Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-18
2002-12-03
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S443000, C514S912000
Reexamination Certificate
active
06489335
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to therapeutic treatment of ocular diseases such as dry eye disease.
BACKGROUND
Dry eye disease encompasses any condition where the tear film loses water and becomes more concentrated. It is a common complaint, affecting three million people in the United States alone, yet it is difficult to diagnose and treat. The loss of water from the tear film causes a corresponding rise in tear osmolarity. The increased osmolarity results in symptoms such as a sandy-gritty feeling in the eye, burning, irritation, or a foreign-body sensation that worsens during the day. Patients suffering from dry eye disease complain of mild to severe symptoms, with signs ranging from minimal superficial punctate keratitis to corneal perforation.
Dry eye disease has a chronic remitting and relapsing nature and may result from a number of factors. The disease may be a natural part of the aging process, affecting 15%-20% of adults over age 40. It may also result from pathological processes such as diseases of the lacrimal glands, mucus glands, and/or lipid producing glands, and may occur with cell infiltration or atrophy of the lacrimal gland (Sjogren's Syndrome). Estrogen deficiency in postmenopausal women is also postulated to result in dry eye disease.
One method to treat dry eye disease is by topical administration of over-the-counter drugs that serve as artificial tears. Numerous varieties of these artificial tears are available (TheraTears® (Advanced Vision Research), Refresh® and Celluvisc® (Allergan), Tears Natural® and Bion Tears® (Alcon), GenTeal® and HypoTears® (CIBA Vision), each of which contain electrolytes and has varying pH levels, osmolarities, and surface tensions. Another method to treat dry eye disease is by surgery to close the lacrimal drainage ducts using punctum plugs. Neither method, however, is completely desirable. Artificial tears do not have a constant flow rate as do human tears, and treat the symptoms rather the cause of the disease. Surgery has its attendant risks, and may not be a viable option in older patients.
It is known that Cyclosporin A (cyclosporine, Allergan Inc.), may treat dry eye disease since patients administered cyclosporine for other disorders have shown a marked increase in tear flow. A topical formulation containing Cyclosporin A (Arrestase®, Allergan Inc.) is currently under review by the Food and Drug Administration. Cyclosporin A is an immunomodulator, suggesting that immune-mediated inflammation contributes to dry eye disease. Cyclosporin A has been used to treat various ocular pathologies such as glaucoma, corticosteroid-induced ocular hypertension, allograft rejection, infections, and ocular surface disease. It is also known that Cyclosporin A may be used in the eye to treat uveitis (inflammation of the uvea) by topical, intravitreal or systemic administration. Doses of 0.05%, 0.1%, and 0.5% cyclosporine have been reported. Cyclosporin A has good penetration into the cornea but not into the anterior chamber, and does not increase intraocular pressure or cause cataracts.
Tacrolimus (Prograf®, previously known as FK-506) is an immunomodulating drug that has been applied topically to treat a variety of dermatoses. Topical administration of tacrolimus at doses ranging from 0.03%-0.3% resulted in significant clinical improvement in atopic dermatitis after 2-3 weeks treatment, and tacrolimus treatment of other dermatologic diseases shows promise. Tacrolimus, like cyclosporine, blocks the signal transduction pathway needed to induce interleukin-2 gene expression and thereby activate T lymphocytes. In addition to suppressing T cell activation, tacrolimus inhibits anti-lgE-triggered histamine release and inhibits prostaglandin D2 synthesis in human skin mast cells. While oral administration produces limiting adverse effects (systemic immunosuppression, infection, neural toxicity, nephrotoxicity, and hypertension), topical administration for treatment of dermatoses at concentrations up to 0.3% showed no significant difference in effects between treated and control groups. In addition, tacrolimus is well tolerated locally and only occasionally causes mild irritation.
The non-systemic use of tacrolimus in the treatment of ocular diseases including dry eye disease would be advantageous.
SUMMARY OF THE INVENTION
The invention is directed to a method of treating ocular disease, such as dry eye disease, uveitis, scleritis, neuritis, and/or papilitis, by providing an effective amount of tacrolimus in a pharmaceutically acceptable formulation to a diseased eye. In one embodiment, the formulation is applied topically. In an alternative embodiment, the formulation is injected intraocularly, for example by subconjuctival, intravitreal, or retrobulbar injection. For subconjunctival injection a concentration in the range of about 1 ng/ml to 500 &mgr;g/ml tacrolimus may be used. For intravitreal injection a concentration in the range of 1-1000 &mgr;g/0.1 ml may be used, with a preferred concentration of about 50 &mgr;g/0.1 ml tacrolimus. For retrobulbar injection, a concentration in the range of about 20-1000 &mgr;g/ml tacrolimus may be used. Tacrolimus may be administered in an aqueous-based solution, for example tacrolimus bound to liposomes, or tacrolimus dissolved in an organic solvent. Tacrolimus may also be provided in an inert physiologically acceptable carrier by surgical implantation, injection, or topical application.
The invention is also directed to a composition for treating dry eye disease. The composition contains an effective amount of tacrolimus in a pharmaceutically acceptable formulation. The formulation may be an aqueous cream or liquid containing, for example, about 1 ng to 10 &mgr;g tacrolimus. The formulation may be an inert carrier such as a microsphere, liposome or polymeric matrix containing tacrolimus. Tacrolimus may be dissolved in an aqueous solvent such as 0.9% saline or 5% dextrose, or an organic solvent such as dimethylsulfoxide (DMSO) or an alcohol.
The invention is additionally directed to a composition for intraocular injection to treat ocular disease. An effective amount of tacrolimus is dissolved in either an aqueous solvent such as 0.9% saline or 5% dextrose, or an organic solvent such as DMSO or alcohol.
REFERENCES:
patent: 5457182 (1995-10-01), Wiederrecht et al.
patent: 5770607 (1998-06-01), Honbo et al.
patent: 5952371 (1999-09-01), Baker et al.
patent: 6004565 (1999-12-01), Chiba et al.
Gholam A. Peyman, et al.,Keratitis(Noninfectious), Principles and Practice of Ophthalmology, W.B. Saunders Company, 1980, pp. 446-449.
Graeme M. Lipper, et al.,Recent therapeutic advances in dermatology,JAMA, vol. 283, No. 2, Jan. 12, 2000, pp. 175-177.
Eric D. Donnenfeld, et al.,Cyclosporine provides effective treatment for dry eye,Therapeutic Updates in Opthalmology, Special Issue, Jul. 1999, pp. 1-3.
Maxine Lipner,Dry Eye 101: Developing etiologies and treatments for the widespread syndrome,EyeWorld, Feb. 1999, pp. 19ff.
Jeffrey P. Gilbard,EW Interview: Electrolyte balance is key to dry-eye product's success,EyeWorld, Feb. 1999, pp. 20ff.
Fay Zohreh
Wood Herron & Evans L.L.P.
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