WO1997005890A1

WO1997005890A1 - Method of increasing tear production by topical administration of muramyl peptide

Info

Publication number: WO1997005890A1
Application number: PCT/US1996/012928
Authority: WO
Inventors: Martin A. Voet
Original assignee: Allergan
Priority date: 1995-08-08
Filing date: 1996-08-06
Publication date: 1997-02-20
Also published as: AU6693396A

Abstract

The present invention provides a method of treating an aqueous-deficient dry eye state in a patient suffering therefrom, which method includes the step of administering a muramyl peptide, e.g. N-acetyl-D-glucosaminyl-(β 1-4)-acetyl muramyl-L-alanyl-D-isoglutamine (GMDP).

Description

METHOD OF INCREASING TEAR PRODUCTION BY TOPICAL ADMINISTRATION OF MURAMYL PEPTIDE

FIELD OF THE INVENTION

The present invention relates to a method of increasing tear production in a patient suffering from deficient tears in the eye due to an autoimmune dysfunction of the lacrimal (tear) glands. More specifically, this invention relates to a method of treating immune mediated keratoconjunctivitis sicca (KCS or dry eye disease) in a patient suffering therefrom, which method includes administering a muramyl peptide, e.g. N-acetyl-D-glucosaminyl- (β 1-4) -acetyl muramyl-L- alanyl-D-isoglutamine (GMDP) .

BACKGROUND OF THE INVENTION

The exposed part of a normal eye is covered by a thin tear film. The presence of a continuous tear film is important for the well-being of the corneal and conjunctival epithelium and provides the cornea with an optically high quality surface. In addition, the aqueous part of the tear film acts as a lubricant to the eyelids during blinking of the lids. Furthermore, certain enzymes contained in the tear fluid, for example immunoglobulin A, lysozyme and beta lysin, are known to have bacteriostatic properties. A sound lacrimal system functions to form and maintain a properly structured, continuous tear film. The lacrimal system consists of the secretory system (the source) , the distribution system and the excretory system (the sink) . In the secretory system, aqueous tears are supplied by the main and accessory lacrimal glands. The bulk of the tear film is made of such aqueous tears. The continuous production and drainage of aqueous tear is important to maintaining the corneal and conjunctival epithelium in a moist state, in providing nutrients for epithelial respiration, in supplying bacteriostatic agents and in cleaning the ocular surface by the flushing action of tear movement.

Abnormalities of the tear film include an absolute or partial deficiency in aqueous tear production (keratoconjunctivitis sicca or KCS) .

In relatively mild cases, the main symptom of KCS is a foreign body sensation or a mild "scratchiness" . This can progress to become a constant, intense burning irritative sensation which can be debilitating to the patient.

More severe forms progress to the development of filimentary keratitis, a painful condition characterized by the appearance of numerous strands or filaments attached to the corneal surface. Recent evidence suggests that these filaments represent breaks in the continuity of the normal corneal epithelial cells. The shear created by lid motion pulls these filaments, causing pain. Management of this stage of KCS is very difficult. A frequent complication of KCS is secondary infection. Several breakdowns in the eye's normal defense mechanism seem to occur, presumably attributable to a decrease in the concentration of antibacterial lysozyme in the aqueous tears of a patient suffering from KCS.

Although KCS can develop in the absence of any other overt systemic abnormality, there is a frequent association of KCS with system disease. KCS can occur as part of a larger systemic involvement known as Sjogren's syndrome. This classically consists of the triad of dry eyes, dry mouth, and arthritis.

Histologically in KCS (as part of Sjogren's syndrome or in isolation) , the initial changes seen in the lacrimal gland are those of focal lymphocytic and plasma cell infiltrates associated with degeneration of glandular tissue. These changes resemble those seen in autoimmune disease in other tissue, giving rise to the speculation that KCS has an autoimmune basis. Sjogren's syndrome is recognized as an exocrine gland dysfunction. Characteristically, the lacrimal glands show a mononuclear cell infiltration that ultimately leads to destruction of the glandular structure. Conventional treatment of KCS is symptomatic. Normally, aqueous-deficient dry eye states are treated by supplementation of the tears with artificial tear substitutes. However, relief is limited by the retention time of the administered artificial tear solution in the eye. Typically, the effect of an artificial tear solution administered to the eye dissipates within about thirty to forty-five minutes. The effect of such products, while soothing initially, does not last long enough. The patient is inconvenienced by the necessity of repeated administration of the artificial tear solution in the eye as needed to supplement the normal tears. Moreover, such treatment merely acts to alleviate the symptoms of the dry eye state and does not cure any underlying disorders or causes of the dry eye state.

Histologic studies of the lacrimal glands in patients suffering from Sjogren's syndrome have shown some evidence of lacrimal gland inflammation. Such inflammation may simply be due to the normal aging of the patient. It h as been suggested that the use of antiinflammatory agents might serve to decrease the glandular inflammation. The systemic use of corticosteroids has been advocated in these conditions.

However, the merit of systemic corticosteroids in dry eye states has not been established. In most dry eye cases the hazards of long term use of antiinflammatory agents would seem to outweigh their potential merit.

Surgical procedures have also been suggested in the management of dry eye states . Where there has been significant conjunctival destruction, mucous membrane transplants have been advocated. It has also been suggested that parotid (saliva) duct transplantation can be useful in the management of dry eyes. However, since surgical alterations to combat dry eye conditions constitute such a drastic remedy and the benefit resulting from these alterations is questionable, these methods are usually used in dry eye patients only as a last resort.

It has also been suggested to administer orally a dilute solution of pilocarpine to stimulate the autonomic nervous system to effect increased aqueous tear production. This method of treatment has not met with universal favor because of the unpleasant side effects of ingested pilocarpine. Animal models of Sjogren's syndrome have been instrumental in basic ophthalmic research. A Sjogren's- like disease has been found in dogs with systemic lupus erythematosus.

Canine KCS is a common, chronic progressive, and potentially blinding disease. A continuum of corneal and conjunctival lesions ensues from the dry eye state. The cause of KCS in canines is often not identified. Usually, canine KCS is not an isolated ophthalmic disease. It has been speculated in Kaswan et al, Am. J. Vet. Res. 46, 376-383 (1985), that most cases of canine

KCS occur via autoimmune mechanisms.

The term autoimmunity is used to indicate immunologic self injury, but not a singular etiology. Autoimmune disease is multifactorial, including hormonal, environmental, and polygenetic factors. A reasonable concept of autoimmune pathogenesis proposes that autoimmunity may arise whenever there exists a state of immunologic imbalance in which B-cell activity is excessive and/or suppressor T-cell activity is diminished.

To date, there has been no suggestion to treat a lacrimal gland dysfunction or an aqueous-deficient dry eye state with a muramyl peptide, e.g. GMDP, either topically or systemically.

It can thus be readily appreciated that provision of a method of increasing tear production in a patient suffering from deficient tears in the eye due to an autoimmune dysfunction of the lacrimal glands, which method provides improved treatment of KCS and eliminates the previously discussed problems, would be a highly desirable advance over the current state of the art in

KCS treatment.

OBJECTS OF THE INVENTION

It is therefore an object of this invention to provide a method of increasing tear production for a tear-deficient eye.

It is a second object of this invention to provide a method of increasing tear production in an eye of a patient suffering from an immune mediated dysfunction of the lacrimal glands.

It is an additional object of this invention to provide a method of treating KCS in a patient suffering therefrom. It is also an object of this invention to provide a method of treating a disorder caused by excessive immune activity in a lacrimal gland of a patient.

It is a further object of this invention to provide a muramyl peptide-based treatment of the lacrimal glands.

These and other objects and advantages of the present invention will become more readily apparent after consideration of the following:

STATEMENT OF THE INVENTION

In one aspect, the present invention is directed to a method of treating a dry eye state in a patient by administering a muramyl peptide topically to the patient's eye.

In another of its aspects, the present invention provides a muramyl peptide-based treatment of an autoimmune dysfunction of the lacrimal glands.

In still another of its aspects, the present invention relates to a muramyl peptide in a carrier adaptable to topical administration into a patient's eye.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention, as well as other objects and features thereof, will be understood more clearly and fully from the following description of certain preferred embodiments.

The present invention provides a method of treating an aqueous-deficient dry eye state due to an autoimmune dysfunction of the lacrimal glands in a patient suffering therefrom, which method includes the step of administering to the patient, an effective amount of a muramyl peptide. Preferably, the method of the present invention includes the step of administering a muramyl peptide topically to the patient's eye. Surprisingly, this topical administration of a muramyl peptide to the eye provides muramyl peptide treatment to the lacrimal glands, and such treatment increases tear production in a patient suffering from KCS.

Conventional treatment of KCS involves alleviating the symptoms of the dry eye state without treating the underlying disorders of causes of the dry eye state.

Symptomatic treatment of the dry eye state, such as by supplementation of the aqueous tears with artificial tear substitutes, necessarily involves continuous and repeated attention as needed to alleviate the recurring symptoms.

To date, there has been no suggestion to treat a lacrimal gland dysfunction of an aqueous-deficient dry eye state with muramyl peptide, either topically or systemically.

Topical administration to a patient's eye has surprisingly been found to be an excellent method for providing a muramyl peptide to the lacrimal glands of the patient to treat KCS. Additionally, since by its very nature topical administration does not require dispersion throughout the patient's system as is the case with systemic administrations, the present invention provides a means for directing muramyl peptide to the desired location without the accompanying high risk of adverse responses and high cost associated with systemic treatments.

In accordance with the present invention, the muramyl peptide may be used in any efficacious concentration, e.g., 0.01 to saturation (e.g., greater than 20 weight percent) , in a pharmaceutically acceptable excipient. From 0.01 to 50 weight percent, preferably from 0.1 to 20 weight percent, of a muramyl peptide in a pharmaceutically acceptable excipient is used. Such pharmaceutically acceptable excipients are, for example, animal oil, vegetable oil, an appropriate organic or aqueous solvent, e.g. ethanol, an artificial tear solution, a natural or synthetic polymer or an appropriate membrane. Examples of these pharmaceutically acceptable excipients are olive oil, arachis oil, castor oil, mineral oil, petroleum jelly, dimethyl sulphoxide, chremophor, an alcohol (e.g. ethanol, n-propyl alcohol or iso-propyl alcohol), liposomes or liposome-like products or a silicone fluid. A preferred excipient is ethanol, e.g. in combination with water. Mixtures of at least two of any suitable excipients may be used.

An example of useful polymeric excipient is a polyoxyethylated castor oil. Examples of pharmaceutically acceptable membranes which can advantageously be used in the practice of this invention are: microdone, an artificial lipid membrane, polyvinylalcohol, or methylcellulose.

The muramyl peptide is advantageously administered topically as an ophthalmic drop (solution or suspension) or ophthalmic ointment containing a effective amount of the muramyl peptide. Concentration of 0.01 to 50 weight percent, preferably 0.1 to 20 weight percent, of a muramyl peptide is used. In accordance with the method of the present invention, a muramyl peptide is administered topically in any quantity required to provide the degree of treatment needed. For example, 5 microliters to 1 milliliter of a solution, suspension or ointment containing an effective amount of a muramyl peptide, such as 0.01 to 50 weight percent, preferably 0.1 to 20 weight percent, of muramyl peptide is advantageously used.

Muramyl peptides are generally known as will be evidenced by reference to the following United States Patent Nos . 4 , 317 , 771 ; 4 , 082 , 735 , 4 , 082 , 736 and

4 , 235 , 771 .

Preferably, muramyl peptides which are useful in the practice of the present invention are disclosed in United States Patent No. 4,395,399 which is hereby incorporated in its entirety. Most preferably, the muramyl peptide is

N-acetyl-D-glucosaminyl- (β 1-4) -acetyl muramyl-L-alanyl-

D-isoglutamine (GMDP) , the structure of which is:

GMDP

This compound (Compound II in United States Patent No.

4,395,399), also known as glycopin, has already undergone preclinical toxicity testing and pharmacokinetic investigations required for licensing for clinical uεe in the USSR (as it then was) . The acute toxicity in mice, measured by the LD50 test is 7 g/kg.

Mixtures of at least two different muramyl peptides may be used.

Numerous advantages accrue with the practice of the present invention. Topical administration of a muramyl peptide into a patient's tear deficient eye increases tear production in the eye. Thus, such treatment further serves to correct corneal and conjunctival disorders exacerbated by tear deficiency and KCS, such as corneal scarring, corneal ulceration, inflammation of the cornea or conjunctiva, filamentary keratitis, mucopurulent discharge and vascularization of the cornea.

Furthermore, muramyl peptide directly decreases the immune response of granulation and neovascularization in the cornea.

Further objects of this invention, together with additional features contributing thereto and advantages accruing therefrom, will be apparent from the following examples of the invention.

Example

A one year old standard female poodle with conjunctivitis exhibits mild aqueous tear deficiency in both eyes .

The dog is treated with dexamethasone by topical administration in both eyes four times daily; however, the same dog at approximately six years old still exhibits conjunctivitis in both eyes. Topical dexamethasone is used in both eyes twice daily for nine weeks without benefit.

The dog is then treated by topical application of 2% GMDP in an aqueous ethanol solution in both eyes once daily without any other medications. After ten days, the dog shows markedly increased tear production.

The treatment by topical application of 2% GMDP in an aqueous ethanol solution in both eyes once daily is continued for an additional three weeks. At this time, the dog exhibits plentiful aqueous tear production and the treatment was stopped for one week. After this week, the dog has adequate tear production.

In this case, a dog with chronic tear deficiency in which prior use of corticosteroids fails to improve tear secretion shows a surprising increase in tear production with treatment.

Claims

I claim :

1. A method for enhancing or restoring lacrimal gland tearing comprising topically administering a muramyl peptide to the eye in a pharmaceutically acceptable vehicle.

2. The method of claim 1 for increasing tear production in a tear-deficient eye comprising topically administering a therapeutically effective amount of a muramyl peptide to said eye.

3. The method of claim 2 wherein said muramyl peptide is administered as a solution, suspension or ointment comprising 0.01 to 50 weight percent of muramyl peptide in a pharmaceutically acceptable excipient.

4. The method of claim 3 wherein said muramyl peptide is administered in an amount of 0.1 to 20 weight percent.

5. The method of claim 3 wherein the pharmaceutically acceptable excipient is ethanol, olive oil, arachis oil, castor oil, polyoxyethylated castor oil, mineral oil, petroleum jelly, dimethyl sulphoxide, an alcohol, liposome, silicone fluid or a mixture thereof.

6. The method of claim 2, wherein said muramyl peptide is N-acetyl-D-glucosaminyl- (β 1-4) -acetyl muramyl-L- alanyl-D-isoglutamine (GMDP) .

7. The method of claim 2 for increasing tear production in the eye of a patient suffering from an autoimmune dysfunction of the lacrimal glands comprising administering a therapeutically effective amount of a muramyl peptide topically to the patient's eye.

8. The method of claim 2 for treating keratocon- junctivitis sicca in a patient comprising the step of administering a therapeutically effective amount of a muramyl peptide to the patient's eye.

9. The method of claim 1 for treating a disorder caused by immune activity in a lacrimal gland of a patient comprising the step of topically administering to the patient's eye a therapeutically effective amount of a muramyl peptide to enhance or restore tearing.

10. The method of claim 9 wherein said muramyl peptide is administered as a solution, suspension or ointment comprising 0.01 to 50 weight percent of muramyl peptide in a pharmaceutically acceptable excipient.

11. The method of claim 10 wherein said muramyl peptide is administered in an amount of 0.1 to 20 weight percent.

12. The method of claim 10 wherein the pharmaceutically acceptable excipient is ethanol, olive oil, arachis oil, castor oil, polyoxyethylated castor oil, mineral oil, petroleum jelly, dimethyl sulphoxide, an alcohol, liposome, silicone fluid or a mixture thereof.

13. The method of claim 9, wherein said muramyl peptide is N-acetyl-D-glucosaminyl- (β 1-4) -acetyl muramyl-L- alanyl-D-isoglutamine (GMDP) .

14. The method of claim 1 for treating a disorder exacerbated by deficient tear production in a patient comprising topically administering a therapeutically effective amount of a muramyl peptide to the patient's eye to enhance or restore tearing.

15. The method of claim 14 wherein said muramyl peptide is administered as a solution, suspension or ointment comprising 0.01 to 50 weight percent of muramyl peptide in a pharmaceutically acceptable excipient.

16. The method of claim 15 wherein said muramyl peptide is administered in an amount of 0.1 to 20 weight percent.

17. The method of claim 15 wherein the pharmaceutically acceptable excipient is ethanol, olive oil, arachis oil, castor oil, polyoxyethylated castor oil, mineral oil, petroleum jelly, dimethyl sulphoxide, an alcohol, liposome, silicone fluid or a mixture thereof.

18. The method of claim 14, wherein said muramyl peptide is N-acetyl-D-glucosaminyl- (β 1-4) -acetyl muramyl-L- alanyl-D-isoglutamine (GMDP) .

19. A method of treating a disorder caused by immune activity in a lacrimal gland of a patient or enhancing or restoring lacrimal gland tearing of a patient which comprises administering a therapeutically effective amount of a muramyl peptide to said patient.

20. The method of claim 19 wherein said muramyl peptide is N-acetyl-D-glucosaminyl- (β 1-4) -acetyl muramyl-L- alanyl-D-isoglutamine (GMDP) .