WO1999030716A1

WO1999030716A1 - The use of nitric oxide generations for the treatment of dry eye disorders

Info

Publication number: WO1999030716A1
Application number: PCT/US1998/023806
Authority: WO
Inventors: Daniel A. Gamache; Steven T. Miller; John M. Yanni
Original assignee: Alcon Laboratories Inc
Current assignee: Alcon Vision LLC
Priority date: 1997-12-16
Filing date: 1998-11-10
Publication date: 1999-06-24
Anticipated expiration: 2000-06-16
Also published as: AU1388999A; AR017215A1

Abstract

Compositions containing a nitric oxide generator and methods of use for treating dry eye are disclosed. The compounds of the present invention promote NO production when administered to the eye. It is believed that NO stimulates mucin production in human conjunctival epithelium and are therefore believed to be useful in treating dry eye. A further requirement of a NOG of the present invention is that it stimulates mucin production and/or secretion of the conjunctival epithelium and/or ocular goblet cells following topical ocular application. Examples of NOGs include: nitroglycerin, sodium nitroprusside, spermine NONO ate, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK-409), 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl 1-triazene (NOC-7), S-nitrosoglutathione, 4-phenyl-3-furoxancarbonitrile, S-nitroso-N-acetyl-penicillamine (SNAP), isosorbide denitrate, GEA 3268, GEA 5145, GEA 3175, glyceryl trinitrate, molsidomine, 3-morpholinosydnonimine (SIN-1), hydroxylamine, linsidomine, NOC-18, CHF-2363, pirsidomine, N,N'-dimethylhexanediamine (DMHD/NO), 2,2-diethyl-1-nitroso-oxyhydrazine (DEA/NO), Et 2NN(O)NONa, NO-ketoprofen, NO-diclofenac, NO-flurbiprofen. The most preferred NOG of the present invention is molsidomine.

Description

THE USE OF NITRIC OXIDE GENERATIONS FOR THE TREATMENT OF DRY EYE DISORDERS

The present invention is directed to compositions containing nitric oxide generators

and methods for their use in treating dry eye.

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, vision may be substantially impaired. 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 United States Patent Nos. 4,131,651 (Shah et

al.), 4,370,325 (Packman), 4,409,205 (Shively), 4,744,980 and 4,883,658 (Holly), 4,914,088

(Glonek), 5,075,104 (Gressel et al.) and 5,294,607 (Glonek et al.).

United States Patents directed to the use of ocular inserts in the treatment of dry eye

include 3,991,759 (Urquhart). Other semi-solid therapy has included the administration of

carrageenans (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. United States Patent 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, United States Patent No. 5,041,434

(Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye

condition in post-menopausal women; United States Patent No. 5,290,572 (MacKeen)

discloses the use of finely divided calcium ion compositions to stimulate preocular tear film;

and United States Patent 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.

Mucins are proteins which are heavily glycosylated with glucosamine-based moieties.

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 discovered 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.

Mucins are also produced and secreted in other parts of the body including lung airway

passages, and more specifically from goblet cells interspersed among tracheal/bronchial

epithelial cells.

Nitric oxide has been researched extensively for its effects on vascular dilation, as well

as other possible physiological roles. Nitric oxide is produced by enzymes generally known as

nitric oxide synthases. Several different forms are known to exist, and they operate by

oxidizing one of the two guanidino nitrogens of L-arginine to produce nitric oxide (Rawls,

Bioinorganic Reactions of Nitric Oxide Underlie Diverse Roles in Living Systems, Chemical

and Engineering News, May 6, 1996, Pages 38-42). It is believed that nitric oxide may be

produced in vivo by other mechanisms as well. Nitric oxide has been shown to bind to heme

or hemoglobin and to regulate blood pressure.

It has also been suggested that nitric oxide may play a role in mucin secretion in

chronic otitis (Nitric Oxide Mediates Mucin Secretion in Endotoxin-Induced Otitis Media With

Effusion, Otolaryngology - Head and Neck Surgery, Volume 1 16, Number 3, Pages 308-316

(1997)); and epithelial cell exocytosis (Stimulation Of Mucin Exocytosis From Human

Epithelial Cells by Nitric Oxide: Evidence for a cGMP -Dependent and a cGMP -Independent

Pathway, Biochemistry Journal, Volume 323, Part 2, Pages 521-524 (1997)). Nowhere in the art. however, has the use of nitric oxide or nitric oxide generators 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 and other disorders requiring the wetting of the eye. More specifically, the present

invention discloses compositions containing nitric oxide generators and methods for treating

dry eye type disorders.

Preferred compositions include an effective amount of one or more nitric oxide

generator(s) for the production of mucins. The compositions are administered topically to the

eye for the treatment of dry eye.

Detailed Description of the Invention

Nitric oxide ("NO") is produced in vivo and has been shown to be physiologically

active and useful. For example, NO has been shown to be involved in a number of

physiological phenomena including activities in the brain and cardiovasculature. See

generally, Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition,

McGraw-Hill, New York (1996). NO may be enzymatically synthesized by nitric oxide

synthase ("NOS"). NOS has been shown to exist in at least four isoforms and has been found

in a number of different cell types (Goodman and Gilman's The Pharmacological Basis of

Thereapeutics, pages 286 and 827). - The compounds of the present invention promote NO production when administered to

the eye. It is believed that NO stimulates mucin production in human conjunctival epithelium

and are therefore believed to be useful in treating dry eye. As used herein, the terms "Nitric

Oxide Generator" or "NOG" refer to any compound that is either enzymatically or non-

enzymatically catalyzed to form NO, or stimulates the production of NO by catalytic means.

A further requirement of a NOG of the present invention is that it stimulates mucin production

and/or secretion in the conjunctival epithelium and/or ocular goblet cells following topical

ocular application.

As stated above, the NOGs of the present invention may be selected from a number of

different chemical classes, and may operate in one of several different mechanisms in

promoting the generation of NO. The NOGs of the present invention may provide the nitrogen

source necessary for the enzyme NOS to catalyze the formation of NO. The NOGs of the

present invention may not provide the nitrogen source, but instead stimulate NOS to form NO.

The NOGs of the present invention may also be compounds that stimulate, non-enzymatically,

the formation of NO.

Examples of NOGs include, but are not limited to: nitroglycerin, sodium nitroprusside,

spermine NONO ate, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK-409),

l-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl 1-triazene (NOC-7), S-

nitrosoglutathione, 4-phenyl-3-fiιroxancarbonitrile, S-nitroso-N-acetyl-penicillamine (SNAP),

isosorbide denitrate, GEA 3268, GEA 5145, GEA 3175, glyceryl trinitrate, molsidomine, 3-

morpholinosydnonimine (SIN-1), hydroxylamine, linsidomine, NOC-18, CHF-2363,

pirsidomine, N,N'-dimethylhexanediamine (DMHD/NO), 2,2-diethyl-l-nitroso-oxyhydrazine

(DEA/NO), Et 2NN(O)NONa, NO-ketoprofen, NO-diclofenac, NO-flurbiprofen. The most

preferred NOG of the present invention is molsidomine. The NOGs of the present invention may be obtained from natural sources or

synthesized. The NOGs contemplated by the present invention are those already known to be

nitric oxide generators or those yet to be elucidated.

NOGs may be obtained bio-synthetically or by organic synthesis. Methods of

synthesis for the examples of NOGs disclosed herein have been disclosed in the art. NOGs are

also commercially available from various sources including Sigma Chemical Co. (St. Louis,

Missouri).

The NOGs of the present invention are intended for administration to a human patient

suffering from dry eye. Preferably, the NOGs of the present invention will be administered

topically.

The NOGs of the present invention may be contained in various types of

pharmaceutical compositions, in accordance with formulation techniques known to those

skilled in the art. In general, the NOGs will be formulated in solutions for topical ophthalmic

administration. Solutions, suspensions and other dosage forms are particularly preferred for

the treatment of dry eye.

The ophthalmic compositions of the present invention will include one or more

NOG(s) in a pharmaceutically acceptable vehicle. Various types of vehicles may be used.

Aqueous solutions are generally preferred, based on ease of formulation, biological

compatibility, as well as a patient's ability to easily administer such compositions by means of

instilling one to two drops of the solutions in the affected eyes. However, the NOGs may also

be readily incorporated into other types of compositions, such as suspensions, viscous or semi-

viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred

for NOGs which are less soluble in water. The ophthalmic compositions of the present invention may also include various other ingredients, such as buffers, preservatives, co-

solvents and viscosity building agents.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate or sodium

borate) may be added to prevent pH drift under storage conditions.

Antioxidants may be added to compositions of the present invention to protect the

NOGs from oxidation during storage. Examples of such antioxidants include vitamin E and

analogs thereof, ascorbic acid and butylated hydroxytoluene (BHT).

Ophthalmic products are typically packaged in multidose form. Preservatives are thus

required to prevent microbial contamination during use. Suitable preservatives include:

benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben,

phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known

to those skilled in the art. Such preservatives are typically employed at a level of from 0.001

to 1.0% weight/volume ("% w/v").

In general, the dosage of the nitric oxide generators used for the above described

purposes will vary, but will be in an effective amount to increase mucin production in the eye

and thus eliminate or improve dry eye conditions. As used herein, the term "pharmaceutically

effective amount" refers to an amount which improves the dry eye condition in a human

patient. When the compositions are dosed topically, they will generally be in a concentration

range of from 0.001 to about 1.0% w/v, with 1-2 drops administered 1-4 times per day.

As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation

which is safe, and provides the appropriate delivery for the desired route of administration of an

effective amount of at least one nitric oxide generator of the present invention. The compositions of the present invention are further illustrated by the following

formulation Examples 1-3. The ingredient "nitric oxide generator" denotes a compound of the

present invention.

Example 1

A topical ophthalmic formulation:

Ingredient Amount (wt%)

Molsidomine 0.01-1.0% Phosphate Buffered Saline 1.0 Polysorbate 80 0.5 Purified water q.s. to 100%

Example 2

A topical ophthalmic formulation:

Ingredient Amount (wt%)

nitric oxide generator 0.01-1.0%

Monobasic sodium phosphate 0.05

Dibasic sodium phosphate 0.15 (anhydrous)

Sodium chloride 0.75

Disodium EDTA (Edetate disodium) 0.05

Cremophor EL 0.1

Benzalkonium chloride 0.01

HC1 and/or NaOH pH 7.3 - 7.4

Purified water q.s. to 100% Example 3

A topical ophthalmic formulation:

Ingredient Amount (wt%)

nitric oxide generator 0.01-1.0%

Phosphate Buffered Saline 1.0

Hydroxypropyl-β-cyclodextrin 4.0

Purified water q.s. to 100%

The invention in its broader aspects is not limited to the specific details shown and

described above. Departures may be made from such details within the scope of the

accompanying claims without departing from th2e principles of the invention and without

sacrificing its advantages.

Claims

What is claimed is:

1. A composition for the treatment of dry eye comprising a pharmaceutically acceptable

carrier and a pharmaceutically effective amount of one or more nitric oxide generators.

2. The composition of Claim 1 , wherein the nitric oxide generator is selected from the

group consisting of: nitroglycerin, sodium nitroprusside, spermine NONO ate, (+/-)-(E)-4-

ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK-409), 1 -hydroxy-2-oxo-3-(N-methyl-3-

aminopropyl)-3 -methyl 1-triazene (NOC-7), S-nitrosoglutathione, 4-phenyl-3-

furoxancarbonitrile, S-nitroso-N-acetyl-penicillamine (SNAP), isosorbide denitrate, GEA

3268, GEA 5145, GEA 3175, glyceryl trinitrate, molsidomine, 3-morpholinosydnonimine

(SIN-1), hydroxylamine, linsidomine, NOC-18, CHF-2363, pirsidomine, N,N'-

dimethylhexanediamine (DMHD/NO), 2,2-diethyl-l-nitroso-oxyhydrazine (DEA/NO), Et

2NN(O)NONa, NO-ketoprofen, NO-diclofenac, NO-flurbiprofen.

3. The composition of Claim 1, wherein the nitric oxide generator is molsidomine.

4. The composition of Claim 1, wherein the composition is a topical ophthalmic

formulation.

5. The composition of Claim 2, wherein the composition is a topical ophthalmic

formulation.

6. - The composition of Claim 3, wherein the composition is a topical ophthalmic

formulation.

7. A method for the treatment of dry eye comprising administering to a patient a

composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective

amount of one or more nitric oxide generators.

8. The method of Claim 8, wherein the nitric oxide generator is selected from the group

consisting of nitroglycerin, sodium nitroprusside, spermine NONO ate, (+/-)-(E)-4-ethyl-2-

[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK-409), l-hydroxy-2-oxo-3-(N-methyl-3-

aminopropyl)-3 -methyl 1-triazene (NOC-7), S-nitrosoglutathione, 4-phenyl-3-

(SIN-1), hydroxylamine, linsidomine, NOC-18, CHF-2363, pirsidomine, N,N'-

2NN(O)NONa, NO-ketoprofen, NO-diclofenac, NO-flurbiprofen.

9. The method of Claim 8, wherein the nitric oxide generator is molsidomine.

10. The method of Claim 8, wherein the composition is a topical ophthalmic formulation.

11. The method of Claim 9, wherein the composition is a topical ophthalmic formulation.

12. The method of Claim 10, wherein the composition is a topical ophthalmic formulation.