ARTIFICIAL TEAR SOLUTION CONTAINING POLY(ETHYLENE GLYCOL) PEG LIPIDS

This invention relates to artificial tear formulations. More particularly, this invention relates to artificial tear formulations particularly suitable for the alleviation of dry eye conditions.

A diminution of the quantity of tears produced and distributed through the lachrymal ducts or a decrease in the stability of the tear film produced, results in a condition of the eye referred to as dry eye. Dry eye states act to decrease visual acuity, produce discomfort ranging from mild to intense and eventually, if allowed to remain untreated and uncorrected, result in permanent damage with degradation of the exposed ocular tissues, with a complete breakdown of corneal tissue necessitating, in the extreme, corneal transplants.

There has been no diagnostic method findings associated with these dry eye states. Rather, therapy is usually predicated on the symptoms rather than on results of objective testing. Thus, in the consideration of dry eye states, replenishment or buttressing of the deficient tear flow or certain tear components is necessary to prevent permanent damage to the ocular tissue. BACKGROUND OF THE PRIOR ART

The condition of dry eye is not new and various compositions for treating dry eye have been proposed and put into use over the years. For example, the treatments employed by ancient Greek physicians for this condition dominated medical practice throughout the Middle Ages and into the nineteenth century. The selection of components for ancient collyria, or for any of the eye treatment preparations of the time, suggests either an instinctive or empirical knowledge of the composition of tears and tear

films. Egg whites, very rich in albumen which is a major tear protein, and goose fat, a lipid admixture which, like meibomian lipids, become fluid at temperatures approximating normal body temperatures.

Use has also been made of substances which serve to induce a measure of irritation, presumably to induce reflex tearing. Such substances as alcohols, acetic acid values of vinegar, onion fermentates and the like have been utilized in this approach. Obviously, such methods are less than totally acceptable.

Other solutions offered for the alleviation of dry eye in more recent years, i.e., during the 19th century and early 20th century, have included aqueous solutions of common table salt, glycerol, various oils, and isotonic solutions of various salts, known as Ringer's and Locke's solutions.

Approximately thirty years ago, the employment of aqueous solutions of inert, substituted cellulose ethers such as methyl cellulose was proposed, and such formulations are currently in use. Other substituted cellulose ethers such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose have been subsequently utilized as polymeric components in artificial tear formulations. Each of these polymeries imparts high viscosities to the tear formulations, even when employed in relatively low concentrations as, for example, on the order of from about 4 to about 500 Cps. It has been this impartation of high viscosity to the formulations which has been believed to prolong retention time of the tear substitute in the fornices and over the preocular surface.

However, it has been subsequently demonstrated that the ocular retention time is not a direct function of the vehicle viscosity. Further, the use of highly viscous polymeric solutions also results in unpleasant side effects to the user thereof. For

example, insufficient lubrication of the lids and the tendency for encrustations to form at the lid margins produces irritation and discomfort.

Subsequently, other hydrophilic polymeries such as polyvinyl alcohol and polyvinyl pyrrolidone, among others, combining good film-generating properties with relatively low viscosities in aqueous solution. Such formulations, however, remain less than satisfactory inasmuch as they do not provide good wettability. Phosopholipids have been patented for their utility in the artificial tear solution to enhance the tear film stability.

Localized dysfunctions of the glands, which produce the ocular tear film, can also contribute to dry eye. The most common disorder, anterior blepharitis, is an inflammation of the eye lids, affecting the meibomian glands that secret the lipid layer of the ocular surface. The lack of an adequate lipid layer contributes to rapid evaporation of the water component of the tear film thus causing discomfort. OBJECTS OF THE INVENTION

Recently, certain ώ-methyl-polyethyleneglycol-conjugated anionic lipids have been developed and used as liposomes, notably ώ -Me-PEG-phosphatidylethanolamines (MePEG-PE).

A PEG-lipid, such as PEG-DMPE (l,2-diacyl-sn-glydero-3- phosphoethanolamine-N-[poly(ethylene glycol)]), would be useful in providing additional artificial tear solutions. Because of their possession of the extremely hydrophilic PEG tail, the PEG-lipids could more favorably interact with both the superficial lipid layer and the underlying mucous layer of the natural tear film. Because the hydrophilic component such as PEG contains a hydrophobic component at only a single end of the hydrophilic molecule, the tendency of the PEG-lipids to form liposomes

would be minimized. Further, the composition containing PEG-lipids should not interfere with the integrity of the tear lipid film, mix with tear biopolymers and affect the clarity of the aqueous tear layer. Collectively, in-eye application of the PEG-lipids- containing composition is expected to effectively relieve the dry eye symptoms with great comfort. The PEG-lipids can be used in combination with viscosity-adjusting agents , such as celluloses and their derivatives as well as other materials commonly used in ophthalmic solutions.

It is an object of the present invention to provide an artificial tear formulation.

Another object of the present invention is to provide an artificial tear formulation which in use will effectively alleviate dry eye symptoms.

A further object of the present invention is to provide an artificial tear formulation which is non-contaminating and non-interfering with visual clarity. STATEMENT OF THE INVENTION

According to the present invention, there is provided an artificial tear composition comprising a sterile, hypotonic aqueous solution of PEG-lipid and a viscosity-adjusting agent.

Suitable formulations contain PEG-lipid, preferably PEG-DMPE, in an amount of from about 0.01 to about 2 percent weight/weight, preferably in an amount of from 0.1 to about 0.5 percent weight/weight.

The amphiphilic molecules of the invention or "amphiphiles" will preferably include a biocompatible hydrophilic compound or polymeric residue. By the term "biocompatible", is meant that the hydrophilic compound and the resultant amphiphilic molecule do not elicit significant adverse or untoward reactions upon administration to the particular animal in which they are intended for use. Determinations of

biocompatibility are readily made by those of ordinary skill in the art, and include assessing the known properties of compounds, as described in the scientific literature, prior to generating an amphiphilic molecule and the testing of the molecule in appropriate in vitro and in vivo studies.

The hydrophilic compound or polymer components of the amphiphiles will preferably have an average molecular weight of between about 100 and about 100,000 Daltons, with all intermediate molecular weights between these ranges being contemplated. For example, an appropriate hydrophilic compound for use herewith may have an average molecular weight of about 100, 200, 500, 1,000, 2,000, 5,000, 10,000, 20,000, 50,000, 75,000 and about 100,000 or more. In certain preferred embodiments, the molecular weight of the hydrophilic component will be between about 100 and about 20,000, between about 100 and about 10,000, between about 2,000 and about 20,000, between about 2,000 and about 10,000, or between about 100 and about 10,000 or so.

Carboxy-containing polymers may also be used in the formulations of the invention herein. Typical carboxy-containing polymers are carboxymethylcellulose (CMC), Alginate, Caopomers, Pectin, Xanthan gum etc.

The "hydrophobic moiety or residue" is preferably a hydrophobic component that is sterically compatible with typical lamellar lipid bilayers, such that they are capable of spontaneously forming bilayers, or intercalating into bilayers, and are generally selected so as to achieve a good steric fit without significant perturbation of the normal packing geometry of lamellar bilayers. Wide varieties of such molecules are known to those of skill in the art and are suitable for use herewith.

In general terms, hydrophobic residues of short, medium or long lipid chains may be employed. Short chain lipids generally have less than about eight carbon atoms (8C).

In more preferred embodiments, it is believed that advantages will result from the use of hydrophobic residues having between about 8 carbon atoms (8C) and about 30 carbon atoms (30C), with those having between about 12 carbon atoms (12C) and about 20 carbon atoms (20C) being generally preferred.

Examples of preferred PEG-lipid compound for use in this invention is provided in general formula I below:

wherein Rl = C12 to C30, saturated and unsaturated

X = CO or

CO(CH2)2CO or CO(CH2)3CO Another example of suitable PEG-lipids for use in the invention herein is provided in general formula II below:

wherein Rl = C12 to Cl 8, identical fatty acid X: Na Yet another example of suitable PEG-lipids for use in the invention herein is provided in general formula III below:

wherein Rl and R2 are different fatty acid residues.

The compositions of the present invention may also contain mono or divalent cations typically found in tear fluids.

The viscosity-adjusting agent of the composition is present in amounts of from about 0.1 to about 20 percent weight/weight, preferably in amounts of from about 2.5 to about 5.0 percent weight/weight. It has been found that suitable viscosity-adjusting agent for the purposes of this invention are those selected from methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol and hydroxyethyl cellulose. Suitable viscosities will typically be below 50 cps.

It has been found that such compositions not only possess surface tensions approximating those of natural tears, providing corneal wetting, but additionally spread uniformly over the coated surface.

The tonicity of the artificial tear composition may be adjusted to the desired values by the addition thereto of sodium chloride or other soluble salts, such as potassium chloride, in amounts sufficient to impart the desired tonicity thereto. Other tonicity adjusting agents, such as dextrose, and sorbitol may also be advantageously employed, in combination with water-soluble salts. Suitable tonicity values are achieved by the inclusion of the tomcity-adjusting agent, or agents, in amounts of from about 1 to about 5 percent weight/weight.

Preferably, the basic compositions include such additional components as non- ionic surfactants and sequestering, preservative and buffering agents.

Suitably, a non-ionic surfactant such as polyoxyalkylene oleic esters of sorbitol anhydrides may be included in amounts of from about 2 to about 10 percent weight/weight.

Disodiurn edentate, citric acid, sodium citrate and the like, or combination thereof, in amounts of from about 0.05 to about 2.0 percent weight/weight, are suitable as sequestering agents in the present compositions. Disodium edentate is particularly desirable, providing as it does a measure of protection against pseudomonal contamination while additionally functioning as a chelating or wateτ-softening agent.

Suitable preservative agents include sodium ethylmecurithiosalicylate, benzalkonium chloride, Alexidine hydrochloride or the like, present in amounts of from about 0.001% to about 0.5%.

As buffering agents, alkali metal borates such as sodium and potassium borate, or mixtures thereof, along with boric acid are particularly suitable for use in the present compositions, generally present in amounts of from about 0.1 to about 1.0 percent weight/weight. Other suitable buffers would include phosphate buffer, borate buffer, MOPS buffer, citrate buffer, an aminoalcohol buffer and combinations thereof.

Formulation of the artificial tear compositions may be effected in any convenient manner known to the art, such as by simply admixing the desired amount of the specified ingredients and providing the necessary amount of sterile water to provide the necessary dilution.

The compositions of the present invention, topically applied, provides relief for both aqueous-deficient and mucus-deficient eyes; provide highly effective Kpid-masking

and scavenging layers, effective also therapeutically in situations where lipid abnormalities exist.

Use of the artificial tear compositions is conveniently effected by instilling the composition, drop-wise, into the eye or eyes of the user.

Non-limiting examples of the composition of this invention is set forth below: EXAMPLES

EXAMPLE 1

EXAMPLE 2

EXAMPLE 5

EXAMPLE 6

Tear Breakup Times(TFBUT in Sec.) for Systane™ and Examples 1-5

Conclusion: The tear breakup times (TFBUT) have been improved with all of the formulations based on the formulation of example 1. This result suggests that example 1 based formulations not only provide fast release (from polyols) but also improve the ocular condition of entire ocular surface.

The invention, in its broader aspects, is not limited to the specific details shown and described, and departures may be made from such details without departing from the principles thereof and without sacrificing the chief advantages thereof.