Surgery – Means for introducing or removing material from body for... – Treating material applied to or removed from external...
Reexamination Certificate
2002-01-30
2003-12-09
Lo, Weilun (Department: 3761)
Surgery
Means for introducing or removing material from body for...
Treating material applied to or removed from external...
C514S912000
Reexamination Certificate
active
06659985
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method to use transdermal administration of androgens. More specifically, this invention involves the transdermal delivery of androgenic hormones to the adnexa of the eye for the treatment of dry eye disease. Additionally, this invention relates to a method to increase contact lens wear time through the transdermal delivery of androgenic hormones to the tissue adjacent to and surrounding the eyeball.
DESCRIPTION OF THE RELATED ART
Dry eye, keratoconjunctivitis sicca, is the most common treatable eye disease in the United States. An estimated 58 million Americans suffer from dry eye. Dry eye disease includes keratoconjunctivitis (KCS), age-related dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, occular cicatrical pemphigoid, blepharitis, Riley-Day syndrome, and congenital alacrima. Dry eye disease can also be caused by nutritional disorders or deficiencies (including vitamins), pharmacologic side effects, eye stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune and other immunodeficient disorders, and comatose patients who are unable to blink.
Currently, the pharmaceutical treatment of dry eye disease is mostly limited to administration of artificial tears (saline solution) to temporarily rehydrate the eyes. However, relief is short-lived and frequent dosing is necessary. In addition, artificial tears often have contra-indications and incompatibility with soft contact lenses (Lemp Cornea 9 S48-550 (1990)). The use of phosphodiesterase inhibitors, such as 3-isobutyl-1-methylxanthine (IBMX) to stimulate tear secretion is disclosed in U.S. Pat. No. 4,753,945. The effectiveness of these phsphodiesterase inhibitors is currently being investigated (Gilbard, et al.,
Arch. Opthal
, 109
—
1672-76 (1991) and 112:1614-16 (1994); idem,
Inv. Opthal. Vis. Sci
. 31:1381-88 (1990)). Stimulation of tear secretion by topical application of melanocyte stimulating hormones is described in U.S. Pat. No. 4,868,154.
In addition, a topical ophthalmic formulation of cyclosporine (Restasis) has been investigated as a treatment of immune-based dry eye disease (Stern et al.,
Adv. Exp. Med. Biol
., 438:643-651 (1998)). Stimulation of ocular mucin secretion has also been demonstrated with hydroxyeicosatetraenoic acid derivatives (Yanni, et al., U.S. Pat. No. 5,696,166), gefarnate (Nakamura et al.,
Exp. Eye Res
., 65-569-574 (1997)). U.S. Pat. No. 5,900,407 and WO 98/34593 (Yerxa et al.) disclose a method of stimulating tear secretion from lacrimal tissue by administering to the eyes an effective amount of purinergic receptor agonists such as uridine 5′-triphosphate, cytidine 5′-triphosphate, adenosine 5′-triphosphate, dinucleotides, and their analogs. Jumblatt and Jumblatt (Exp.
Eye Res
. 67:341-346 (1998)) demonstrate the effects of adenine analogues on secretion of high molecular weight, mucin-like glycroprotein by conjunctival goblet cells.
Additionally, a method for increasing hydration and lubrication of lacrimal tissues has been suggested by Yerxa, U.S. Pat. No. 6,277,855 (hereby specifically incorporated by reference in its entirety). This method involves administering to the subject a nicotinic acetylcholine receptor agonist such as nicotine and its analogs, such as transmetanicotine in an effective amount to stimulate mucus secretion in the lacrimal system.
Various physiological abnormalities have been proposed for the cause of dry eye. These physiological abnormalities include lack of tear volume and deficiencies in the precomeal tear film. Dry eye, however, is not caused by lack of tear volume alone, but a deficiency of tear components that result in epithelial pathology and inflammation of the ocular surface. Androgens have been demonstrated to modulate the anatomy, physiology, and the immune system of the lacrimal gland in rats, rabbits, hamsters, and humans. Decreased lacrimal output has been observed during pregnancy, oral contraceptive use, and post-menopause. Testosterone levels correlate with tear production in menopausal women. Patients who report severe dry eye are more likely to have low testosterone levels. If a male rat is castrated, lacrimal output is diminished and androgen supplementation will reverse the decrease. The levels of androgens that protect the ocular surface from inflammation decrease with age. When the level is reduced as in menopause, ocular cells make more cytokines that attract T cells to the conjunctiva, producing surface damage and increased symptoms of dry eye disease.
Because of the ability of androgens to modulate the immune system of the lacrimal gland, Applicants were motivated to study the inclusion of androgens in eye drops. It was found that androgens were not very soluble in water and difficult to deliver as an eye drop. The application of an androgen to the eye in the form of an eye drop would bum, sting and cause discomfort.
BRIEF SUMMARY OF THE INVENTION
It has been surprisingly and unexpectedly discovered that transdermal delivery of androgenic hormones to the adnexa of the eye results in a method to increase contact lens wear. This method involves transdermally administering a composition to a subject in need of such treatment, the composition being made of a therapeutically effective amount of an androgenic hormone in a pharmaceutically effective carrier. Additionally, it has been discovered that transdermal delivery of androgenic hormones to the adnexa of the eye results in a method of treating dry eye disease.
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Handbook of Ocular Disease Managment;Keratitis Sicca/Dry Eye Syndrome.
Worda et al.; “Treatment of Keratoconjunctivitis Sicca with Topical Androgen” Maturitas 37 (2001) 209-212; published Jan. 13, 2001.
Tsubota, Kazuo “Tear Dynamics and Dry Eye,” Department of Ophthalmology, Toyoko Dental College, Chiba, Japan and Department of Ophthalmology Keio University School of Medicine, Tokyo, Japan.
Sullivan et al. “Androgen Influence on the Meibomian Gland,” Investigative Ophthalmology and Vision Science (2000).
Sullivan, et al. “Are Women with Sjogren's Syndrome Androgen Deficient?” Investigative Ophthalmology and Visions Science (2000).
Connor, et al. “A Weak Androgenic Artificial Tear Solution Decreases the Osmolarity of Dry Eye Patients,” Investigative Opthalmology and Vision Science (2001).
Bacman et al. “MuscarinicAcetylocholine Receptor Antibodies as a New Marker of Dry Eye Sjogren Syndrome.” Investigative Ophthalomology and Vision Science (2001).
Connor et al. “The Efficacy of Androgenic Artificial Tears in the Treatment of Dry Eye,” Optometry & Vision Science, Dec. 2001.
Bogart Michael
Butler Snow et al.
Lo Weilun
Southern College of Optometry
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