Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-04-19
2001-08-14
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C514S887000, C514S944000
Reexamination Certificate
active
06274160
ABSTRACT:
The present invention is directed to compositions containing histamine H
2
agonists and methods for their use in treating dry eye. The H
2
agonists of the present invention stimulate the release of mucins in the eye. The invention is also directed to methods of preventing and treating dry eye with the compositions of the present invention.
BACKGROUND OF THE INVENTION
Dry eye, also known generically as keratoconjunctivitis sicca, is a common ophthalmological disorder affecting millions of Americans each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, corneal damage may occur leading to impaired vision. Other diseases, such as Sjogren's disease and cicatricial pemphigoid manifest dry eye complications.
Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the complication share a common effect, that is the breakdown of the pre-ocular tear film, which results in dehydration of the exposed outer surface and many of the symptoms outlined above (Lemp, Report of the Nation Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes,
The CLAO Journal,
volume 21, number 4, pages 221-231 (1995)).
Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day. Another approach has been the use of ocular inserts that provide a tear substitute or to stimulate endogenous tear production.
Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Examples of these treatment approaches are disclosed in U.S. Pat. No. 4,131,651 (Shah et a l.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S. Pat. No. 4,744,980 and U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.) and U.S. Pat. No. 5,294,607 (Glonek et al.).
U.S. Pat. No. 3,991,759 (Urquhart) is directed to the use of ocular inserts in the treatment of dry eye. Other semi-solid therapy has included the administration of carrageenans (U.S. Pat. No. 5,403,841, Lang) which gel upon contact with naturally occurring tear film.
Another recent approach involves the provision of lubricating substances in lieu of artificial tears. U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating, liposome-based composition.
Aside from the above efforts, which are directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the dry eye condition have also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye condition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate preocular tear film; and U.S. Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient's waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is not only cumbersome and time consuming, but is also potentially very expensive.
The use of ocular inserts is also problematic. Aside from cost, they are often unwieldy and uncomfortable. Further, as foreign bodies introduced in the eye, they can be a source of contamination leading to infections. In situations where the insert does not itself produce and deliver a tear film, artificial tears must still be delivered on a regular and frequent basis.
In view of the foregoing, there is a clear need for an effective treatment for dry eye that is capable of alleviating symptoms, as well as treating the underlying physical and physiological deficiencies of dry eye, and that is both convenient and inexpensive to administer. Therapeutics which promote the production of endogenous tear components, such as mucins, will meet these needs.
Mucins are proteins which are heavily glycosylated. Mucins provide protective and lubricating effects to epithelial cells, especially those of mucosal membranes. Mucins have been shown to be secreted by vesicles and discharged on the surface of the conjunctival epithelium of human eyes (Greiner et al., Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses,
Archives of Ophthalmology,
volume 98, pages 1843-1846 (1980); and Dilly et al., Surface Changes in the Anaesthetic Conjunctiva in Man, with Special Reference to the Production of Mucus from a Non-Goblet-Cell Source,
British Journal of Ophthalmology,
volume 65, pages 833-842 (1981)). A number of human-derived mucins which reside in the apical and subapical corneal epithelium have been isolated and cloned (Watanabe et al., Human Corneal and Conjunctival Epithelia Produce a Mucin-Like Glycoprotein for the Apical Surface,
Investigative Ophthalmology and Visual Science,
volume 36, number 2, pages 337-344 (1995)). Recently, Watanabe discovered a new mucin which is secreted via the cornea apical and subapical cells as well as the conjunctival epithelium of the human eye (Watanabe et al.,
IOVS,
volume 36, number 2, pages 337-344 (1995)). These mucins provide lubrication, and additionally attract and hold moisture and sebaceous material for lubrication and the corneal refraction of light. Nowhere in the art, however, has the use of histamine H
2
agonists been proposed to stimulate mucin production in ocular tissues as a treatment for dry eye.
SUMMARY OF THE INVENTION
The present invention is directed to compositions and methods for the treatment of dry eye. More specifically, the present invention discloses ophthalmic compositions containing histamine H
2
agonists and methods for treating dry eye.
The H
2
agonists work by increasing mucin production and secretion from ocular surface epithelial cells of the cornea and conjunctiva. The increased mucin provides the base level of lubricant and aqueous attractant to provide the necessary layer of tear fluid. The increased production of tear fluid lubricates the surface of the eye and prevents the symptoms associated with dry eye.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that histamine H
2
agonists stimulate mucin production in conjunctival epithelium and are therefore believed to be useful in treating dry eye. As used herein, the terms “histamine H
2
agonists” or “H
2
agonists” refer to those molecules which stimulate H
2
receptors of the ocular surface, evoking mucin release.
The present invention contemplates all known and yet to be discovered H
2
agonists. Examples of H
2
agonists of the present invention include dimaprit, amthamine and impromidine. The most preferred H
2
agonist of the present invention is dimaprit.
The histamine H
2
agonists of the present invention are available from numerous sources. For example, the H
2
agonists may be obtained from Sigma Chemical (St. Louis, Mo.), Research Biochemicals International (Natick, Mass.) and Biomol (Plymouth Meeting, Pa.). As stated above, other H
2
agonists may become available through discovery, and these molecules and their methods o
Gamache Daniel A.
Miller Steven T.
Yanni John M.
Alcon Laboratories Inc.
Di Nola -Baron Liliana
Mayo Michael C.
Page Thurman K.
Ryan Patrick M.
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