Technical field The present invention relates generally to methods and materials for use treatment of "red eye".

Background art "Red eye" is a common condition arising from surface vessel dilation (hyperemia) in the eye, particularly of the conjunctiva , tenon and episclera\sclera layers.

The ocular inflammation underlying red eye can be caused by several conditions including dry eyes, blepharitis, infection, inflammation such as uveitis, injury surgical or non-surgical such as corneal abrasion, contact lens wear, allergy, corneal ulcer and sub conjuctival haemorrhage.

Treatment of red eye is thus sometimes based on treatment of these causes - for example "artificial tears" for dry eyes, and antihistamine drops for allergic eyes.

Although some of the causes of red eye are relatively benign, ocular redness is generally a condition associated with reduced quality of life and negative social connotations such as drinking and drug abuse, in addition to general fatigue and cosmetic concerns The most common treatment or relief of red eye itself is by the use of vasoconstrictors.

Vasoconstrictors are commonly referred to as "get the red out" eye drops, as they shrink the small blood vessels in the conjunctiva. The use of vasoconstrictors in treating red eye is reviewed by Abelson & Smith ("Vasoconstrictors: Myths and Realities"

http://www.revophth.eom/content/d/therapeutic_topics/i/20 59/c/35994/dnnprintmode/ )

For example OTC vasoconstrictors have regulatory approval for relief of redness of the eye due to minor eye irritations. Vasoconstriction provides temporary relief from tissue congestion. The mechanism by which vasoconstrictors act is adrenergic receptor activation. All ocular vasoconstrictors available today, including Naphazoline (Allerest, Clear Eyes, Naphcon, Opcon), Oxymetazoline (Visine LR), Phenylephrine (Prefrin, Relief) and Tetrahydrozoline (Murine, visine) act as adrenergic receptor (AR) agonists. ARs mediate the physiological response to catecholamines, norepinephrine and epinephrine, and are central to cardiovascular and central nervous system activity. They are members of the superfamily of G-protein coupled receptors, classified as a1-AR, a2-AR and β-AR, each with multiple and mixed sub-types. Local sub-type concentrations, distributions and ligand binding affinities all define a given tissue's response to adrenergic agonists. The ophthalmic vasoconstrictors are a1- or mixed a1/a2-adrenergic receptor agonists.

There are two classes of vasoconstrictors: sympathomimetic amines and imidazoles. Sympathomimetic amines mimic the actions of the sympathetic nervous system through the pre-synaptic release of norepinephrine in sympathetic nerves. Norepinephrine then binds post-synaptically to a-ARs, resulting in vasoconstriction. The imidazoles can be a2- AR agonists (e.g., brimonidine), or mixed a1-AR/a2-AR agonists (e.g., naphazoline), and act post-synaptically on sympathetic nerves to cause vasoconstriction. They may also lower production of norepinephrine, thus decreasing blood flow and reducing congestion.

Unfortunately adrenergic-mediated vasoconstriction is associated with unwanted pharmacological and clinical phenomena, such as tachyphylaxis, tolerance, rebound vasodilation, toxicity and the potential for abuse. With emerging evidence that tachyphylaxis appears to be an a1-AR-related phenomenon, research efforts have shifted to a2-AR agonists as potential vasoconstrictors. Studies have shown that nasal decongestion evoked by a2-AR activation might have lower cardiovascular side effects than a1- or non-selective a-AR vasoconstrictors such as phenylephrine and oxymetazoline.

US2011/0160214 relates to compositions and methods for achieving cosmetic eye whitening which utilize low concentrations of selective a-2 adrenergic receptor agonists.

Although vasoconstrictors can be effective, it can be appreciated from the foregoing that the provision or characterisation of further therapeutics, particularly those not associated with tachyphylaxis, abuse and \or toxicity, would provide a contribution to the art.

Disclosure of the invention The present inventors have demonstrated that red eye may be treated by compounds which are opioid receptor agonists. That is surprising because many opioids are known in the art to be vasodilators, whereas the treatment of red eye is believed to proceed via microvascular vasoconstriction of the vessels and microvessels of the eye e.g. in conjunctiva , tenon and episclera\sclera layers.

A preferred compound is Tramadol or an analog thereof.

Tramadol is a centrally acting synthetic analgesic used to treat moderate to moderately- severe pain.

PCT patent application PCT/GB2012/000330 was filed but not published prior to the present application. That patent application concerns products and methods for reduction of pain, discomfort, inflammation and the like, in and around the human and animal eye. It further relates to products and methods for alleviating the problem of an eye lacking in natural lubrication. It discloses, inter alia _s Tramadol-based compositions for these purposes.

"A Stability-Indicating HPLC Method for the Determination of Benzalkonium Chloride in 0.5 % Tramadol Ophthalmic Solution" Parhizkari, Chromatographia Vol. 40, No. 3/4, February 1995, 155-158 reports a high-performance liquid chromatographic procedure employing ultraviolet detection for the analysis of benzalkonium chloride in 0.5 % Tramadol ophthalmic solution. The 0.5 % Tramadol ophthalmic solution was envisioned to provide post-operative relief from cataract surgery.

In one aspect of the invention there is provided a method of treating redness in the human or animal eye, the method comprising the step of administering a composition comprising a compound which is an opioid receptor agonist, e.g. a μ-opioid receptor agonist e.g. a synthetic opioid.

Thus the invention provides, inter alia, methods of reducing eye redness. These points are discussed in more detail hereinafter.

A preferred compound is Tramadol or an analog thereof (or a pharmaceutically acceptable salt of either). When the term "Tramadol" is used hereinafter in relation to any aspect or embodiment of the invention, it will be appreciated (unless context demands otherwise) that this aspect or embodiment should be taken as relating mutatis mutandis to analogs which share its opioid receptor agonist activity and their pharmaceutically acceptable salts. The compounds is preferably administered direct to the eye as a pharmaceutically acceptable composition including a suitable ophthalmic carrier e.g. water-soluble polymeric ophthalmic lubricating medium. Other preferred compositions and modes of administration are discussed below. The subject will typically be a mammalian subject, which can be an animal or a human subject but which is most preferably a human subject.

The methods using the compounds described herein may be used to increase whiteness of an eye.

The methods using the compounds described herein may be used to reduce redness of an eye.

The compounds in the present invention may be given or treatment or prophylaxis.

The methods using the compounds described herein may be used for cosmetic purposes. For example the individual who is treated may have healthy eyes.

The methods using the compounds described herein may be used to reduce hyperemia in an eye which is due to a disease or a condition. For example conjunctivitis; blepharitis, acute glaucoma, injury, subconjunctival hemorrhage, keratitis, iritis, episcleritis, scleritis, inflamed pterygium, inflamed Pinguecula, dry eye syndrome, airborne contaminants, a burst blood vessel, tick borne illnesses like Rocky Mountain spotted fever, high stress levels and drug use including cannabis or alcohol. The invention is applicable also to red eye which occurs naturally with no cause ascribed. The methods using the compounds described herein may be used to reduce hyperemia or treat redness or erythema caused by drugs e.g. Brimonidine, lopidine, prostaglandin agonists such as Travaprost, Bimatoprost, latanoprost, Tafluprost Thus in some embodiments the subject may have a clinical diagnosis of one or more of these indications or conditions.

Importantly, in some embodiments the methods using the compounds described herein may be used for symptomatic treatment.

The methods using the compounds described herein may be used to treat an individual wherein the redness is believed to be allergic in origin.

The methods using the compounds described herein may be used to treat an individual wherein the redness is believed to be non-allergic in origin.

The methods using the compounds described herein may be used to treat an individual wherein the redness results from episodic irritation. The methods using the compounds described herein may be used for relief of redness of the eye due to minor eye irritations.

The methods using the compounds described herein may be used for temporary relief e.g. for up to or equal to 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 or 24 hours or more.

The methods may be used for long lasting relief, and administration may be repeated at intervals, or be continuous, or be based on slow-release formulations.

As noted above, in preferred embodiments of the invention, the compositions are delivered as ophthalmic solutions into the eyes.

In aspects of the invention, the composition may consist of, or consist essentially of, the compound as an active ingredient. The composition may, by way of non-limiting example, be a solution for application as drops, or an ointment, a gel, and\or formulated as a long acting or slow release compound.

The administration may optionally be by injection around or into the eye e.g. intra vitreal or subconjunctival or sub tenon.

However preferred examples include ocular moisture drops, ocular comfort drops or ocular lubricants. In these cases, the drops would be conveniently applicable as one or two drops, either directly to the cornea or in the cul de sac of the eye. Other kinds of ophthalmic ointments and creams may also be prepared by known methods. Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.

The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.

In one embodiment, the composition may be a lubricating composition, such as "artificial tears", dilute solutions of water soluble polymers (such as sodium hyaluronate, hypromellose and/or carbomer gel) that substitute for the missing natural tears. The invention further provides compounds or compositions as described herein, for use in the methods of treatment or prophylaxis described herein.

The invention further provides use of the compounds or compositions as described herein in the preparation of a medicament for use in the methods of treatment or prophylaxis described herein.

Proper dosages of the compositions of the present invention are concentration- dependent. To determine the specific dose for whitening of eyes of a specific person, a skilled artisan would have to take into account kinetics and absorption characteristics of the particular compound. The dosages may also be dependent on the severity of the redness, or degree of whitening, required or desired by the individual being treated.

Generally the compound may be administered as a therapeutically-effective amount or prophylactically effective amount.

Compositions for use in the present invention may include the compound at a

concentration from between about 0.01 % to about 2% weight by volume, or more.

Optionally, the aqueous composition comprises at least 0.1 % ^w / _v tramadol.

The aqueous composition may comprise between 0.25% and 1.25% ^w / _v tramadol. For example at least, at most, exactly, or about 0.01 , 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 %. For example at least, at most, exactly or about 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2%.

As will be familiar to those skilled in the art, administration to the eye will most preferably be a "drop" or number of drops (e.g. of a 1 % or 0.5% Tramadol solution) from a dropper or pipette or other dedicated sterile device. Such drops will typically be up to 25 microlitres in volume, but maybe smaller e.g. less than 10 microlitres.

The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy of a human, in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis, prevention) is also included. "Prophylaxis" in the context of the present specification should not be understood to circumscribe complete success i.e. complete protection or complete prevention. Rather prophylaxis in the present context refers to a measure which is administered in advance of detection of a symptomatic condition with the aim of preserving health by helping to delay, mitigate or avoid that particular condition.

The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound of the invention, or a material, composition or dosage from comprising said compound, which is effective for producing some desired therapeutic effect,

commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.

Similarly, the term "prophylactically effective amount," as used herein pertains to that amount of a compound of the invention, or a material, composition or dosage from comprising said compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.

The term "treatment" (or "prophylaxis") includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.

For example, as described above, it may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1 , 2, 3, 4) agents or therapies. The particular combination would be at the discretion of the physician or optician or ophthalmologist who would select dosages using his/her common general knowledge and dosing regimens known to a skilled practitioner. The agents (i.e., a compound as described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).

The agents (i.e., a compound as described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

The reduction in redness and\or increase in whiteness according to the present invention can be confirmed or measured by methods well known to those skilled in the art, including visual assessment by a professional. Other methods are described in

US2011/0160214 which refers scales such as the McMounies/Chapman-Davies scale (MC-D); the Institute for Eye Research scale (IER, previously known as CCLRU scale); the Efron scale; and a validated bulbar redness scale (VBR) developed at the Centre for Contact Lens Research. (The Use of Fractal Analysis and Photometry to Estimate the Accuracy of Bulbar Redness Grading Scales, Marc M. Schulze et a!, Investigative Ophthalmology and Visual Science, 2008; 49: 1398-1406).

As noted above preferred compounds of the present invention are Tramadol and analogs thereof. Tramadol is marketed as a racemic mixture of the (1 R,2R)- and (1 S,2S)-enantiomers of 2-[(dimethylamino)methyl]- 1-(3-methoxyphenyl) cyclohexanol.

Tramadol is usually marketed as the hydrochloride salt (tramadol hydrochloride); however other salts are known in the art (e.g. tartrate) and the compounds per se can also be obtained as a solution. All such pharmaceutically acceptable salts are embraced by the present invention.

Other preferred compounds of the invention are discussed below - such compounds share one or more of the biological activities of Tramadol, or provide related activities. Other compounds of the invention thus include other opioids e.g. other μ-opioid receptor agonists.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and

"comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment. Any sub-titles herein are included for convenience only, and are not to be construed as limiting the disclosure in any way.

The invention will now be further described with reference to the following non-limiting Figures and Examples. Other embodiments of the invention will occur to those skilled in the art in the light of these.

The disclosure of all references cited herein, inasmuch as it may be used by those skilled in the art to carry out the invention, is hereby specifically incorporated herein by cross- reference.

Examples

Example 1- Use of compound of the invention for the treatment of red eves. Tramadol 1 % was applied to a patient with red eyes. The red eyes cleared within 1-2 minutes and lasted for at least 2 hours with the eye not being red but white and normal looking.

Example 2 - Formulations

Wthout limitation, an example composition, for use in the methods according to the invention, may be modified from existing opthalmically acceptable compositions such as "artificial tears". In "artificial tears", cellulose derivatives may be used for this purpose, such as CMC (carboxymethylcellulose) or HPMC (hydroxypropyl methyl cellulose, also known as hypromellose - see above). Glycerol is a low-molecular weight demulcent, while dextrans are high-molecular weight demulcents (dextran-70, a dextran having a molecular weight of around 70 kiloDaltons is believed to be particularly suitable). The choice of high or low molecular weight components depends on the viscosity requirements of the composition (for details, see below); the above cellulose derivatives will increase viscosity

significantly, for example.

It is hypothesised that polyols in general would be beneficial components for such lubricating compositions. In the context of the present application, the term "polyol" should be understood to refer to any organic compound having at least two adjacent hydroxyl (- OH) groups, in which these -OH groups are not held in a trans conformation, relative to each other. Such polyols may have a linear, branched or cyclic structural backbone, and may be substituted or unsubstituted, as long as they are water-soluble and

pharmaceutically acceptable. The term "polyol" thus includes short-chain molecules, including diols and triols, as well as longer-chain, higher molecular weight molecules with large or even indeterminate numbers of hydroxyl groups. Mixtures of polyols are equally possible. Examples of suitable polyols include sugars, sugar alcohols, sugar acids and uronic acids. Preferred sugar alcohols include mannitol and sorbitol. Short-chain polyols such as glycerol or propylene glycol are also very useful in these formulations, glycerol being a particularly suitable component in this regard. Mixtures of glycerol with other polyols, such as glycerol/sorbitol and glycerol/propylene glycol, are also found to be particularly useful.

To form a higher-viscosity or even slightly gelled composition, conventional viscosity modifiers such as cellulosics or even gelatin may be used, but it is not essential to use such high-molecular weight polymeric reagents. With polyols present, the addition of an additive such as a borate will result in a degree of loose cross-linking between hydroxyl groups on different molecules (the borate will tend to form labile complexes with the hydroxyl groups). Thus, the viscosity of the composition will rise, and can for example be controlled by regulating the precise level of borate added. This action will also depend on pH, so a system could be produced that would thicken or gel once administered, as its pH changed to that of its immediate environment in or adjacent the eye. Thus, a polyol such as glycerol may act both as a demulcent and as a viscosity regulator.

Emulsions and gels of various compounds may also be included.

Natural tears contain lipids, and analogous compounds may be used in artificial tears. Phospholipids, particularly anionic phospholipids may be included (both of the

hydroxypropyl guar gel group and of the carbomer-based lipid gel group). Surfactants, particularly non-ionic surfactants such as polysorbates, poloxamers and tetrafunctional block copolymers, may be used to lower the surface tension of the tear composition and thus enhance wetting of the surface of the eye; ionic surfactants may also be included. Other water-soluble polymers that have successfully been incorporated into strtificial tears formulations include polyvinyl alcohol (PVA), polyethyleneglycol (PEG) and carbomers (which are mainly polyacrylate polymers - Carbopol carbomers are a good example). Polyvinylpyrrolidone (PVP) has also been used with some success.

Some artificial tears formulations may contain hydrocarbons, such as white petrolatum, mineral oil and white soft paraffin, although such materials are in general more appropriate to corresponding eye lubricant ointment formulations.

It is usually desired for artificial tear compositions, such as those of the present invention, to have an enhanced viscosity or even to be slightly gelled. This increases the retention time of the liquid compositions in the eye and/or increases the

comfort/soothing/cushioning effect experienced by the patient when the composition is administered to the dry, sore eye.

A viscosity of from about 1 to about 20 centiPoises is generally required, preferably from about 2 to 20 centiPoises and ideally in the range of about 5 to 20 centiPoises.

The artificial tears should also be formulated to have a pH and osmolality compatible with the eye. Thus, the compositions will have a pH in the range of about 6.8 to 7.8. Alternatively, as mentioned above, the artificial tears could have a pH slightly outside this range, so that as the artificial tears change pH in use, towards that of the eye, their effective viscosity increases.

The desired osmolality of the compositions will generally be in the range of about 250 to 350 milliosmoles/kilogram water. This will usually be adjusted with sodium or potassium chloride, although if other salts such as borates are present (see above), these will also contribute.