Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
Reexamination Certificate
1998-08-06
2002-08-13
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
C514S912000
Reexamination Certificate
active
06432934
ABSTRACT:
This invention relates to therapeutic ophthalmic preparations and methods of using the preparations locally to treat eye surface inflammation including meibomianitis and related dry eye disease. More particularly, it relates to topical ophthalmic solutions containing tetracycline compounds to suppress eye surface inflammation, including meibomianitis, while maintaining or restoring conjunctival mucus-containing goblet cells.
Systemic tetracyclines are currently used to treat ocular rosacea, a condition characterized by eye surface inflammation, and a variety of related eye disorders such as blepharitis, meibomianitis, keratitits, conjunctival hyperemia, and eyelid hyperemia. Open-label prospective studies have been published describing a decrease in blepharitis and conjunctival hyperemia associated with ocular rosacea following systemic administration of tetracycline (1, 2). Systemic oxytetracycline treatment of ocular rosacea has also been tested in a double-masked trial and found to be more effective than placebo in inducing remissions (3). In the trial, it was reported that eyelid and conjunctival hyperemia responded well, as did the associated blepharitis.
Based on these studies and clinical experience, oral tetracyclines has been recommended for treating meibomianitis, blepharitis and eye surface inflammation (4, 5, 6). Meibomianitis is a disorder characterized by inflammation centered about the meibomian glands. When inflammation includes most of the eye lid, the general term “blepharitis” may be applied. When inflammation includes the conjunctiva, the term “conjunctivitis” applies. When inflammation involves the cornea, the term “keratitis” applies. The eye surface includes the eye lids, cornea and conjunctiva. Recently, it was observed that meibomianitis and eye surface inflammation develops in a rabbit model for meibomian gland dysfunction (7). Analogous findings have been reported in humans (8, 9). These studies show that meibomianitis leads to meibomian gland dysfunction, with loss of meibomian gland oil from the tear film, an increase in tear film evaporation, a loss of water from the tear film and the development of dry eye surface disease.
Specifically, in the aforementioned rabbit model of meibomian gland dysfunction, meibomian gland orifice closure increases tear film osmolarity and decreases corneal epithelial glycogen and conjunctival goblet-cell density. These decreases are analogous to those seen with keratoconjunctivitis sicca (commonly known as “dry eye”) from lacrimal gland disease (10, 11). The clinical relevance of these data has been further supported by studies demonstrating that patients with meibomian gland drop out have significantly elevated tear film evaporative rates and tear film osmolarity (12).
Just how tetracyclines work in the treatment of ocular surface inflammatory disorders, such as ocular rosacea, meibomianitis, blepharitis, conjunctivitis and keratitis has previously been unknown. However, elsewhere in the body it has been known that tetracyclines have potent antibacterial properties, inhibit collagenase activity (15, 16, 17), and decrease leukocyte chemotaxis (18, 19, 20, 21) and phagocytosis (22). When administered systemically, tetracycline enters into the tears (13) and concentrates in goblet cells, around blood vessels, and on the external surface of the conjunctival epithelium (14). Systemic administration of tetracycline, however, has several drawbacks. For example, it often results in adverse side effects, including gastrointestinal irritation, vaginal yeast infection, sunlight sensitivity and systemic allergic reactions.
Accordingly, it is an object of this invention to provide an improved ophthalmic preparation for locally delivering a tetracycline compound to ocular surfaces. It is another object of this invention to provide an ophthalmic solution for locally delivering a tetracycline compound to ocular surfaces, while maintaining or restoring essentially normal levels of conjunctival mucus-containing goblet cells. It is a further object of this invention to provide an electrolyte-based tetracycline formulation for simultaneously treating inflammatory eye diseases, such as meibomianitis, and associated blepharitis and dry eye disorders.
Additional objects of the invention will be apparent from the following description.
SUMMARY OF THE INVENTION
A therapeutic preparation for ophthalmic use has been developed that provides the advantage of drug delivery and treatment or prevention of dry eye disease. The preparation contains an anti-inflammatory agent, such as a tetracycline compound, in an electrolyte-based solution which can be applied topically to the eye, permitting the maintenance or restoration of essentially normal levels of conjunctival mucus-containing goblet cells and corneal glycogen. The ophthalmic preparation thus provides the advantages of local tetracycline delivery to ocular surfaces without a substantial decrease in mucus-containing goblet cells or corneal glycogen typically associated with the use of standard ophthalmic preparations. The ophthalmic preparation provides the further advantage of increasing low goblet cell density and corneal glycogen levels associated with the dry eye surface disease resulting from meibomian gland dysfunction. In contrast, standard ophthalmic preparations have been shown in studies described herein to exacerbate the loss of goblet cells and corneal glycogen.
In general, the ophthalmic preparation contains an aqueous solution of a tetracycline compound in an amount sufficient to treat an ocular disease characterized by eye surface inflammation with our without dryness. The preparation preferably also includes a balance of electrolytes found in natural tear fluid required for ocular surface maintenance, function and repair. In preferred embodiments, these electrolytes are present in amounts sufficient to maintain or restore essentially normal levels of conjunctival goblet cells and corneal glycogen, thereby maintaining mucus-mediated lubrication and the potential for normal healing. In a particularly preferred embodiment, the tetracycline compound is contained in Solution 15, described in U.S. Pat. No. 4,911,933, the contents of which are hereby incorporated by reference.
Principal electrolytes employed in the invention include, but are not limited to, sodium and chloride, in combination with lesser amounts of potassium and bicarbonate. Typically, these electrolytes are present in the following concentration ranges:
Potassium between about 22.0 to 43.0 millimoles per liter (mM/l), preferably between about 23.0 to 42.0 mM/l;
Bicarbonate between about 29.0 to 50.0 mM/l, preferably between about 31.0 to 48.0 mM/l;
Sodium between about 130.0 to 140.0 mM/l, preferably between about 131.0 to 139.0 mM/l; and
Chloride between about 118.0 to 136.5 mM/l, preferably between about 124.0 to 136.0 mM/l.
Additional electrolytes which can be employed in the ophthalmic preparation, in combination with the above-listed electrolytes include, but are not limited to, calcium, magnesium and phosphate. Typically, these electrolytes are typically present in the following concentration ranges:
Magnesium between about 0.3 to 1.1 mM/l, preferably between about 0.5 to 0.6 mM/l,
Calcium between about 0.5 to 2.0 mM/l, preferably between about 0.6 to 0.8 mM/l, and
Phosphate between about 0.8 to 2.2 mM/l, preferably between about 1.8 to 2.0 mM/l.
The concentration of the tetracycline compound will vary depending on the nature and severity of the eye surface inflammation being treated and the specific tetracycline compound used. Generally, for tetracycline, the concentration in solution will range from about 0.125% to 2% when the solution is isotonic or attains isotonicity. Any suitable tetracycline compound (including tetracycline derivatives, analogs and salts thereof) known in the art can be used, such as those described in further detail below.
Ophthalmic preparations of the present invention can be used in methods of treating ocular disorders characterized by eye surface inflammation, such as meibomianiti
Advanced Vision Research
Fay Zohreh
Lahive & Cockfield LLP
Loren, Esquire Ralph A.
Remillard, Esquire Jane E.
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