Patent Description:
There exists a need for topical ophthalmic pharmaceutical products to effectively treat allergic conjunctivitis, a disorder that presents with both acute allergic symptoms (i.e., seasonal allergy) and late phase inflammatory reactions (i.e., chronic, refractory or persistent allergy), as well as allergic rhinoconjunctivitis. It has been estimated that <NUM>% (~ <NUM> million) of the adult allergy patients in the United States suffer from both the acute and late phase conditions of allergic conjunctivitis, whereas only <NUM>% suffer from only acute or late phase allergy, respectively. It is estimated that allergic rhinoconjunctivitis (a combination of ocular and nasal symptoms) may occur in up to <NUM>% of patients with allergies. The average age of allergy sufferers - between <NUM> and <NUM> years - coincides with the average age of the work force and the most productive period of an individual's life.

Both seasonal and perennial allergic conjunctivitis (ocular allergies) are characterized by itchy, red, swollen, and watery eyes. Allergic rhinitis (nasal allergies) manifests as a runny nose, sneezing, congestion, and similar symptoms. It can be difficult for a physician to distinguish allergic conjunctivitis from allergic rhinoconjunctivitis because both allergic reactions can occur simultaneously or be triggered by the same types of stimuli. It is further difficult to distinguish acute allergic symptoms from late phase symptoms of allergic conjunctivitis, as each of these conditions can persist simultaneously or morph back and forth in any given individual. The signs and symptoms of allergic conjunctivitis and allergic rhinoconjunctivitis can significantly impact the quality of life of patients, from social interactions, productivity at work and school, to the ability to perform visual tasks such as working on a computer or reading.

Acute symptoms of allergic conjunctivitis are characterized by the clinical signs and symptoms of eye itching, redness, and swelling. Late phase or allergic inflammation reactions of allergic conjunctivitis include redness, lid swelling and tearing, and in some cases itching, as well as the predominance of congestion in the nose. Acute allergic symptoms are predominantly caused by the activation of mast cells, which when stimulated by an allergen (pollen, dust, dander) releases a host of substances that produce the signs and symptoms of allergic conjunctivitis (itching, redness, swelling, and tearing). Histamine is the primary mediator released and stimulates receptors on nerve endings and blood vessels to produce itching and redness. There are two histamine receptors that have been identified on the ocular surface. H1 receptors on nerve endings lead to itching, and H1 and H2 receptors on blood vessels lead to dilation of the blood vessels, leading to redness, and leakage of fluid from the vessels into the surrounding tissue producing swelling. Late phase inflammatory reactions are mediated by activation of inflammatory cells.

Like allergic conjunctivitis, allergic rhinoconjunctivitis is an allergen-induced, mast cell-mediated response. The reaction is triggered when airborne allergens bind to antibodies attached to the surface of mast cells in the eye and/or nose. Mast cells, in turn, release chemical mediators, which account for the immediate reaction in sensitized individuals exposed to allergen. Some of these mediators, such as histamine, directly affect blood vessels and nerves, leading to the signs and symptoms of allergic disease. Other released mediators cause the influx of white blood cells to the site, which leads to sustained symptoms in severe cases and particularly congestion in the nose.

Allergic conjunctivitis and rhinoconjunctivitis may also co-exist with other external ocular conditions and diseases, such as dry eye, or irritations caused by pollutants or other causes. This leads to a compromised tear film, which serves to protect the ocular surface from allergens.

Currently available treatments for eye allergy include: drops which can wash allergens off the ocular surface and act as a barrier for the eye (e.g. artificial tears), drugs which block histamine from binding to the histamine receptors (e.g. antihistamines), drugs that block the release of histamine and other substances from the mast cell (e.g. mast cell stabilizers), drugs with multiple modes of action (e.g. antihistamine/mast cell stabilizing agents), and drugs that can actively constrict blood vessels thus reducing redness and swelling (e.g. vasoconstrictors). The criteria which may be considered in evaluating the appropriateness of an agent for a patient include: efficacy at onset of action, duration of action, how well it controls the individual signs and symptoms of allergic conjunctivitis, comfort of the formulation when instilled in the eye, and safety of the formulation when instilled in the eye. The comfort of an ophthalmic product depends on the active pharmaceutical ingredient itself, as well as the nature of the formulation and the vehicle that makes up the product. Oral antihistamines have been shown to induce decreased tear production and lead to dryness of the ocular surface, which can exacerbate ocular discomfort and can make the eye susceptible to irritation by an ophthalmic product.

The currently available treatments which contain a single active agent, such as an antihistamine or a mast cell stabilizer, typically provide relief for only acute allergic conjunctivitis and don't address the signs and symptoms of the late phase inflammatory reactions (i.e., chronic, refractory, or persistent allergy).

Currently available treatments for allergic rhinoconjunctivitis include eyedrops, nasal sprays, and systemic oral agents. Currently approved anti-allergy eyedrops are indicated for ocular allergy and nasal sprays are targeted for nasal allergy. Systemic agents, while they have indications to treat both nasal and ocular symptoms, several well controlled clinical trials conducted to ophthalmic standards have shown that systemic antihistamines are inferior to eyedrops in treating the ocular signs and symptoms (<NPL>), are not in fact clinically effective on eye allergy, and actually have been shown by objective measures to reduce tear production on the eye by <NUM>%, causing ocular dryness (<NPL>)). Further studies have shown that the combination of an eyedrop and nasal steroid is more effective than a systemic agent in treating the ocular and nasal signs and symptoms of allergy (<NPL>)).

Cetirizine hydrochloride is a racemic selective H1 receptor inverse agonist which functions as an antihistamine. It is a major metabolite of hydroxyzine and a derivative of piperazine. The levorotary enantiomer of cetirizine is known as levocetirizine. Cetirizine hydrochloride is FDA approved for oral use and is used as a systemic antihistamine for the treatment of allergies, hay fever, angioedema, and urticaria. It has been historically difficult to prepare cetirizine as an ophthalmic solution with satisfactory safety and stability profiles. Cetirizine has the disadvantage of forming aggregates in solution at low concentrations (typically less than <NUM>% (w/v)), thereby decreasing the stability as an aqueous solution. Moreover, higher concentrations of cetirizine (<NUM>% and above) are strongly irritating and thus unsuitable for direct ocular or nasal administration.

<CIT> addresses these issues by using a cyclodextrin compound to increase the solubility and stability of cetirizine for ophthalmic use. However, a cyclodextrin-free stable ophthalmic formulation containing cetirizine as the only active ingredient that is both comfortable in the eye and effective to mitigate the symptoms of allergic conjunctivitis has never been previously achieved.

<CIT> and <CIT> are members of the same patent family. <CIT> describes antiallergic cetirizine ophthalmic solutions for ophthalmic or nasal use. The cetirizine ophthalmic solutions have satisfactory safety and stability and no irritating properties to eyes. <CIT> describes that the addition of a cyclodextrin compound into the cetirizine aqueous solutions reduces the deposition of insoluble molecular aggregates of cetirizine that form in aqueous solutions at low concentration of cetirizine. Moreover, the cyclodextrin compound can suppress the irritating effects elicited by aqueous solutions containing high concentration of cetirizine when applied to eyes or nasal mucosae.

There thus exists a need to develop an effective, stable yet comfortable and safe cetirizine formulations for ophthalmic administration for the treatment of allergic conjunctivitis (i.e., the acute phase, the late inflammatory phase, or both) and allergic rhinoconjunctivitis. Such formulations for administration directly to the eye would be advantageous over systemic oral formulations and nasal sprays due to faster action and avoidance of the side effects associated with systemic administration.

The present invention provides comfortable topical ophthalmic formulations for the treatment of both acute and late phase signs of allergic conjunctivitis as well as rhinoconjunctivitis which contain a combination of ingredients which act synergistically to relieve the signs and symptoms of allergic conjunctivitis and/or rhinoconjunctivitis, particularly ocular itching and/or nasal symptoms (e.g., itchy, running nose, sneezing, nasal/sinus congestion). In particular, the formulations described herein provide stable formulations comprising a low concentration of cetirizine suitable for ophthalmic use in a comfortable ophthalmic formulation when instilled in the eye.

The present invention is based on the surprising discovery that stable topical ophthalmic formulations comprising a low concentration of cetirizine can be prepared without the use of a cyclodextrin or other solubilizer compound, that is both comfortable when instilled in the eye and effective to mitigate the symptoms of allergic conjunctivitis and/or rhinoconjunctivitis, particularly ocular itching and/or nasal symptoms (e.g., itchy, running nose, sneezing, nasal/sinus congestion). The invention also provides methods for the treatment of allergic conjunctivitis and/or rhinoconjunctivitis in a subject in need of such treatment by administering a cetirizine formulation of the invention directly to the eye of the subject. Surprisingly, once a day dosing of the low concentration cetirizine formulations of the invention is effective to mitigate the symptoms of allergic conjunctivitis and/or rhinoconjunctivitis, particularly ocular itching and/or nasal symptoms (e.g., itchy, running nose, sneezing, nasal/sinus congestion).

The formulation of the present invention is a topical ophthalmic formulation in the form of aqueous solution comprising <NUM>% to <NUM>% w/v cetirizine hydrochloride or cetirizine dihydrochloride calculated as cetirizine free base, a tear substitute composition in the form of aqueous solution comprising <NUM>% to <NUM>% w/v hydroxypropylmethyl cellulose or carboxymethyl cellulose, having a viscosity from <NUM> to <NUM> cpi and buffered to pH <NUM> to <NUM>, wherein cetirizine hydrochloride or cetirizine dihydrochloride is the only active agent and the aqueous formulation does not contain a cyclodextrin. Surprisingly, the stable cetirizine formulation is achieved without the use of a cyclodextrin, or other solubilizing compound, which were described as being required in <CIT>.

In an embodiment, the cetirizine alone formulation of the invention is formulated in a vehicle comprising <NUM>% Polyethylene Glycol <NUM>, NF; <NUM>% Dibasic Sodium Phosphate, Anhydrous, USP; <NUM>% Hypromellose, USP; <NUM>% Polysorbate <NUM>, NF; <NUM>% to <NUM>% Glycerin (or any specific value within said range), USP; <NUM>% Edetate Disodium, USP; <NUM>% Benzalkonium Chloride, NF (pH <NUM>).

The stable ophthalmic cetirizine formulations of the invention comprise a tear substitute. In particular embodiments, the tear substitute is hydroxypropylmethyl cellulose (Hypromellose or HPMC). According to some embodiments, the concentration of HPMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range. According to some embodiments, the concentration of HPMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range. In a preferred embodiment not encompassed by the claims, the concentration of HPMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range (e.g., <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%; about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>%).

In another particular embodiment the tear substitute is carboxymethyl cellulose (CMC). According to some embodiments, the concentration of CMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range. According to some embodiments, the concentration of CMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range. In a preferred embodiment not encompassed by the claims, the concentration of CMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range (i.e., about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>%).

Optionally, the formulations of the invention contain a preservative. In particular embodiments the preservative is benzalkonium chloride or a derivative thereof (e.g., Polyquad®), or a stabilized oxychloro complex (e.g., Purite®).

The invention also provides methods of treating and preventing the symptoms of allergic conjunctivitis by administering the stable cetirizine formulation of the invention (i.e., cetirizine alone) directly to the eye of a subject in need of such treatment or prevention. Preferably, the formulation of the invention is administered once a day (q. In certain embodiments, the methods of the invention (i.e., administration of a formulation of the invention directly to the eye) are also effective to treat nasal symptoms associated with allergic conjunctivitis. The invention also provides methods of treating and preventing the symptoms of allergic rhinoconjunctivitis by administering the stable cetirizine formulation of the invention (i.e., cetirizine alone) directly to the eye of a subject in need of such treatment or prevention. By providing a treatment option in eye drop form, the present invention will improve quality of life in patients with allergic rhinoconjunctivitis/rhinitis (See e.g.,<NPL>).

Any reference in the description to a method of treatment refers to pharmaceutical formulation of the present invention for use in a method for the treatment human body by therapy. Other features and advantages of the invention will become apparent from the following detailed description and claims.

Object of the invention is the subject matter defined in claims <NUM> to <NUM>.

The invention is based in part on the discovery that low concentrations of cetirizine (i.e., less than <NUM>%) can be prepared as a stable ophthalmic formulation, without the use of a cyclodextrin or other solubilizing compound. Such formulations are comfortable and safe for ocular use and effective at reducing the symptoms of allergic conjunctivitis and/or allergic rhinoconjunctivitis, particularly ocular itching and/or nasal symptoms (e.g., itchy, running nose, sneezing, nasal/sinus congestion).

The historical difficulty in preparing cetirizine as an ophthalmic solution with satisfactory safety and stability profiles is well recognized in the art due to the fact that cetirizine aggregates in solution at low concentrations, and is highly irritating to the ocular surface at high concentrations, being a strong acid. Without intending to be bound by any theory, it was believed necessary to reduce the possibility of salt formation and metal based degradation in order to arrive at a stable formulation. As such, the addition of counter ions or metal based buffers that could promote salt formation, precipitation, or metal based degradation were minimized or excluded from the cetirizine formulations of the invention. Furthermore, it was discovered that the pH could be adjusted to approximately <NUM> with no adverse effects on stability, to improve the comfort of the formula.

The invention features novel topical ophthalmic formulations comprising an effective amount of cetirizine, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. Pharmaceutically acceptable cetirizine salts include cetirizine hydrochloride or cetirizine dihydrochloride. In particular embodiments, the invention provides stable ophthalmic formulations of cetirizine as the only active agent in the formulations.

The comfort, safety, efficacy, solubility, and stability of the ophthalmic formulations of the invention could not have been predicted by one skilled in the art. Many antihistamines have been developed over the years by various companies for different indications. However, not all of these can be formulated or are effective as an eyedrop. Likewise not all antihistamines have the same duration of action. For example the potent antihistamine levocabastine has a duration of <NUM>-<NUM> hours; recently approved bepotastine (Bepreve®-ISTA), indicated for twice daily dosing, has an <NUM> hour duration; olopatadine <NUM>% (Patanol®) indicated for twice daily dosing, has an <NUM> hour duration; and olopatadine <NUM>% (Pataday®), indicated for once daily dosing, has a <NUM> hour duration of action. Therefore the efficacy is not predictable. In one study (Berdy et al, <NUM>), a panel of antihistamines were screened yet only a few were suitable for the eye based on comfort, formulation, irritation, and efficacy. As evidenced by Berdy et al. , one skilled in the art could not have predicted which of the antihistamines would be ideal for ocular use or for treating ocular allergy.

The cetirizine formulations of the invention comprise one or more tear substitute components. The cetirizine component provides relief of the symptoms of allergic conjunctivitis, and the one or more tear substitute component provides ocular surface protection via enhancement of the tear film (as evident by increased tear film break up time), and can act to enhance dwell time on the ocular surface thus increasing duration of activity. An effective amount of such formulations may be used to treat and/or prevent signs and symptoms associated with acute and/or late phase allergic conjunctivitis and/or general eye irritation. An effective amount of such formulations may also be used to treat and/or prevent signs and symptoms of allergic rhinoconjunctivitis.

The superior efficacy of the combination cetirizine/tear substitute formulations is attributed to, among other things, the synergistic effect of the combination of ingredients in them. The combination of cetirizine and tear substitute, act synergistically to provide a longer dwell time of the cetirizine on the ocular surface, thus increasing duration and efficacy of action, and to prolong the integrity of the tear film thereby providing protection of the ocular surface (e.g., by increasing the tear film break up time and/or the Ocular Protection Index). As such, the compositions of the invention are comfortable upon instillation into the eye, and may be used for relief of acute or chronic allergic conjunctivitis, and are particularly suitable for both intermittent and long term use.

In the context of this patent all concentrations are given for the cetirizine free base. The concentration for the cetirizine salt (e.g. cetirizine hydrochloride or dihydrochloride) can be calculated by multiplying the free base concentration by <NUM>. e.g. <NUM>% cetirizine free base is equivalent to <NUM>% cetirizine hydrochloride salt (<NUM>% x <NUM> = <NUM>%).

The ophthalmic formulations according to the present invention are formulated as solutions. Aqueous solutions are generally preferred, based on ease of formulation, 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. In one embodiment, the cetirizine formulations of the invention are aqueous formulations. The aqueous formulations of the invention are typically more than <NUM>%, preferably more than <NUM>%, and most preferably more than <NUM>% by weight water. Preferably, the aqueous formulation does not contain a cyclodextrin or other solubilizer compound. Stable aqueous formulations of cetirizine are achieved by minimizing/excluding the addition of counter ions or metal based buffers that could promote salt formation, precipitation, or metal based degradation.

Cetirizine is the only active agent in the formulations of the invention. Cetirizine is in the form of cetirizine hydrochloride or dihydrochloride. In one embodiment, the cetirizine formulation of the invention comprises cetirizine hydrochloride or dihydrochloride as the only active ingredient at a concentration of <NUM>% to <NUM>% (w/v), more preferably <NUM>% to <NUM>% (w/v) (or any specific value within said ranges).

The term "allergic conjunctivitis" refers to any allergic disease of the eye, e.g., seasonal/perennial allergic conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, perennial allergic conjunctivitis and atopic keratoconjunctivitis. The signs and symptoms of ocular allergies include chemosis, eye itching, tearing, redness and swelling, and may also co-exist with nasal symptomatology. The term "allergic rhinoconjunctivitis" refers to a combination of nasal and ocular symptoms characterized by inflammation of the lining of the tissue of the eyes and nose due to an allergy or infection, causing nasal discharge, mucus, sneezing, irritation, and red, water, itchy eyes.

The cetirizine formulations of the invention may comprise one or more pharmaceutically acceptable excipients. The term excipient as used herein broadly refers to a biologically inactive substance used in combination with the active agents of the formulation. An excipient can be used, for example, as a solubilizing agent, a stabilizing agent, a surfactant, a demulcent, a viscosity agent, a diluent, an inert carrier, a preservative, a binder, a disintegrant, a coating agent, a flavoring agent, or a coloring agent. Preferably, at least one excipient is chosen to provide one or more beneficial physical properties to the formulation, such as increased stability and/or solubility of the active agent(s). A "pharmaceutically acceptable" excipient is one that has been approved by a state or federal regulatory agency for use in animals, and preferably for use in humans, or is listed in the U. Pharmacopeia, the European Pharmacopeia or another generally recognized pharmacopeia for use in animals, and preferably for use in humans.

Further examples of excipients include certain inert proteins such as albumins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as aspartic acid (which may alternatively be referred to as aspartate), glutamic acid (which may alternatively be referred to as glutamate), lysine, arginine, glycine, and histidine; fatty acids and phospholipids such as alkyl sulfonates and caprylate; surfactants such as sodium dodecyl sulphate and polysorbate; nonionic surfactants such as such as TWEEN®, PLURONICS®, or a polyethylene glycol (PEG) designated <NUM>, <NUM>, <NUM>, or <NUM>; a Carbowax designated <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>; carbohydrates such as glucose, sucrose, mannose, maltose, trehalose, and dextrins, including cyclodextrins; polyols such as mannitol and sorbitol; chelating agents such as EDTA; and salt-forming counter-ions such as sodium.

Examples of carriers that may be used in the formulations of the present invention include water, mixtures of water and water-miscible solvents, such as C<NUM>- to C<NUM>-alkanols, vegetable oils or mineral oils comprising from <NUM> to <NUM>% non-toxic water-soluble polymers, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenan, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products, such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid, such as neutral Carbopol, or mixtures of those polymers. The concentration of the carrier is, typically, from <NUM> to <NUM> times the concentration of the active ingredient.

Another example of carrier is a polymeric mucoadhesive vehicle. Examples of mucoadhesive vehicles suitable for use in the methods or formulations of the invention include but are not limited to aqueous polymeric suspensions comprising one or more polymeric suspending agents including without limitation dextrans, polyethylene glycol, polyvinylpyrolidone, polysaccharide gels, Gelrite®, cellulosic polymers, and carboxy-containing polymer systems. In a particular embodiment, the polymeric suspending agent comprises a crosslinked carboxy-containing polymer (e.g., polycarbophil). In another particular embodiment, the polymeric suspending agent comprises polyethylene glycol (PEG). Examples of cross-linked carboxy-containing polymer systems suitable for use in the topical stable ophthalmic cetirizine formulations of the invention include but are not limited to Noveon AA-<NUM>, Carbopol®, and/or DuraSite® (InSite Vision).

The cetirizine formulations of the invention comprise a tear substitute and one or more excipients selected from among the following: a tonicity enhancer, a preservative, a solubilizer, a viscosity enhancing agent, a demulcent, an emulsifier, a wetting agent, a sequestering agent, and a filler. The amount and type of excipient added is in accordance with the particular requirements of the formulation and is generally in the range of from about <NUM>% to <NUM>% by weight.

The term "tear substitute" refers to molecules or compositions which lubricate, "wet," approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye signs or symptoms and conditions upon ocular administration. A variety of tear substitutes are known in the art and include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium and hydroxy propylcellulose; dextrans such as dextran <NUM>; water soluble proteins such as gelatin; vinyl polymers, such as polyvinyl alcohol, polyvinylpyrrolidone, and povidone; and carbomers, such as carbomer 934P, carbomer <NUM>, carbomer <NUM> and carbomer 974P. Many such tear substitutes are commercially available, which include, but are not limited to cellulose esters such as Bion Tears®, Celluvisc®, Genteal®, OccuCoat®, Refresh®, Systane®, Teargen II®, Tears Naturale®, Tears Natural II®, Tears Naturale Free®, and TheraTears®; and polyvinyl alcohols such as Akwa Tears®, HypoTears®, Moisture Eyes®, Murine Lubricating®, and Visine Tears®, Soothe®. Tear substitutes may also be comprised of paraffins, such as the commercially available Lacri-Lube® ointments. Other commercially available ointments that are used as tear substitutes include Lubrifresh PM®, Moisture Eyes PM® and Refresh PM®.

In one preferred embodiment of the invention, the tear substitute comprises hydroxypropylmethyl cellulose (Hypromellose or HPMC). According to some embodiments, the concentration of HPMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range. According to some embodiments, the concentration of HPMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range. According to some embodiments, the concentration of HPMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range. According to some embodiments, the concentration of HPMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range. In a preferred embodiments, the concentration of HPMC ranges from about <NUM>% to about <NUM>% w/v, or any specific value within said range (i.e., <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%, <NUM>-<NUM>%; about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>%).

For example, without limitation, a tear substitute which comprises hydroxypropyl methyl cellulose is GenTeal® lubricating eye drops. GenTeal® (CibaVision - Novartis) is a sterile lubricant eye drop containing hydroxypropylmethyl cellulose <NUM>/g and preserved with sodium perborate.

In another preferred embodiment, the tear substitute comprises carboxymethyl cellulose sodium. For example, without limitation, the tear substitute which comprises carboxymethyl cellulose sodium is Refresh® Tears. Refresh® Tears is a lubricating formulation similar to normal tears, containing a, mild non-sensitizing preservative, stabilised oxychloro complex (Purite®), that ultimately changes into components of natural tears when used.

In a preferred embodiment, the tear substitute, or one or more components thereof, is an aqueous solution having a viscosity in a range which optimizes efficacy of supporting the tear film while minimizing blurring, lid caking, etc. Preferably, the viscosity of the tear substitute, or one or more components thereof, ranges from <NUM>-<NUM> centipoise (cpi), e.g., <NUM>-<NUM> cpi, <NUM>-<NUM> cpi, <NUM>-<NUM> cpi, <NUM>-<NUM> cpi, <NUM>-<NUM> cpi (or any specific value within said ranges). In a particular embodiment not encompassed by the claims, the viscosity of the tear substitute, or one or more components thereof, is about <NUM>-<NUM> cpi, or any specific value within said range (for example without limitation, <NUM> cpi).

Viscosity may be measured at a temperature of <NUM>° C +/- <NUM> using a Brookfield Cone and Plate Viscometer Model VDV-III Ultra+ with a CP40 or equivalent Spindle with a shear rate of approximately <NUM> +/- approximately <NUM> (<NUM>/sec), or a Brookfield Viscometer Model LVDV-E with a SC4-<NUM> or equivalent Spindle with a shear rate of approximately <NUM> +/- approximately <NUM> (<NUM>/sec). Alternatively, viscosity may be measured at <NUM> +/- <NUM> using a Brookfield Cone and Plate Viscometer Model VDV-III Ultra+ with a CP40 or equivalent Spindle with a shear rate of approximately <NUM> +/approximately <NUM> (<NUM>/sec), or a Brookfield Viscometer Model LVDV-E with a SC4-<NUM> or equivalent Spindle with a shear rate of approximately <NUM> +/- approximately <NUM> (<NUM>/sec).

In some embodiments, the tear substitute, or one or more components thereof is buffered to pH <NUM> to <NUM>, more preferably pH <NUM> to <NUM> (or any specific value within said ranges), with a suitable salt (e.g., phosphate salts). In some embodiments, the tear substitute further comprises one or more ingredients, including without limitation, glycerol, propylene glycerol, glycine, sodium borate, magnesium chloride, and zinc chloride.

The formulations of the present invention may also contain pharmaceutically acceptable salts, buffering agents, or preservatives. Examples of such salts include those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, boric, formic, malonic, succinic, and the like. Such salts can also be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts. Examples of buffering agents include phosphate, citrate, acetate, and <NUM>-(N-morpholino)ethanesulfonic acid (MES).

For the adjustment of the pH, preferably to a physiological pH, buffers may especially be useful. The pH of the present solutions should be maintained within the range of <NUM> to <NUM>, more preferably about <NUM> to <NUM>. Suitable buffers may be added, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na<NUM>HPO<NUM>, NaH<NUM>PO<NUM> and KH<NUM>PO<NUM>) and mixtures thereof. Borate buffers are preferred. Generally, buffers will be used in amounts ranging from about <NUM> to <NUM> percent by weight, and preferably, from <NUM> to <NUM> percent.

In certain embodiments, the topical formulations additionally comprise a preservative. A preservative may typically be selected from a quaternary ammonium compound such as benzalkonium chloride, benzoxonium chloride or the like. Benzalkonium chloride is better described as: N-benzyl-N-(C<NUM>-C<NUM> alkyl)-N,N-dimethylammonium chloride. Further examples of preservatives include antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium; the amino acids cysteine and methionine; citric acid and sodium citrate; and synthetic preservatives such as thimerosal, and alkyl parabens, including for example, methyl paraben and propyl paraben. Other preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzethonium chloride, phenol, catechol, resorcinol, cyclohexanol, <NUM>-pentanol, m-cresol, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, sodium perborate, sodium chlorite, alcohols, such as chlorobutanol, butyl or benzyl alcohol or phenyl ethanol, guanidine derivatives, such as chlorohexidine or polyhexamethylene biguanide, sodium perborate, Polyquad®, Germal®II, sorbic acid and stabilized oxychloro complexes (e.g., Purite®). Preferred preservatives are quaternary ammonium compounds, in particular benzalkonium chloride or its derivative such as Polyquad (see <CIT>), alkyl-mercury salts, parabens and stabilized oxychloro complexes (e.g., Purite®). Where appropriate, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection against secondary contaminations during use caused by bacteria and fungi.

The cetirizine formulations of the invention may comprise a preservative selected from among the following: benzalkonium chloride, <NUM>% to <NUM>%; benzethonium chloride, up to <NUM>%; sorbic acid, <NUM>% to <NUM>%; polyhexamethylene biguanide, <NUM> ppm to <NUM> ppm; polyquaternium-<NUM> (Omamer M) - <NUM> ppm to <NUM> ppm; hypochlorite, perchlorite or chlorite compounds, <NUM> ppm or less, preferably between <NUM> and <NUM> ppm); stabilized hydrogen peroxide solutions, a hydrogen peroxide source resulting in a weight % hydrogen peroxide of <NUM> to <NUM>% along with a suitable stabilizer; alkyl esters of p-hydroxybenzoic acid and mixtures thereof, preferably methyl paraben and propyl paraben, at <NUM>% to <NUM>%; chlorhexidine, <NUM>% to <NUM>%; chlorobutanol, up to <NUM>%; and stabilized oxychloro complex (Purite®) <NUM>% to <NUM>%.

In another embodiment, the topical formulations of this invention do not include a preservative. Such formulations would be useful for patients who wear contact lenses, or those who use several topical ophthalmic drops and/or those with an already compromised ocular surface (e.g. dry eye) wherein limiting exposure to a preservative may be more desirable.

Viscosity enhancing agents may be added to the cetirizine formulations of the invention. Examples of such agents include polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family, vinyl polymers, and acrylic acid polymers.

The cetirizine formulations of the invention may comprise ophthalmic demulcents and/or viscosity enhancing polymers selected from one or more of the following: cellulose derivatives such as carboxymethylcellulose (<NUM> to <NUM>%) hydroxyethylcellulose (<NUM>% to <NUM>%), hydroxypropyl methylcellulose or hypromellose (<NUM>% to <NUM>%), and methylcellulose (<NUM>% to <NUM>%); dextran <NUM> / <NUM> (<NUM>% to <NUM>%); gelatin (<NUM>% to <NUM>%); polyols such as glycerin (<NUM>% to <NUM>%), polyethylene glycol <NUM> (<NUM>% to <NUM>%), polyethylene glycol <NUM> (<NUM>% to <NUM>%), polysorbate <NUM> (<NUM>% to <NUM>%), propylene glycol (<NUM>% to <NUM>%), polyvinyl alcohol (<NUM>% to <NUM>%), and povidone (<NUM>% to <NUM>%); hyaluronic acid (<NUM>% to <NUM>%); and chondroitin sulfate (<NUM>% to <NUM>%).

Viscosity of the stable ophthalmic cetirizine formulations of the invention may be measured according to standard methods known in the art, such as use of a viscometer or rheometer. One of ordinary skill in the art will recognize that factors such as temperature and shear rate may effect viscosity measurement. In a particular embodiment, viscosity of the is measured at <NUM> +/- <NUM> using a Brookfield Cone and Plate Viscometer Model VDV-III Ultra+ with a CP40 or equivalent Spindle with a shear rate of approximately <NUM> +/- approximately <NUM> (<NUM>/sec), or a Brookfield Viscometer Model LVDV-E with a SC4-<NUM> or equivalent Spindle with a shear rate of approximately <NUM> +/- approximately <NUM> (<NUM>/sec). In another embodiment, viscosity of the ophthalmic formulations of the invention is measured at <NUM> +/- <NUM> using a Brookfield Cone and Plate Viscometer Model VDV-III Ultra+ with a CP40 or equivalent Spindle with a shear rate of approximately <NUM> +/approximately <NUM> (<NUM>/sec), or a Brookfield Viscometer Model LVDV-E with a SC4-<NUM> or equivalent Spindle with a shear rate of approximately <NUM> +/- approximately <NUM> (<NUM>/sec).

Tonicity is adjusted if needed typically by tonicity enhancing agents. Such agents may, for example be of ionic and/or non-ionic type. Examples of ionic tonicity enhancers are alkali metal or earth metal halides, such as, for example, CaCl<NUM>, KBr, KCl, LiCl, NaI, NaBr or NaCl, Na<NUM>SO<NUM> or boric acid. Non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose. The aqueous solutions of the present invention are typically adjusted with tonicity agents to approximate the osmotic pressure of normal lachrymal fluids which is equivalent to a <NUM>% solution of sodium chloride or a <NUM>% solution of glycerol. An osmolality of about <NUM> to <NUM> mOsm/kg is preferred, more preferably <NUM> to <NUM> mOsm.

In one embodiment, the cetirizine formulation comprises cetirizine as the only active ingredient at <NUM>% to <NUM>% (w/v) and optionally one or more tear substitutes. Preferably, the cetirizine formulations do not contain a cyclodextrin or other solubilizing compound.

Where the formulation comprises one or more tear substitutes, the tear substitute preferably contains hydroxypropylmethyl cellulose or carboxymethyl cellulose. In some embodiments, the hydroxypropylmethyl cellulose or carboxymethyl cellulose is present at a concentration of <NUM>% to <NUM>% (w/v) (or any specific value within said range) and the resulting viscosity of the solution is <NUM>-<NUM> cpi. In a particular embodiment, the hydroxypropylmethyl cellulose or carboxymethyl cellulose is present at a concentration of <NUM>% to <NUM>%. In another particular embodiment, the hydroxypropylmethyl cellulose or carboxymethyl cellulose is present at a concentration of <NUM>% to <NUM>% and the resulting viscosity of the solution is <NUM>-<NUM> cpi. Optionally, the formulation also comprises a preservative, preferably benzalkonium chloride at a concentration of from <NUM>% to <NUM>% (w/v) (or any specific value within said range) or its derivative (e.g., Polyquad®), or a stabilized oxychloro complex (e.g., Purite®). The pH of the formulation is between <NUM> and <NUM>. For example, the pH of the formulation is <NUM>, <NUM>, <NUM>, <NUM> or <NUM>.

The formulations of the present invention provide for the chemical stability of the formulated cetirizine of the formulation, without the use of a cyclodextrin or other solubilizing compound. "Stability" and "stable" in this context refers to the resistance of the cetirizine to chemical degradation under given manufacturing, preparation, transportation and storage conditions. The "stable" formulations of the invention also preferably retain at least <NUM>%, <NUM>%, <NUM>%, <NUM>%, or <NUM>% of a starting or reference amount under given manufacturing, preparation, transportation, and/or storage conditions. The amount of cetirizine can be determined using any art-recognized method, for example, as UV-Vis spectrophotometry and high pressure liquid chromatography (HPLC).

In certain embodiments not encompassed by the claims, the cetirizine formulations are stable at temperatures ranging from about <NUM> to <NUM> for at least <NUM> week, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks. In other embodiments, the cetirizine formulations are stable at temperatures ranging from about <NUM> to <NUM> for at least <NUM> month, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, or at least <NUM> months. In one embodiment, the formulation is stable for at least <NUM> months at <NUM>-<NUM>.

In other embodiments not encompassed by the claims, the cetirizine formulations are stable at temperatures ranging from about <NUM> to <NUM> for at least <NUM> month, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, or at least <NUM> months. In one embodiment, the formulation is stable for at least <NUM> months at <NUM> to <NUM>.

In other embodiments not encompassed by the claims, the cetirizine formulations are stable at temperatures of about -<NUM> for at least <NUM> month, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, at least <NUM> months, or at least <NUM> months. In one embodiment, the formulation is stable for at least <NUM>-<NUM> months at -<NUM>.

In a particular embodiment not encompassed by the claims, a cetirizine formulation of the invention is stable at temperatures of about <NUM>-<NUM> at concentrations up to <NUM>% for at least <NUM> months. In another embodiment, the formulation is stable at temperatures from about <NUM>-<NUM> at concentrations up to <NUM>% for at least <NUM> months.

The cetirizine formulations of the invention are useful for the treatment and prevention of the signs and symptoms of both the acute phase (i.e., seasonal) and late phase inflammatory reactions (i.e., chronic, persistent or refractory) of allergic conjunctivitis, such as ocular itching, redness, and eyelid swelling, as well as associated nasal symptoms. The formulations of the invention are also useful for the treatment and prevention of the signs and symptoms of allergic rhinoconjunctivitis, such as itchy, running nose, sneezing, nasal/sinus congestion, and red, watery and/or itchy eyes.

The invention provides methods of treating or preventing allergic conjunctivitis and/or allergic rhinoconjunctivitis in a subject in need thereof comprising topically administering to the eye surface of the subject an ophthalmic formulation comprising an effective amount of cetirizine. In certain embodiments, the administration of cetirizine to the eye of a subject in need of treatment or prevention of allergic conjunctivitis and/or rhinoconjunctivitis is also effective to mitigate or reduce one or more nasal symptoms associated with the either allergy (e.g., itchy, running nose, sneezing and/or nasal/sinus congestion). Topical administration of the ophthalmic formulations directly to the eye of a subject will significantly reduce nasal signs and symptoms via drainage from the ocular surface into the nasal cavity through the nasolacrimal duct (See e.g., <NPL>); <NPL>); and <NPL>). Furthermore, significantly less active agent is required to treat the nasal symptoms when instilled through the eye of a subject as compared to administration through the nose of the subject. As such, the methods of the present invention are more effective than the currently available treatment options for nasal symptoms of allergic conjunctivitis and allergic rhinoconjunctivitis.

The subject is preferably a human, but may be another mammal, for example a dog, a cat, a horse, a rabbit, a mouse, a rat, or a non-human primate.

The formulations of the present invention contain an amount of cetirizinethat is effective for the intended use (i.e., to mitigate the signs and symptoms of allergic conjunctivitis and/or rhinoconjunctivitis). In certain embodiments, once a day administration of the formulations of the present invention is effective to mitigate the symptoms of allergic conjunctivitis and/or rhinoconjunctivitis. However, particular dosages are also selected based on a number of factors including the age, sex, species and condition of the subject. Effective amounts can also be extrapolated from dose-response curves derived from in vitro test systems or from animal models. The term "effective amount" means an amount of cetirizine that is sufficient to eliminate or reduce a symptom of allergic conjunctivitis and/or rhinoconjunctivitis. In certain embodiments, the effective amount is the amount sufficient for the treatment or prevention of allergic conjunctivitis and/or rhinoconjunctivitis. "Treatment" in this context refers to reducing or ameliorating at least one symptom of allergic conjunctivitis and/or rhinoconjunctivitis. "Prevention" in this context refers to a reduction in the frequency of, or a delay in the onset of, symptoms associated with allergic conjunctivitis and/or rhinoconjunctivitis, relative to a subject who does not receive the composition. The effective amount of cetirizine in the formulation will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the compound from the formulation. Particular dosages may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, a dosing regimen will be determined using techniques known to one skilled in the art.

Examples of dosing regimens that can be used in the methods of the invention include, but are not limited to, once daily, twice daily, three times, and four times daily. In certain embodiments, the method comprises administering a cetirizine formulation of the invention to the eye of the subject once a day. In some embodiments, the administration is <NUM> to <NUM> times a day.

In certain embodiments, once a day administration (q. ) is effective to mitigate the symptoms of ocular and/or nasal allergy. However, particular dosages may also selected based on a number of factors including the age, sex, species and condition of the subject. Effective amounts can also be extrapolated from dose-response curves derived from in vitro test systems or from animal models.

In a particular embodiment, a formulation comprising cetirizine as the only active agent in the formulation is administered to the eye of a subject in need of treatment or prevention of an allergic conjunctivitis and/or rhinoconjunctivitis once daily (q. In certain embodiments, the combination formulation is administered two to four times a day.

The formulations of the present invention may be packaged as either a single dose product or a multi-dose product. The single dose product is sterile prior to opening of the package and all of the composition in the package is intended to be consumed in a single application to one or both eyes of a patient. The use of an antimicrobial preservative to maintain the sterility of the composition after the package is opened is generally unnecessary.

Multi-dose products are also sterile prior to opening of the package. However, because the container for the composition may be opened many times before all of the composition in the container is consumed, the multi-dose products must have sufficient antimicrobial activity to ensure that the compositions will not become contaminated by microbes as a result of the repeated opening and handling of the container. The level of antimicrobial activity required for this purpose is well known to those skilled in the art, and is specified in official publications, such as the United States Pharmacopoeia ("USP") and corresponding publications in other countries. Detailed descriptions of the specifications for preservation of ophthalmic pharmaceutical products against microbial contamination and the procedures for evaluating the preservative efficacy of specific formulations are provided in those publications. In the United States, preservative efficacy standards are generally referred to as the "USP PET" requirements. (The acronym "PET" stands for "preservative efficacy testing.

The use of a single dose packaging arrangement eliminates the need for an antimicrobial preservative in the compositions, which is a significant advantage from a medical perspective, because conventional antimicrobial agents utilized to preserve ophthalmic compositions (e.g., benzalkonium chloride) may cause ocular irritation, particularly in patients suffering from dry eye conditions or pre-existing ocular irritation. However, the single dose packaging arrangements currently available, such as small volume plastic vials prepared by means of a process known as "form, fill and seal", have several disadvantages for manufacturers and consumers. The principal disadvantages of the single dose packaging systems are the much larger quantities of packaging materials required, which is both wasteful and costly, and the inconvenience for the consumer. Also, there is a risk that consumers will not discard the single dose containers following application of one or two drops to the eyes, as they are instructed to do, but instead will save the opened container and any composition remaining therein for later use. This improper use of single dose products creates a risk of microbial contamination of the single dose product and an associated risk of ocular infection if a contaminated composition is applied to the eyes.

While the formulations of this invention are preferably formulated as "ready for use" aqueous solutions, alternative formulations are contemplated within the scope of this invention. Thus, for example, the active ingredients, surfactants, salts, chelating agents, or other components of the ophthalmic solution, or mixtures thereof, can be lyophilized or otherwise provided as a dried powder or tablet ready for dissolution (e.g., in deionized, or distilled) water. Because of the self-preserving nature of the solution, sterile water is not required.

A placebo controlled, double-blind study was conducted to evaluate the efficacy of cetirizine <NUM>% (N=<NUM>) compared to vehicle (N=<NUM>). Subjects underwent <NUM> screening visits (an allergen titration and confirmation) followed by a drug evaluation visit. At the drug evaluation visit, one drop of masked study medication was instilled in each eye and comfort assessments were taken. Sixteen hours later the subjects were challenged with allergen and allergic assessments were taken. The results are presented in Tables <NUM> and <NUM> and in <FIG>. The ocular itching score ranges from <NUM>, no itching, to <NUM>, severe itching. The comfort score ranges from <NUM>, very comfortable, to <NUM>, very uncomfortable (Note: The most uncomfortable commercially available allergy drop=<NUM>). The results demonstrate that a single drop of cetirizine (<NUM>%) ophthalmic solution (q. ) was effective to prevent ocular itching associated with allergic conjunctivitis when administered <NUM> hours prior to conjunctival allergen challenge (CAC), but had little effect on reducing conjunctival redness (<FIG> and <FIG>). Differences between cetirizine and vehicle groups were both clinically (≥<NUM> unit difference) and statistically significant (P<<NUM>). In addition, as shown in Table <NUM>, and <FIG>, the cetirizine formulation was comfortable (i.e., well-tolerated) by the subjects.

Seasonal allergic conjunctivitis (hay fever conjunctivitis) develops in a subset of atopic individuals (those with a genetic disposition of hypersensitivity to allergens). The signs and symptoms of the condition are elicited by airborne allergens (e.g. ragweed, tree and grass pollens, animal dander). Seasonal allergic conjunctivitis is the most common form of ocular allergic disease and may account for up to <NUM>% of allergic disorders seen.

The most common and distressing ocular signs and symptoms associated with allergic conjunctivitis are itching and redness. Swelling, mucous discharge and excessive tearing are frequently involved. In allergic conjunctivitis, airborne allergens presumably dissolve in the tear film, traverse the conjunctiva, and then bind with IgE antibodies attached to the surface of the conjunctival mast cell to trigger an allergic response. This attachment results in mast cell degranulation and release of chemical mediators that lead to signs and symptoms of allergic disease. Some of these substances, e.g. histamines and prostaglandins, directly affect blood vessels and nerves, whereas others influence the migration of inflammatory cells such as neutrophils, eosinophils and macrophages, causing inflammation.

The major chemical mediator involved in producing ocular symptoms is histamine. Several types of histamine have been identified in the human conjunctiva. Stimulation of H1 receptors results mainly in itching while stimulation of H2 receptors results largely in vasodilation (redness). However, studies with antihistamines known to be highly specific for H1 receptors have suggested that H1 receptors may also have a secondary effect on redness.

The purpose of this study was to investigate the potential of cetirizine/fluticasone combination formulations in preventing signs of allergic conjunctivitis in a murine active anaphylaxis model. In this model, mice are systemically sensitized to short ragweed allergen (SRW) and then challenged by instilling SRW in the eyes. Therapeutic treatment is given after sensitization but prior to topical challenge. Allergens present in the SRW preparation cross-link IgE antibodies bound to conjunctival mast cells causing degranulation and release of histamine and other allergic mediators, which in turn produce the characteristic signs and symptoms of allergic conjunctivitis.

Four test formulations, containing combination <NUM>% Cetirizine/<NUM>% Fluticasone ("low dose"), combination <NUM>% Cetirizine/<NUM>% Fluticasone ("high dose"), <NUM>% Cetirizine or <NUM>% Fluticasone, were compared with vehicle alone (<NUM>% Polyethylene Glycol <NUM>, NF; <NUM>% Dibasic Sodium Phosphate, Anhydrous, USP; <NUM>% Hypromellose, USP; <NUM>% Polysorbate <NUM>, NF; <NUM>% Glycerin, USP; <NUM>% Edetate Disodium, USP; <NUM>% Benzalkonium Chloride, NF (pH <NUM>)) and two commercial positive controls, Pred Forte® (prednisolone acetate <NUM>%) and Pataday® (olopatadine <NUM>%).

Systemic sensitization to short ragweed allergen (SRW) was induced by injecting SRW plus alum adjuvant systemically into Balb/c mice (Day <NUM>), and by administration of topical SRW eyedrops on days <NUM>-<NUM>. Topical ocular drug treatment was administered daily on days <NUM>-<NUM> after SRW injection. After <NUM> days of treatment, the animals were assessed for signs of allergic conjunctivitis in response to challenge with topical SRW administration. Clinical assessments included conjunctival hyperemia, chemosis, discharge and lid swelling, each graded biomicroscopically on a <NUM>-<NUM> severity scale.

After <NUM> days of drug treatment, the animals treated with the combination <NUM>% Cetirizine/<NUM>% Fluticasone demonstrated the least severity in three clinical signs (conjunctival hyperemia, chemosis, and lid swelling) as compared Cetirizine or Fluticasone alone or as compared to most other treatment groups. Cetirizine or Fluticasone alone produced no significant treatment effects.

The reduction in clinical signs in response to SRW challenge after <NUM> days of treatment with the combination <NUM>% Cetirizine/<NUM>% Fluticasone was statistically significantly lower than Fluticasone alone for hyperemia (p<_0. <NUM>), chemosis (p<_0. <NUM>), lid swelling (p≤<NUM>) and total clinical score (p<_0. <NUM>); and than Cetirizine alone for chemosis (p<_0. Borderline Additionally, statistical significance was almost achieved against Cetirizine alone for total clinical score (p=<NUM>). Surprisingly, the reduction with the combination was more than could have been expected from the efficacy of the individual components.

Furthermore, the combination of <NUM>% Cetirizine/<NUM>% Fluticasone performed better than either the steroid (Pred Forte®) or antihistamine (Pataday®), commercial products used as positive controls in this study. Additionally, the higher concentration of the combination (<NUM>% Cetirizine/<NUM>% Fluticasone) was minimally effective in this model under this dosing regimen and conditions.

The results of this study indicate that a substantial clinical benefit may be achieved with the combination of low dose Cetirizine/Fluticasone over its individual components, over the high dose combination and over existing lead commercial products.

On Day <NUM>, animals received injections containing a suspension of <NUM>µg of short ragweed allergen (SRW, Greer, Lenoir, NC, USA) in <NUM>µL alum (aluminum hydroxide gel). Additional sensitization was achieved by topical dosing with <NUM> SRW in <NUM>µl PBS on Days <NUM> and <NUM> after injection.

On days <NUM> through <NUM>, topical treatment was administered once daily. Mice were dosed topically to the central cornea using a calibrated micropipette, with a <NUM>µL drop of treatment in each eye. The dose groups are outlined in the table below:.

On day <NUM>, twenty minutes after ocular treatment dosing, animals were challenged with topical doses of <NUM>µg SRW suspension in <NUM>µl PBS in each eye. SRW was prepared fresh and used within <NUM> hours of mixing, and mixed well before administration to ensure homogeneity.

Ophthalmic exams were performed at baseline (study entry) according to the Ocular Irritation Grading Scale (Appendix <NUM>) to verify that the eyes did not exhibit any signs of ocular irritation.

Ophthalmic exams were also performed on day <NUM>, <NUM> minutes after the allergen challenge. Exams were performed under dissecting microscope, and included conjunctival hyperemia, chemoosis, tear/discharge, and lid swelling, each graded on a <NUM>-<NUM> scale (<NUM> units were allowed for any ocular score).

There were no abnormal ophthalmic findings in any animals used in the study and no unscheduled deaths during this study.

Immediately after euthanasia (CO<NUM> inhalation and cervical dislocation), eyes and surrounding lid tissue was collected and placed immediately in <NUM>% paraformaldehyde for <NUM> hours, after which they were transferred to <NUM>% ethanol for storage prior to paraffin embedding and sectioning for histology.

Both eyes of each animal were averaged and all animals within a group were averaged to obtain an average score for each treatment group for each measurement parameter. Statistically significant differences between groups were determined using the <NUM>-tailed, <NUM>-sample t-test.

Day <NUM> baseline exams ensured that all mice were free of any redness, swelling, and tearing.

After <NUM> days of drug treatment, the animals treated with the combination <NUM>% Cetirizine/<NUM>% Fluticasone demonstrated the least severity in three of the four clinical signs (conjunctival hyperemia, chemosis, and lid swelling) as compared to Cetirizine or Fluticasone alone, and as compared to most other treatment groups. Total clinical score (sum of scores of all clinical signs in both eyes) was lowest in the <NUM>% Cetirizine/<NUM>% Fluticasone combination group as compared to all other treatment groups. Cetirizine or Fluticasone alone produced no significant treatment effects.

The reduction in clinical signs in response to SRW challenge after <NUM> days of treatment with the combination <NUM>% Cetirizine/<NUM>% Fluticasone was statistically significantly lower than Fluticasone alone for hyperemia (p<_0. <NUM>), chemosis (p<_0. <NUM>), lid swelling (p≤<NUM>) and total clinical score (p<_0. <NUM>); and than Cetirizine alone for chemosis (p<_0. Borderline significance was achieved against Cetirizine alone for total clinical score (p=<NUM>).

Surprisingly, the high dose combination of <NUM>% Cetirizine/<NUM>% Fluticasone was less effective than the low dose combination in this model for all clinical signs, with the exception of an effect on chemosis. The only statistically significant decrease in any clinical sign after high dose combination treatment was for chemosis as compared to Fluticasone alone (p≤<NUM>).

Under these treatment conditions (<NUM> days of once-daily dosing), neither of the positive control test articles, commercially available Pred Forte (prednisolone acetate <NUM>%), a steroid, or Pataday (olopatadine <NUM>%), the leading anti-histamine, produced significant treatment effects, with the exception of a decrease in chemosis produced by olopatadine, comparable to the effect seen with the combination <NUM>% Cetirizine/<NUM>% Fluticasone. This chemosis effect was statistically significantly different from Fluticasone alone (p<_0.

The results are summarized in Table <NUM> below and in <FIG>.

The low dose combination of <NUM>% Cetirizine/<NUM>% Fluticasone was the most effective at preventing signs of allergic conjunctivitis in the murine ragweed sensitization model. Neither component of the combination used alone, at the same concentrations, produced a substantial treatment effect. The low-dose combination, assessed after <NUM> days of treatment and <NUM> minutes after ragweed challenge, reduced conjunctival hyperemia, chemosis, and lid swelling, and resulted in the lowest clinical summary score of any of the treatment arms, including the cetirizine or fluticasone alone, and commercial ophthalmics Pataday® and Pred Forte®.

Surprisingly, the higher concentration of the combination (<NUM>% Cetirizine/<NUM>% Fluticasone) was minimally effective in this model under this dosing regimen and conditions. These results indicate that the <NUM>% Cetirizine/<NUM>% Fluticasone formulation has excellent potential for the prevention and treatment of allergic conjunctivitis and that a substantial clinical benefit might be achieved with the combination of Cetirizine/Fluticasone over either medication used alone.

In summary, the results consistently favored <NUM>% cetirizine/<NUM>% fluticasone combination (low dose) over both the individual components alone as well as the high dose combination (<NUM>% cetirizine/<NUM>% fluticasone), which is surprising because one skilled in the art might expect the higher dose formulation to work at least equally well if not better than the low dose formulation. The low dose combination also worked better than would be expected from the results of the individual components, thus showed a synergistic effect between the cetirizine and fluticasone.

Additionally, the low dose combination worked better than well known, leading ocular antihistamines and ocular steroids - these results confirm the effectiveness of the specific combination of cetirizine/fluticasone at the preferred low dose concentrations.

Lastly, the low dose combination was more efficacious than its comparison arms across all endpoints, including total ocular composite score.

Tables <NUM>-<NUM> below show that a <NUM>% formulation of cetirizine was stable for at least three months both at room temperature (Table <NUM>) and at higher temperatures (Table <NUM>).

Cetirizine concentrations were quantified by high pressure liquid chromatography (HPLC). Impurities are shown as "relative retention time" or RRT in the table, which relates the unknown peak to the elution time of the parent peak, cetirizine (or fluticasone). At no time did the total impurities exceed <NUM>%. Sterility, particulate matter, and preservative efficacy were determined only at the initial time point because these should remain unchanged provided that the sealed container is not compromised.

The data herein demonstrates cetirizine formulation t is stable without the inclusion of a cyclodextrin or other solubilizing compound. Without intending to be bound by any theory, the stability was achieved by minimizing/excluding the addition of counter ions or metal based buffers that could promote salt formation, precipitation, or metal based degradation.

Claim 1:
A topical ophthalmic formulation in the form of aqueous solution comprising <NUM>% to <NUM>% w/v cetirizine hydrochloride or cetirizine dihydrochloride calculated as cetirizine free base, a tear substitute composition in the form of aqueous solution comprising <NUM>% to <NUM>% w/v hydroxypropylmethyl cellulose or carboxymethyl cellulose, having a viscosity from <NUM> to <NUM> cpi and buffered to pH <NUM> to <NUM>, wherein cetirizine hydrochloride or cetirizine dihydrochloride is the only active agent and the aqueous formulation does not contain a cyclodextrin.