Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-09-27
2002-10-08
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C514S912000
Reexamination Certificate
active
06462082
ABSTRACT:
The present invention is directed to the use of hydroxyeicosatetraenoic acid derivatives during intraocular surgery. In particular, the invention relates to the use of such derivatives for the protection of the corneal endothelium during intraocular surgery.
BACKGROUND OF THE INVENTION
Mucins are proteins which are heavily glycosylated with glucosamine-based moieties. Mucins provide protective and lubricating effects to epithelial cells, especially those of mucosal membranes. Mucins have been shown to be secreted by vesicles and discharged on the surface of the conjunctival epithelium of human eyes (Greiner et al., Mucous Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses,
Archives of Ophthalmology
, volume 98, pages 1843-1846 (1980); and Dilly et al., Surface Changes in the Anaesthetic Conjunctiva in Man, with Special Reference to the Production of Mucous from a Non-Goblet-Cell Source,
British Journal of Ophthalmology
, volume 65, pages 833-842 (1981)). A number of human-derived mucins which reside in the apical and subapical corneal epithelium have been discovered and cloned (Watanabe et al., Human Corneal and Conjunctival Epithelia Produce a Mucin-Like Glycoprotein for the Apical Surface,
Investigative Ophthalmology and Visual Science
, volume 36, number 2, pages 337-344 (1995)). Recently, Watanabe discovered a new mucin which is secreted via the cornea apical and subapical cells as well as the conjunctival epithelium of the human eye (Watanabe et al.,
IOVS
, volume 36, number 2, pages 337-344 (1995)). These mucins provide lubrication, and additionally attract and hold moisture and sebaceous material for lubrication and the corneal refraction of light.
Mucins are also produced and secreted in other parts of the body including lung airway passages, and more specifically from goblet cells interspersed among tracheal/bronchial epithelial cells. Certain arachidonic acid metabolites have been shown to stimulate mucin production in these cells. Yanni reported the increased secretion of mucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid (“HETE”) derivatives (Yanni et al, Effect of Intravenously Administered Lipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness,
International Archives of Allergy And Applied Immunology
, volume 90, pages 307-309 (1989)). Similarly, Marom has reported the production of mucosal glycoproteins in human lung by HETE derivatives (Marom et al., Human Airway Monohydroxy-eicosatetraenoic Acid Generation and Mucous Release,
Journal of Clinical Investigation
, volume 72, pages 122-127 (1983)).
Agents claimed for increasing ocular mucin and/or tear production include vasoactive intestinal polypeptide (Dartt et. al., Vasoactive intestinal peptide-stimulated glycocongiugate secretion from conjunctival goblet cells.
Experimental Eye Research
, volume 63, pages 27-34, (1996)), gefarnate (Nakmura et. al., Gefarnate stimulates secretion of mucin-like glycoproteins by corneal epithelium in vitro and protects corneal epithelium from dessication in vivo,
Experimental Eye Research
, volume 65, pages 569-574 (1997)), liposomes (U.S. Pat. No. 4,818,537), androgens (U.S. Pat. No. 5,620,921), melanocycte stimulating hormones (U.S. Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No. 4,753,945), and retinoids (U.S. Pat. No. 5,455,265). None of these agents, however, have been reported to have an effect on the corneal endothelium.
U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositions containing HETE derivatives and methods of using them topically for treating dry eye. Yanni et al. discovered that compositions comprising HETE derivatives increase ocular mucin secretion and are thus useful in treating dry eye. This patent does not disclose the use of the HETE derivatives during intraocular surgery for the protection of the corneal endothelium.
During intraocular surgery, such as cataract surgery, the corneal endothelium is susceptible to damage by physical contacts with instrumentation or implants and fluid turbulence and ultrasonic disturbance during phacoemulsification. The corneal endothelium does not regenerate. Corneal endothelial cell damage can lead to a reduction in corneal endothelial cell density and an impairment of ion-pumping function, both of which can lead to corneal edema and visual impairment. Irrigating solutions containing nutrients (ions, glucose, etc.) and/or anti-oxidants have been proposed to maintain or protect the corneal endothelium. Additionally, viscoelastics are used to provide a physical barrier in order to prevent contact damage.
SUMMARY OF THE INVENTION
The present invention is directed to methods of using of HETE derivatives to maintain and protect the corneal endothelium during intraocular surgery. The invention also relates to compositions containing HETE derivatives where the compositions are intended for use during intraocular surgery. Although not wishing to be bound by any theory, it is believed that the HETE derivatives maintain and protect the corneal endothelium by stimulating mucin secretion in the corneal endothelium.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, “HETE derivative” means a compound of formulas I-XI.
wherein:
X is OR or NHR′;
R is H, a cationic pharmaceutically acceptable salt moiety, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is made with a moiety selected from the group consisting of: alkyl, halogen, hydroxy and functionally modified hydroxy;
R′ is H, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is made with a moiety selected from the group consisting of: alkyl, halogen, hydroxy and functionally modified hydroxy; and
Y is
wherein R″ is H or C(O)R;
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;
R
21
is H, or COSR
21
forms a pharmaceutically acceptable salt or a pharmaceutically acceptable thioester;
K is C
2
-C
8
alkyl, alkenyl, or alkynyl, or a C
3
-C
8
allenyl group;
A and X are the same or different and are a direct bond, CH
2
, NR
7
, O, or S, with the proviso that at least one of A and X is NR
7
, O, or S;
B is H, or BB together comprises a double bonded O, S, or NR
8
, with the proviso that BB comprises a double bonded O, S, or NR
8
when A and X are the same or different and are NR
7
, O, or S; wherein:
NR
7
and NR
8
are the same or different and comprise a functionally modified amino group, e.g., R
7
and R
8
are the same or different and are H, alkyl, cycloalkyl, aryl, aralkyl, acyl, OH, or alkoxy;
is 0 or 1;
D—E, G—H are the same or different and are CH
2
CH
2
, CH═CH, or C≡C; and
Y is C(O) (i.e. a carbonyl group) or Y is
wherein R
9
O constitutes a free or functionally modified hydroxy group;
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, where:
R is H or a pharmaceutically acceptable cation, or CO
2
R forms a pharmaceutically acceptable ester moiety;
NR
2
R
3
, NR
5
R
6
are the same or different and comprise a free or functionally modified amino group;
OR
4
comprises a free or functionally modified hydroxy group;
Hal is F, Cl, Br, or I;
R
20
is H, alkyl, acyl;
R
21
is H or a pharmaceuti
Chan Kwan
Karakelle Mutlu
Alcon Universal Ltd.
Fay Zohreh
Ryan Patrick M.
LandOfFree
Use of hydroxyeicosatetraenoic acid derivatives in... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of hydroxyeicosatetraenoic acid derivatives in..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of hydroxyeicosatetraenoic acid derivatives in... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2998746