Title:  Method of treating certain eye diseases

United States Patent:  6,605,640

Issued:  August 12, 2003

Inventors:  Nolan; Gerard M. (P.O. Box 827, Ave., Farmington, CT 06032)

Appl. No.:  773878

Filed:  January 31, 2001

Abstract

The present invention is directed to methods for treating diminished visual acuity in a human patient who has been diagnosed as suffering from a disease or disorder of the posterior region of the eye. These involve topical application to the eye, an amount of acetylcholine esterase inhibitor containing composition is carried out so that it is sufficient to provide a therapeutic benefit to alleviate the diminished visual acuity in the human patient. The composition is administered at bedtime after an eye straining work for about 20 minutes.

SUMMARY OF THE INVENTION

In accordance with the present invention, various eye diseases or disorders of the posterior segment of the eye, especially those related to the retinal and choroidal vascular diseases, are treated by topical administration to the patient's affected eye of an amount of a acetylcholine esterase inhibitor in a concentration effective to increase visual acuity of the diseased eye without adverse effects. Therefore, this invention provides several advantages over prior art laser therapy based methods employed for alleviating visual acuity in patients suffering from an eye disease in the posterior segment of the eye.

In a general aspect, A method of treating a human patient suffering from a retinal or choroidal vascular disease or hereditary retinal or choroidal disease, the method of topically administering to an eye affected with disease, an amount of a acetylcholine esterase inhibitor containing composition sufficient to provide a therapeutic benefit to alleviate the diminished visual acuity.

More specifically, a method of treating a human eye disease in the posterior segement of the eye is provided which involves the step of topically administering to an eye affected with the disease, an amount of a acetylcholine esterase inhibitor containing composition sufficient to provide a therapeutic benefit. The therapeutic benefit can be complete relief or cure from the eye disease or at least preventing the affected eye tissue from further deterioration (and stabilize the disease condition). The therapeutic benefit can also be the alleviation of the diminished visual acuity. The diseases in the posterior segment of the eye that can be treated by the present method included age related macular degeneration, macular cyst, macular hole, solar retinopathy, diabetic retinopathy, branch retinal vein occlusion and Lebers Congenital Amaurosis. The composition is administered at bedtime. In one embodiment, the inhibitor is (2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioate which is present at a concentration of about 0.001% to about 0.25%. The concentration of (2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioate can be about 0.0075%, or about 0.03%, or about 0.12%. The acetylcholine esterase inhibitor is contained in a pharmaceutically acceptable carrier buffer solution.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for treating eye diseases such as retinal or choroidal vascular diseases and certain hereditary eye diseases associated with the pathological state of the tissues and structures in the posterior segment of the eye. The methods use the topical application of acetylcholine esterase inhibitors in very low concentrations but sufficient enough to effectively restore the visual acuity.

By practicing the method of the present invention, alleviation of diminished visual acuity due to, for example, macular cyst, macular hole, solar retinopathy, diabetic retinopathy, branch retinal vein occlusion and AMD can be achieved. By "restoration or alleviation of diminished visual acuity", it is meant that any significant improvement in vision of a patient suffering from blindness or poor vision.

These diseases in human patients are usually diagnosed by opthalmologistis or other physicians familiar with etiology of eye, by means of special photography of the retina. In a typical diagnostic procedure, flourecein angiography, the physician injects a fluorescein vegetable-base dye into a patient's blood. The patient's pupil is also dilated by administering pupil dilating drugs (mydriatic) to the eye. The physician then takes a series of photographs of the retina, using a light source at a particular excitation wavelength so that it causes any leakage of fluid of the drug from the patient's retinal and choroidal vasculature to emit fluorescent light at a different wavelength. The physician then analyzes the series of photographs of the retina to determine the presence and concentration of leakage. If present at abnormal levels as determined a physician skilled in this area, these abnormal levels of fluorescent leakage indicate the presence or onset of a particular retinal or choroid vascular disease.

By practicing the method of the present invention, the disease condition of the yea is at least stabilized without further deterioration of the tissues.

The structure, cellular anatomy physiology, biochemistry and other details of the eye are provided in various ophthalmological and medical school texts that focus specifically on the eye and diseases of the eye e.g. Dwanes Textbook of Ophthalmology, the American Academy of Ophthalmology Clinical Science Course, etc. The practicing physicians in this art can readily determine anatomical structures of a normal and diseased human eye whether the disease be in the anterior or posterior region of the eye ball. Once a human patient is diagnosed as suffering from a disease such as those described in the above paragraph, an amount of a acetylcholine esterase inhibitor containing composition sufficient to provide a therapeutic benefit is administered.

Acetylcholine esterase inhibitors are known to one skilled in the art. There are at least two ACHE inhibitor drugs currently approved for clinical use on the eye in the United States. They are (2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioate sold as PHOSPOHLINE IODIDE.RTM. (Wyeth-Ayerst, Philadelphia, Pa.), and physostigmine (also known as eserine) sold as ANTILIRIUM.RTM. (Forest Pharmaceuticals, St. Louis, Mo.). PHOSPHOLINE IODIDE is dispensed as eyedrops at a desired potency. PHOSPHOLINE IODIDE of various concentrations, such as for example 0.25%, 0.125%, 0.06% and 0.03% and a pharmaceutically acceptable sterile diluent to dilute the concentrated form of this drug are commercially available. PHOSPHOLINE IODIDE is currently used for glaucoma and accommodative esotropia. As such, PHOSPHOLINE IODIDE is not a preferred drug even to treat glaucoma and accommodative esotropia because of many adverse side effects caused by this drug when it is used in the current regimen of multiple times a day at high concentrations. Some of the side effects known to be caused by the currently recommended doses of this drug (for glaucoma at 0.12 and 0.25 BID) are iris cysts, cataract formation especially anterior subcapsular, posterior synechiae and elevated intraocular pressure.

In the new method, the cholinesterase inhibitor, such as phospholine iodide, administered in concentrations many fold more dilute than currently available pharmacological preparations, applied to the eye before sleep will achieve alleviation of the deteriorated or deteriorating vision with none of the unacceptable side effects of the usual pharmacological preparations and without the loss of peripheral vision. The effect of one administration of the inhibitor can last for many days. The present invention shows that the effective concentration of AChE inhibitor in the composition to treat diseases associated with the posterior region of the eye can be very low (for example, as low as at least 0.001% to about 0.0075% of PHOSPHOLINE IODIDE) to be effective. The invention discloses that such a concentration is extremely useful medically. Specifically, this lower dose range is especially useful in providing eye drugs that will contain a concentration of AChE inhibitor that is low enough to be both safe and effective. For example, application of a drop of 0.03% PHOSPHOLINE IODIDE followed by a drop of suitable diluent (e.g., artificial tear) is not incompatible with the drug.

The composition administered to the eye should have a pharmaceutically acceptable carrier and a selected AChE inhibitor suspended or dissolved in the carrier. The concentration of AChE inhibitor in the composition administered to the eye and the method of administration of the composition in accordance with this invention depends on the type of AChE inhibitor containing composition used for therapy. For example, preferred concentrations of PHOSPHOLINE IODIDE in the PHOSPHOLINE IODIDE containing composition are from about 0.25% to about 0.001%. More preferred PHOSPHOLINE IODIDE concentrations are from about 0.15% to about 0.005%. Most preferred PHOSPHOLINE IODIDE concentrations are about 0.12%, 0.03% and 0.0075%. It is preferred to apply PHOSPHOLINE IODIDE topically to the eyes in the form of eyedrops. Although it is preferred that these solutions with various concentrations of PHOSPHOLINE IODIDE are stored in a refrigerator, they an be stored at room temperature for about two months or even beyond two months without losing their efficacy to restore near vision in presbyopic patients.

A solution containing chlorobutanol (0.55%), mannitol (1.2%) boric acid (0.6%) and exsiccated sodium phosphate (0.026%) can be used as a carrier solution and/or as a diluent for PHOSPHOLINE IODIDE. While this solution is presently sold as a diluent in the kit containing PHOSPHOLINE IODIDE, other pharmaceutically acceptable carriers or excipients that are known to enhance membrane permeability and cellular uptake of the drug can be used as diluents with or without modification for application to the eye. Such carriers are known to one skilled in the art.

In a preferred embodiment of the invention, the AChE inhibitor is administered at bedtime. A single topical application of a given AChE inhibitor at bedtime can enhance visual acuity in the phakic emmetropic patients as well as in pseudophakic patients for a few days. For example, application of one to two drops of PHOSPHOLINE IODIDE of a selected concentration at bedtime can alleviate the diminished vision of the patients for at least five days. Preferably, the following steps are followed every time AChE inhibitor is applied to the patient. The first step is to read for about 30 minutes. The second step is to administer an AChE inhibitor of a selected concentration. The third step is to sleep. Without wishing to be bound by any theory or explanation, it is believed that the reading for about 30 minutes preconditions eye muscles and visual pathway to respond better to the AChE inhibitor treatments. It takes about 6 to 8 hours of sleep to notice the restoration. If one is awaken in the middle of sleep, the individual may notice partial effect but after 6 to 8 hours of sleep the effect will be maximized. By the term "bedtime" it is meant that the time when the patient goes to sleep for about 6 to 8 hours, regardless of whether it is during the day or night time. The composition is administered at bedtime, i.e., it is administered just before the patient goes to sleep for about 6 to 8 hours.

AChE inhibitor can be administered to the eye with the disease. It should be noted that the method of this invention can be successfully used to treat diminished visual acuity in phakic as well as pseudophakic patients. The method can also enhance visual acuity of an individual who has no iris. Of particular interest is that this method can be successfully used to treat patients with artificial and rigid intraocular lenses (IOL's). IOL's are inserted at the time of cataract surgery and in refractive procedures to make an individual emmetropic by clear lens extraction. Further, it should be noted that the diminished visual acuity can occasionally be alleviated also in contralateral eye (or untreated eye) to some degree.

Accordingly, by practicing the present invention, one can achieve a definite, measurable gain in visual acuity in patients with retinal vascular or choroidal vascular disease or other known diseases of posterior segment of the eye when administered with the acetylcholinesterase inhibitor, in the dilution and the manner outlined above. Increase in visual acuity can be measured by techniques well known to those skilled in the art. Although the mechanism of action is unknown, it is believed that a suitable dose of AChE inhibitor administered at bedtime may allow the eye to accumulate sufficient stockpiles of acetylcholine by inhibiting acetylcholine esterase activity in the eye and strengthen the eye muscles leading to the normal perfusion of the blood to the posterior region of the eyeball particularly choroid blood vessels. Retinal and choroidal function and health are dependant on normal perfusion of these tissues.

Claim 1 of 47 Claims

What is claimed is:

1. A method of treating a human eye disease, the method comprising topically administering to an eye affected with the disease, an amount of a composition consisting essentially of an acetylcholine esterase inhibitor sufficient to provide a therapeutic benefit, wherein the eye disease is age related macular degeneration, macular cyst, macular hole, solar retinopathy, diabetic retinopathy, branch retinal vein occlusion, or Lebers Congenital Amaurosis.

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