Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
2001-06-20
2002-06-04
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
C514S456000, C514S912000
Reexamination Certificate
active
06399107
ABSTRACT:
This invention relates to pharmaceutical compositions and methods of treatment for the prevention and treatment of corneal haze. The formation of corneal haze is an artifact resulting from exposure of the cornea to laser irradiation. The methods of the present invention involve the application of compositions to the eye prior to, during and after irradiation.
BACKGROUND OF THE INVENTION
Laser surgical techniques have been developed to ablate or otherwise treat corneal defects without mechanical abrasion. These techniques include photorefractive keratectomy, (“PRK”), phototherapeutic keratectomy (“PTK”) in which laser radiation is applied to the cornea with minimal heating effects to ablate or smooth refractive aberrations, and the LASIK procedure which involves slicing a flap from the cornea, directly, laser ablating a portion of the stroma layer, and replacing the corneal flap.
These techniques involve the use of a pulsed laser photoablation apparatus to ablate very thin layers of corneal tissue with greater precision than can typically be achieved with mechanical means. Such procedures are usually performed with a high energy excimer laser (lasers based on the excited state of a halogen atom combining with the ground state of a rare gas such as krypton or xenon) which emits ultraviolet (“UV”) laser radiation capable of ablating biological tissues without thermal damage to surrounding tissue. The laser photoablation procedures typically employ a beam shaping or masking apparatus which varies the size of the exposure area on the corneal surface and interior over time or provides a predefined profile of resistance to the laser radiation, such that areas of the cornea receive different cumulative exposures and thereby are ablated to varying depths. Thus, portions of the epithelium, Bowman's membrane and stroma layers of the cornea are sculpted to effect the correct refractive properties desired. Excimer laser transepithelial photoablation induces significantly less keratocyte loss than manual epithelial debridement. Photoablation, however, is followed by a more intense inflammatory response and a greater increase in backscattering of light, commonly referred to as “corneal haze,” that is associated with increased keratocyte activation and myofibroblast transformation. The magnitude of corneal wound repair and the development and duration of corneal haze appears to increase proportionally with in creasing stromal photoablation depth (ice., the volume of stromal tissue removal) and may be unrelated to depth of initial keratocyte loss (Moller-Pedersen et al., Corneal haze development after PRK is regulated by volume of stromal tissue removal.
Cornea,
volume 17, pages 627-639 (1998)).
Corneal haze, as discussed herein, is an artifact which has not been observed as a result of ophthalmic surgery until the advent of these laser photoablation procedures. The artifact is seen as opacification of the cornea, or a “cloudiness” in vision. The artifact resulting from laser surgery is seen in different parts of the cornea but particularly in the stroma. When the artifact does appear it can usually only be observed by use of a slit lamp. It is not known precisely why the artifact sometimes occurs after photoablation of the cornea. It is hypothesized that the development of clinically observed corneal haze in PRK patients may be related, in part, to activation of corneal keratocytes and to putative changes in the extracellular matrix (Moller-Pedersen et al., Confocal microscopic characterization of wound repair after photorefractive keratectomy,
Invest. Ophthalmol. Vis. Sci.,
volume 39, pages 487-501 (1998)). The development of corneal haze is of potentially greater concern in those procedures affecting a large surface of the cornea versus procedures involving laser incisions.
The corneal haze or artifact to be prevented or treated according to the present invention is not a result of the use of lasers in the work area. It is rather a result of purposeful and direct exposure of the cornea to surgical trauma especially that of laser irradiation during ophthalmic surgery. Recent studies have been performed regarding the corneal haze which results from exposure to lasers. For example, in one study, seven patients received laser corneal ablation with a 193 nm Questek excimer laser. Post ablation examination with a slit beam showed a speckled haze at the interface between the epithelium and stroma (Del Pero, et al., Human Excimer Laser Lamellar Refractive Keratectomy—A Clinical Study,
ARVO Annual Meeting Abstract Issue,
page 281, No. 8 (1988)). In another study ablation with a 193 nm excimer laser resulted in a slight haze in the corneas of rabbits and primates. The haze was observable by slit lamp but disappeared after two weeks. However, in the rabbits a material resembling a plasma membrane was reported in Descemet's membrane, which is located between the posterior surface of the stroma and the anterior surface of the corneal endothelium (Gaster et al., Excimer Laser Ablation and Wound Healing of Superficial Cornea in Rabbits and Primates.
ARVO Annual Meeting Abstract Issue,
page 309, No. 4 (1988)). In another study discs were formed in the corneal stromas of rabbits by excimer laser photoablation at 193 nm. A stromal haze developed by one month, but corneal transparency did improve after 6 months (Tuft et al., Corneal Remodeling Following Anterior Keratectomy,
ARVO Annual Meeting Abstract Issue,
page 310, No. 7 (1988)). In a recent Phase III study on the use of excimer laser PRK for treatment of myopia, 27.8% of the 701 patients undergoing the surgical procedure demonstrated detectable haze formation (Hersh et al., Results of phase III excimer laser photorefractive keratectomy for myopia. The Summit PRK Study Group,
Ophthalmology,
volume 104, pages 1535-1553 (1997)). There exists, therefore, a need to provide methods of treatment to prevent the appearance of and/or treat corneal haze induced by laser irradiation.
For further details on PRK techniques, see Marshall et al., Photo-ablative Reprofiling Of The Cornea Using An Excime, Laser: Photorefractive Keratectomy, volume 1,
Lasers in Ophthalmology,
pages 21-48 (1986) and U.S. Pat. No. 4,856,513 (Muller), U.S. Pat. No. 4,941,093 (Marshall, et. al.), U.S. Pat. No. 4,665,913 (L'Esperance) and U.S. Pat. No. 4,732,148 (L'Esperance) all of which are incorporated herein by reference to the extent that they disclose methods and devices for achieving a predetermined refractive correction by volumetric removal of corneal tissue.
U.S. Pat. Nos. 5,665,373, 5,589,184, 5,582,835, 5,580,570, 5,573,775, 5,525,349, 5,401,510, 5,401,509, 5,271,939, 5,124,392 and 4,939,135, all issued to Robertson et al., disclose compositions and methods for the treatment of post-laser surgery corneal haze. None of these patents, however, disclose the compositions or methods of the present invention.
SUMMARY OF THE INVENTION
The present invention is directed to compositions and methods for treating corneal haze. The compositions comprise inhibitors of glycosaminoglycan (“GAG”) synthesis.
The compositions containing the GAG synthesis inhibitors are formulated as solutions, suspensions, emulsions or gels depending on the characteristics of the particular inhibitor. The compositions can also be delivered via use of a collagen shield, contact lenses or other solid matrixes capable of delivering drugs to the cornea when placed on the ocular surface.
The compositions and/or methods of the present invention may also involve the use of adjunctive agents, e.g., antiinfectives or antiinflammatories, to aid the wound healing process.
The compositions are used to prevent or treat corneal haze and are applied to the eye prior to and/or during surgical exposure to laser radiation and/or postoperatively.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compositions and methods of use for the treatment of corneal haze resulting from laser irradiation of the eye. The compositions of the present invention comprise GAG synthesis inhibito
David Karen C.
Graff Gustav
Kessler Timothy L.
Nixon Jon C.
Alcon Laboratories Inc.
Fay Zohreh
Yeager Sally
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