the administration of carrageenans (U.S. Pat. No. 5,403,841, Lang) which gel upon contact with naturally occurring tear film.
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.
Aside from the above efforts, which are 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 condition 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.
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.
The use of ocular inserts is also problematic. Aside from cost, they are often unwieldy and uncomfortable. Further, as foreign bodies introduced in the eye, they can be a source of contamination leading to infections. In situations where the insert does not itself produce and deliver a tear film, artificial tears must still be delivered on a regular and frequent basis.
U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositions containing naturally occurring HETEs, or derivatives thereof, and their use in methods for treating dry eye. The compositions comprising HETEs increase ocular mucin secretion.
Recent studies have also claimed that known anti-inflammatory agents, such as methylprednisolone, provide relief of symptoms associated with dry eye. See, for example, Marsh, et al., Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome,
Ophthalmology
, Volume 106 (4), pages 811-816 (1999); and U.S. Pat. No. 6,153,607 (Pflugfelder et al.).
SUMMARY OF THE INVENTION
The present invention is directed to compounds, compositions and methods of use. The present invention is particularly directed to compositions and 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. More specifically, the present invention discloses ophthalmic compositions containing 11,12-oxidoarachidonic acid derivatives, and methods using the same for treating dry eye type disorders. The compositions are preferably administered topically to the eye.
DETAILED DESCRIPTION OF THE INVENTION
The 11,12-oxidoarachidonic acid derivatives of the present invention are those of formula (I):
wherein:
R
1
is CO
2
R, CONR
2
R
3
, CH
2
OR
4
, CH
2
NR
5
R
6
, CH
2
N
3
, CH
2
Hal, CH
2
NO
2
, CH
2
SR
20
, COSR
21
, or 2,3,4,5-tetrazol-1-yl, wherein:
R is H or CO
2
R forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester;
NR
2
R
3
and NR
5
R
6
are the same or different and comprise a free or functionally modified amino group, e.g., R
2
, R
3
, R
5
and R
6
are the same or different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at most only one of R
2
and R
3
are OH or alkoxy and at most only one of R
5
and R
6
are OH or alkoxy;
OR
4
comprises a free or functionally modified hydroxy group, e.g., R
4
is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl;
Hal is F, Cl, Br, or I;
SR
20
comprises a free or functionally modified thiol group; and
R
21
is H or COSR
21
forms a pharmaceutically acceptable salt or a pharmaceutically acceptable thioester;
A, B and D are the same or different and are C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, or a C
3
-C
5
allenyl group;
C is an oxirane or cyclopropane;
X is (CH
2
)
m
or (CH
2
)
m
O, wherein m is 1-6; and
Y is a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, acyl, or a free or functionally modified hydroxy, amino, or thiol group; or
X-Y is (CH
2
)
p
Y
1
; wherein p is 0-6; and
wherein:
W is CH
2
, O, S(O)
q
, NR
8
, CH
2
CH
2
, CH═CH, CH
2
O, CH
2
S(O)
q
, CH═N, or CH
2
NR
8
; wherein q is 0-2, and R
8
is H, alkyl, or acyl;
Z is H, alkyl, acyl, halo,
Belanger David B.
Klimko Peter G.
Ryan Patrick M.
Trinh Ba K.
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