Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
1999-03-09
2004-05-11
Prats, Francisco (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C424S094640, C424S094200, C604S058000, C128S898000
Reexamination Certificate
active
06733750
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a process and composition for producing posterior vitreous detachment in the eye of an animal. More, particularly invention relates to a process of introducing a mixture of plasminogen and a plasminogen activator to induce posterior vitreous detachment in the eye and to dissolve blood clots in the vitreous.
BACKGROUND OF THE INVENTION
Vitreous traction is the attachment of vitreous fibrils to the basement membrane of the retina by cellular and molecular interactions between components of the vitreous and the inner limiting membrane. Fibronectin and laminin are extracellular glycoproteins which are known to be the most important components of the attaching mechanism for stabilizing the vitreoretinal attachment. The vitreous is a clear, proteinaceous material which fills the posterior of the eye between the lens and the retina. The vitreous is attached at its posterior face to the retina at the vitreoretinal junction along the inner limiting membrane. The vitreoretinal junction is a layer of basement membrane proximal to the vitreous.
The inner limiting membrane of the retina contains type I and type II collagen, laminin, fibronectin and glycoconjugates. These components have been found to bind collagen fibers between the vitreous and the inner limiting membrane.
Vitreous traction is recognized as a serious and potentially blinding complication in a number of vitreoretinal diseases following vitreoretinal surgery. An important aspect of most vitreoretinal surgery is to relieve the vitreous traction. Improvements have been made in mechanical vitrectomy techniques and instrumentation. However, the complete removal of the cortical vitreous from the retinal surface continues to be a difficult task. In some vitreoretinal proliferative disorders, surgical removal of the cortical vitreous can result in retinal break formation or bleeding from traction on retinal blood vessels.
Numerous studies have been conducted to develop a chemical system to separate the vitreoretinal interface without damage to the retina. These studies typically evaluate the vitreoretinal interface and have devised various pharmacological methods for inducing a traumatic separation between the vitreous and the retina. Intraoperative complications, such as retinal tears and hemorrhage can occur during surgical hyaloidectomy.
A number of enzymes and chemical substances have been used to induce posterior vitreous detachment. For example, chondroitinase did not show any activity but both hyaluronidase and Alpha-chymotrypsin caused posterior vitreous detachment. However, these enzymes produced peripapillary and vitreous hemorrhage in these eyes. Dispase, hyaluronidase, Alpha-chymotrypsin, collagenase, chondroitinase, and expansile gas are pharmacological agents used to induce PVD. Dispase has been used in human and porcine cadaver eyes to separate the attachment of the posterior hyaloid from the inner limiting membrane. Dispase induced posterior vitreous detachment with minor morphologic changes in the inner retina. However, dispase, at low concentrations of 0.05-0.07 U, can cause proliferative vitreoretinopathy in 94% of cases up to 21 days after intravitreal injection. Doses equal to or higher than 0.05 U dispase can cause histologic epiretinal cellular membranes in all animals and 25% to 50% cataract formation which is related to dispase concentration. Some toxicity to the inner layer of the retina 15 minutes after injection of dispase has been reported, in spite of inducing posterior vitreous detachment. Intravitreal injection of hyaluronidase induced PVD in rabbits. The probable mechanism of inducing posterior vitreous detachment using hyaluronidase is vitreous liquefaction.
One study of a pharmacological method of inducing posterior vitreous detachment is described by Verstraeten et al
Arch. Ophthalmol
., vol. 111, June 1993. This study evaluated the effectiveness of plasmin, which is a serine protease, in cleaning the vitreoretinal interface between the posterior vitreous cortex and the internal limiting membrane. The results showed some vitreous detachment and the presence of inflammatory cells. Other studies reported the application of plasmin in the vitreous in pediatric macular hole cases. A less traumatic separation of the vitreous from the retina and optic nerve head was induced by the injection of plasmin intravitreally immediately prior to vitrectomy. Plasmin and a plasminogen activator were evaluated for their effect on the basement membrane where plasmin was shown to be effective in degrading laminin and fibronectin which are found at the vitreoretinal junction and play an important role in vitreoretinal attachment. These processes did not however, produce complete posterior vitreous detachment.
Another example of efforts to induce posterior vitreous detachment is disclosed in U.S. Pat. No. 5,722,428 to Kaplan et al. In this process dispase is selected to specifically clean type IV collagen and fibronectin. The dispase is injected into the eye to promote posterior vitreous detachment. This process was shown to be ineffective in including complete vitreous detachment.
Accordingly, there is a continuing need for an effective process for inducing total or complete posterior vitreous detachment.
SUMMARY OF THE INVENTION
The present invention is directed to a composition and process for inducing posterior vitreous detachment in the eye. More particularly, the invention is directed to a process of introducing a combination of plasminogen and a plasminogen activator into the eye to induce posterior vitreous detachment.
Accordingly, a primary object of the invention is to provide a composition and process for inducing posterior vitreous detachment that is efficient and effective.
Another object of the invention is to provide a composition and process for inducing substantially complete posterior vitreous detachment of the vitreous from the inner limiting membrane of the retina.
A further object of the invention is to provide a process of inducing posterior vitreous detachment substantially without intraocular inflammation, electroretinography abnormalities or histologic abnormalities.
Another object of the invention is to provide a composition for separating the vitreous from the retina.
A further object of the invention is to provide a composition and process for dissolving blood clots in the vitreous.
The objects of the invention are basically attained by providing a process for inducing posterior vitreous detachment of the vitreous from the inner limiting membrane of an eye, comprising the step of introducing a composition of plasminogen and a plasminogen activator into the vitreous of an eye of an animal, said plasminogen and plasminogen activator being introduced in an effective amount to induce posterior vitreous detachment and said plasminogen activator being present in an amount to stimulate the conversion of plasminogen to plasmin.
The objects of the invention are further attained by providing a composition for inducing posterior vitreous detachment in the eye of an animal comprising plasminogen and a plasminogen activator enzyme in an amount sufficient to convert said plasminogen to plasmin, said plasminogen and plasminogen activator being present in amounts to induce substantially complete posterior vitreous detachment from the retina without causing inflammation.
The objects of the invention are also attained by providing a process for dissolving blood clots in the vitreous, comprising injecting a composition into the vitreous of the eye in an effective amount to dissolve blood clots present in the vitreous, the composition comprising a mixture of plasminogen, a plasminogen activator enzyme and an ophthalmologically acceptable carrier.
REFERENCES:
patent: 5292509 (1994-03-01), Hageman
patent: 5304118 (1994-04-01), Trese et al.
patent: 5722428 (1998-03-01), Kaplan et al.
patent: 5767079 (1998-06-01), Glaser et al.
Arthur C. Guyton, Textbook of Medical Physiology, 6th Ed., WB Saunders Co., Phila., pp. 98-99, 1981.*
Chemical Abstracts 124
Minu, L.L.C.
Prats Francisco
Roylance Abrams Berdo & Goodman L.L.P.
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