Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
1999-11-19
2003-08-26
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C424S094610, C424S094600, C424S094100
Reexamination Certificate
active
06610292
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to enzyme preparations for therapeutic administration to the eyes of humans or other mammals, and more particularly to a method for utilizing one or more enzymes to treat disorders of the eye affecting the retina and/or the vitreous body of the mammalian eye.
BACKGROUND OF THE INVENTION
ANATOMY OF THE HUMAN EYE
In human beings, the anatomy of the eye includes a “vitreous body” which occupies approximately four fifths of the cavity of the eyeball, behind the lens. The vitreous body is formed of gelatinous material, known as the vitreous humor. Typically, the vitreous humor of a normal human eye contains approximately 99% water along with 1% macromolecules including: collagen, hyaluronic acid, soluble glycoproteins, sugars and other low molecular weight metabolites.
The retina is essentially a layer of nervous tissue formed on the inner posterior surface of the eyeball. The retina is surrounded by a layer of cells known as the choroid layer. The retina may be divided into an optic portion which participates in the visual mechanism, and a non-optic portion which does not participate in the visual mechanism. The optic portion of the retina contains the rods and cones, which are effectual organs of vision. A number of arteries and veins enter the retina at its center, and splay outwardly to provide blood circulation to the retina.
The posterior portion of the vitreous body is in direct contact with the retina. Networks of fibrillar strands extend from the retina and permeate or insert into the vitreous body so as to attach the vitreous body to the retina.
THE CAUSES, TREATMENTS AND CLINICAL SEQUELAE OF VITREOUS HEMMORRHAGE
Diabetic retinopathy, trauma and other ophthalmological disorders sometimes result in rupture or leakage of retinal blood vessels with resultant bleeding into the vitreous humor of the eye (i.e., “vitreous hemorrhage”). Such vitreous hemorrhage typically manifests as clouding or opacification of the vitreous humor.
Vitreous hemorrhage is sometimes, but not always, accompanied by tearing or detachment of the retina. In cases where the vitreous hemorrhage is accompanied by a retinal tear or detachment, it is important that such retinal tear or detachment be promptly diagnosed and surgically repaired. Failure to promptly diagnose and repair the retinal tear or detachment may allow photoreceptor cells of the retina, in the region of the tear or detachment, to become necrotic. Such necrosis of the photoreceptor cells of the retina may result in loss of vision. Furthermore, allowing the retinal detachment to remain unrepaired for such extended period of time may result in further vitreous hemorrhage and/or the formation of fibrous tissue at the site of the hemorrhage. Such formation of fibrous tissue may result in the formation of an undesirable permanent fibrous attachment between the vitreous body and the retina.
The typical surgical procedure used for repair of retinal tears or detachment requires that the surgeon be able to look through the vitreous humor, to visualize the damaged region of the retina (i.e., “transvitreous viewing of the retina”). When vitreous hemorrhage has occurred, the presence of the hemorrhagic blood within the vitreous can cause the vitreous to become so cloudy that the surgeon is prevented from visualizing the retina through the vitreous. Such hemorrhagic clouding of the vitreous can take 6-12 months or longer to clear sufficiently to permit trans-vitreal viewing of the retina. However, in view of the potential complications which may result from delayed diagnosis or treatment of a retinal tear or detachment, it is generally not desirable to wait for such natural clearance of the hemorrhagic blood to occur.
Furthermore, even when the vitreous hemorrhage is not accompanied by retinal tear or detachment, it is often difficult to verify that retinal tear or detachment has not occurred, because the clouded vitreous prevents the physician from performing routine funduscopic examination of the retina. Moreover, the presence of hemorrhagic blood within the vitreous may significantly impair or completely obscure the patient's vision through the affected eye, and will continue to do so until such time as the hemorrhagic blood has been substantially or fully cleared.
Thus, the presence of hemorrhagic blood within the vitreous body causes multiple clinical problems including a) inability to visually examine and diagnose the site and cause of the hemorrhage and/or any accompanying tear or detachment of the retina, b) full or partial impairment of vision in the affected eye, and c) impairment or prevention of the performance of trans-vitreal surgical procedures of the type of treatment typically utilized to repair the site of hemorrhage and/or to repair any accompanying retinal tear or detachment.
In cases where vitreous hemorrhage has resulted in substantial clouding or opacification of the vitreous, the treating physician may have the option to perform a procedure known as a vitrectomy, wherein all (or a portion of) the vitreous body is removed from the interior of the eye, and replaced with a clear liquid. The performance of this vitrectomy procedure is intended to allow the surgeon to perform the necessary retinal examination and/or surgical repair of the hemorrhage and any accompanying retinal tear or detachment. Such vitrectomy procedures are highly skill intensive, and are associated with several significant drawbacks, risks and complications. Among these drawbacks, risks and complications are the potential that the act of removing the vitreous will cause further detachment or tearing of the retina and/or that such removal of the vitreous will cause further hemorrhage from the already weakened retinal blood vessels.
PRIOR OPHTHALMIC APPLICATIONS OF HYALURONIDASE AND OTHER ENZYMES
In an effort to minimize the potential for causing further detachment or tearing of the retina during performance of the vitrectomy, it has previously been proposed in U.S. Pat. No. 5,292,509 (Hageman), to inject certain protease-free glycosaminoglycanase enzymes into the vitreous body, to cause the vitreous body to become uncoupled or “disinserted” from the retina, prior to removal of the vitreous body. Such disinsertion or uncoupling of the vitreous body is purported to minimize the likelihood that further tearing or detachment of the retina will occur as the vitreous body is removed. Examples of specific protease-free glycosaminoglycanase enzymes which may be used to bring about this vitreal disinsertion purportedly include: chondroitinase ABC, chondroitinase AC, chondroitinase B, chondroitin 4-sulfatase, chondroitin 6-sulfatase, hyaluronidase and B-glucuronidase.
Although hyaluronidase enzyme has been known to be usable for various ophthalmic applications, including the vitrectomy adjunct application described in U.S. Pat. No. 5,292,509 (Hageman), previously published studies have indicated that hyaluronidase is toxic to the retina and/or other anatomical structures of the eye when administered intravitreally at doses in excess of 1 IU, that is, at 15, 30, 50 and 150 IU of hyaluronidase. See,
The Safety of Intravitreal Hyaluronidase;
Gottlieb, J. L.; Antoszyk, A. N., Hatchell, D. L. and Soloupis, P., Invest Ophthalmol Vis Sci 31:11, 2345-52 (1990).
The ophthalmic toxicity of some hyaluronidase preparations has been confirmed by other investigators, who have proposed that such hyaluronidase preparations be used as a toxic irritant for causing experimentally-induced neovascularization of the eye, in animal toxicity models. See,
An Experimental Model of Preretinal Neovascularization in the Rabbit;
Antoszyk, A. N., Gottlieb, J. L., Casey, R. C., Hatchell, D. L. and Machemer, R., Invest Ophthalmol Vis Sci 32: 1, 46-51 (1991).
Unfortunately, it has not been previously known whether the reported therapeutic activities and toxicities of hyaluronidase are universally applicable to all hyaluronidase preparations, or whether such efficacies and/or toxicities are applicable only to hyaluronidase preparation
Aragon Gabriel Arturo Carpio
Flores Jose L. G.
Karageozian Hampar
Karageozian Vicken
Kenney Maria C.
ISTA Pharmaceuticals, Inc.
Knobbe Martens Olson & Bear LLP
Patten Patricia
Weber Jon P.
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