Pharmaceutical compositions containing apraclonidine for the relief of ocular redness - Patent Application 20070122999

Abstract

The present disclosure relates to a pharmaceutical composition comprising apraclonidine and a polymer, wherein the apraclonidine is present in an amount greater than 0.05% (w / v) and not greater than 0.2% (w / v) based on the total volume of the pharmaceutical composition, a method for preparing the same, and a method for reducing ocular redness by administering the same.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 491,051, filed March 18, 2023, entitled "PHARMACEUTICAL COMPOSITIONS COMPRISING APRACLONIDINE FOR OCULAR REDNESS RELIEF AND METHODS OF USING SAME," which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to pharmaceutical compositions comprising apraclonidine and methods for reducing ocular redness in a subject's eye by topically administering such compositions to the eye. [Background technology]

[0003] Eye redness is a transient condition that can be caused by minor irritation, such as fatigue, oversleeping, allergic reactions to environmental allergens, dry eyes, or contact lens wear. Currently available ophthalmic vasoconstrictors are ineffective as long-term decongestant. Available products typically fall into a class of compounds called "adrenergic agonists." Naphazoline hydrochloride, a mixed α1 / α2 adrenergic agonist, and tetrahydrozoline, an α1-selective adrenergic agent, bind to adrenergic receptors on arterial blood vessels. In the short term, arterial vasoconstriction appears to provide relief from redness. However, in the long term, such vasoconstriction can produce several undesirable side effects, such as rebound redness and tachyphylaxis. Selective targeting of blood vessels, particularly venules, may help provide redness relief without undesirable side effects and appears to be a specific mode of action for α2 adrenergic agonists.

[0004] Apraclonidine and brimonidine are both alpha-2 selective adrenergic agonists with the same mode of action. Apraclonidine binds to venular adrenergic receptors, causing capillary constriction, thereby ensuring adequate oxygen delivery to tissues during use. This adequate oxygen delivery prevents rebound redness, a side effect associated with drug efficacy wearoff. Other alpha-2 adrenergic agonists are not as susceptible to desensitization as alpha-1 adrenergic agonists, thereby preventing tachyphylaxis. Apraclonidine is a hydrophilic analog of clonidine, which reaches the target tissue, i.e., the conjunctiva, directly to provide redness relief. Additionally, apraclonidine and brimonidine have previously been used in antiglaucoma management. The commercially available product, IOPIDINE® (apraclonidine ophthalmic solution), contains 0.5% or 1% apraclonidine. Given its use at high concentrations in ophthalmology and for glaucoma management, the safety profile of apraclonidine is well established. However, known high-concentration apraclonidine preparations are complex and have an intraocular pressure-lowering effect, making them unsuitable for chronic use in ocular redness relief. While no apraclonidine product is available for redness relief, a brimonidine product suitable for this purpose is currently available from Bausch + Lomb, marketed as LUMIFY® brimonidine tartrate ophthalmic solution 0.025%. Brimonidine in currently available products does not reach significant tissue levels in the conjunctiva, a potentially key target tissue for redness reduction. Without intending to be bound by any theory, because both the cornea and the conjunctiva are key target tissues for redness relief, a drug that reaches both would be preferable. Therefore, a drug that reaches both of these target tissues may have a shorter onset of action and / or a longer duration of action. Summary of the Invention [Problem to be solved by the invention]

[0005] U.S. Patent No. 9,259,425 ("Horn") reports a pharmaceutical composition containing a selective α2 adrenergic receptor agonist at a concentration of about 0.0001% to about 0.05%. Furthermore, Horn prefers brimonidine over apraclonidine, and reports no experimental data on apraclonidine. Thus, there remains a long-felt and unresolved need for a pharmaceutical composition containing an α2 selective adrenergic agonist that provides high bioavailability of the α2 selective adrenergic agonist in both the cornea and conjunctiva, which is effective in rapidly (e.g., within 1 minute) reducing ocular redness in a subject's eye, as well as having a long duration of action (e.g., greater than 6-8 hours). [Means for solving the problem]

[0006] The present disclosure provides pharmaceutical compositions comprising apraclonidine, wherein the apraclonidine is present at greater than 0.05% (w / v) and not more than 0.2% (w / v).

[0007] The present disclosure also provides a pharmaceutical composition comprising apraclonidine, wherein the apraclonidine is present at greater than 0.05% (w / v) and not more than 0.2% (w / v), the pharmaceutical composition comprising a polymer as a comfort enhancer and / or viscosity enhancer.

[0008] The present disclosure also provides a pharmaceutical composition comprising apraclonidine, wherein the apraclonidine is present at greater than 0.05% (w / v) and not more than 0.2% (w / v), wherein the apraclonidine exhibits greater bioavailability to the cornea than in another pharmaceutical composition comprising brimonidine, wherein the brimonidine is present at 250 ppm.

[0009] The present disclosure also provides a pharmaceutical composition comprising apraclonidine, wherein the apraclonidine is present at greater than 0.05% (w / v) and not more than 0.2% (w / v), such that when the pharmaceutical composition is administered to the eye, the apraclonidine exhibits greater bioavailability to the conjunctiva than another pharmaceutical composition comprising brimonidine, wherein the brimonidine is present at 250 ppm.

[0010] The present disclosure also provides methods of making pharmaceutical compositions comprising apraclonidine, wherein the apraclonidine is present at greater than 0.05% (w / v) and not more than 0.2% (w / v).

[0011] The present disclosure also provides a method of treating a subject having an ocular condition, such as dry eye or allergic redness or irritation, comprising administering a pharmaceutical composition comprising apraclonidine, wherein the apraclonidine is present at greater than 0.05% (w / v) and not more than 0.2% (w / v). The pharmaceutical composition comprises a polymer.

[0012] The present disclosure also provides a method of treating a subject having an ocular condition, comprising administering a pharmaceutical composition comprising apraclonidine, wherein the apraclonidine is present at greater than 0.05% (w / v) and not more than 0.2% (w / v), wherein the apraclonidine exhibits greater bioavailability to the cornea than in another pharmaceutical composition comprising brimonidine, wherein the brimonidine is present at 250 ppm.

[0013] The present disclosure also provides a method for treating a subject having an ocular condition or preventing a subject from developing an ocular condition, comprising administering a pharmaceutical composition comprising apraclonidine, wherein the apraclonidine is present at greater than 0.05% (w / v) and not more than 0.2% (w / v), wherein the apraclonidine exhibits greater bioavailability to the conjunctiva than in another pharmaceutical composition comprising brimonidine, wherein the brimonidine is present at 250 ppm.

[0014] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain features of the present disclosure.

[0015] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0016] [Figure 1A-1B] Figure 1A shows conjunctival bioavailability data for pharmaceutical compositions containing 0.025% (w / w) brimonidine or 0.08% (w / v) apraclonidine 30 minutes and 2 hours after ocular application. Figure 1B shows conjunctival bioavailability data for aqueous pharmaceutical compositions containing 0.025% (w / w) brimonidine or 0.025% (w / v) apraclonidine 30 minutes and 2 hours after ocular application. The vertical axis represents the concentration of brimonidine or apraclonidine in ng / g, and the horizontal axis represents time after administration. Circles represent data for LUMIFY® (brimonidine tartrate); squares represent data for the +HPMC, +BAK apraclonidine composition; triangles represent data for the +HPMC, -BAK apraclonidine composition; inverted triangles represent data for the -HPMC, +BAK apraclonidine composition; and diamonds represent data for the -HPMC, -BAK apraclonidine composition. Four eyes were tested for each data point. [Figure 2A-2B]Figure 2A shows corneal bioavailability data for pharmaceutical compositions containing 0.025% (w / w) brimonidine or 0.08% (w / v) apraclonidine 30 minutes and 2 hours after ocular application. Figure 2B shows corneal bioavailability data for aqueous pharmaceutical compositions containing 0.025% (w / w) brimonidine or 0.025% (w / v) apraclonidine 30 minutes and 2 hours after ocular application. The vertical axis represents the concentration of brimonidine or apraclonidine in ng / g, and the horizontal axis represents time after administration. Circles represent data for LUMIFY® (brimonidine tartrate); squares represent data for the +HPMC, +BAK apraclonidine composition; triangles represent data for the +HPMC, -BAK apraclonidine composition; inverted triangles represent data for the -HPMC, +BAK apraclonidine composition; and diamonds represent data for the -HPMC, -BAK apraclonidine composition. Four eyes were tested for each data point. [Figure 3] Figure 1 shows aqueous humor bioavailability data for pharmaceutical compositions containing 0.025% (w / w) brimonidine or 0.08% (w / v) apraclonidine at 30 minutes and 2 hours after ocular application. The vertical axis represents the concentration of brimonidine or apraclonidine in ng / mL, and the horizontal axis represents time after administration. Circles represent data for LUMIFY® (brimonidine tartrate); squares represent data for the +HPMC, +BAK apraclonidine composition; triangles represent data for the +HPMC, -BAK apraclonidine composition; inverted triangles represent data for the -HPMC, +BAK apraclonidine composition; and diamonds represent data for the -HPMC, -BAK apraclonidine composition. Four eyes were tested for each data point. [Figure 4]

[0023] Figure 1 shows ocular efficacy in a mouse conjunctival allergen challenge ("CAC") model. The vertical axis represents clinical score ranging from 0 to 4 units, while the horizontal axis represents challenge number. Open circles represent data for the +HPMC, +BAK pharmaceutical composition containing 0.08% (w / v) apraclonidine; open squares represent data for the +HPMC, +BAK pharmaceutical composition containing 0.025% (w / v) apraclonidine; triangles represent data for the -HPMC, -BAK pharmaceutical composition containing 0.08% (w / v) apraclonidine; inverted triangles represent data for the -HPMC, -BAK pharmaceutical composition containing 0.08% (w / v) apraclonidine; diamonds represent data for the pharmaceutical composition containing 0.025% (w / w) brimonidine; solid circles represent data for the pharmaceutical composition containing 1% prednisone; and solid squares represent data for phosphate-buffered saline. Ten eyes were examined for each data point. [Figure 5] 1 shows the ocular tissue distribution of a single topically administered 0.2% apraclonidine dose in rabbit eyes at 0.5, 1, 2, 4, and 8 hours. DETAILED DESCRIPTION OF THE INVENTION

[0017] Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong.

[0018] As used herein, the terms "a" or "an" mean "at least one" or "one or more," unless the context clearly dictates otherwise.

[0019] As used herein, the term "animal" includes, but is not limited to, mammals, humans, and non-human vertebrates, such as wild animals, domestic animals, and farm animals. In some embodiments, the animal under treatment, such as a human, is "in need thereof," i.e., the animal is in need of treatment.

[0020] As used herein, the terms "antagonize" and "antagonizing" mean to reduce or completely eliminate one or more effects.

[0021] As used herein, the term "carrier" refers to a diluent, adjuvant, or excipient with which the compound is administered in a composition.

[0022] As used herein, the term "compound" refers to all stereoisomers, tautomers, isotopes, and polymorphs of the compounds described herein.

[0023] As used herein, the terms "comprising" (and any form of comprising, such as "comprise," "comprises," and "comprised"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") are inclusive and open-ended, and include the options that follow the term and do not exclude additional, unrecited elements or method steps.

[0024] As used herein, the terms "individual," "subject," and "patient" are used interchangeably and refer to any animal described herein.

[0025] As used herein, the phrase "ophthalmically acceptable" means that the compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the eye of humans and other animals.

[0026] As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatments and prophylactic or preventative measures aimed at preventing or slowing (alleviating) an undesirable physiological condition, disorder, or disease, or achieving a beneficial or desired clinical or veterinary result. For purposes herein, a beneficial or desired clinical or veterinary result includes, but is not limited to, alleviation of symptoms; a decrease in the severity of the condition, disorder, or disease; a stable (i.e., not worsening) state of the condition, disorder, or disease; a delay in the onset or slowing of the progression of the condition, disorder, or disease; an improvement or remission (whether partial or complete) of the condition, disorder, or disease state, whether detectable or undetectable; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or an enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically or veterinarily significant response, optionally without excessive levels of side effects.

[0027] As used herein, the term "% (w / v)" means the amount (in grams) of a particular solute per 100 mL of solution.

[0028] As used herein, the term "% (w / w)" means the mass of a particular solute divided by the mass of the solution (solute and solvent combined) multiplied by 100 to determine the percentage.

[0029] The present disclosure provides pharmaceutical compositions suitable for topical administration to the eye and comprising apraclonidine, wherein the apraclonidine is present at greater than 0.05% (w / v) and less than or equal to 0.2% (w / v). In some embodiments, the apraclonidine is present in the form of an ophthalmologically acceptable salt. In preferred embodiments, the pharmaceutical composition comprises apraclonidine hydrochloride in an amount equivalent to greater than 0.05% (w / v) and less than or equal to 0.2% (w / v) of the apraclonidine free base. For example, if apraclonidine is present in the form of apraclonidine hydrochloride, a composition containing 0.125% (w / v) apraclonidine as the free base would contain 0.144% (w / v) apraclonidine hydrochloride.

[0030] Apraclonidine (as free base) is present in the pharmaceutical composition at greater than 0.05% (w / v) and up to 0.2% (w / v). In some embodiments, apraclonidine is present at 0.06% (w / v) to 0.2% (w / v). In some embodiments, apraclonidine is present at 0.07% (w / v) to 0.15% (w / v). In some embodiments, apraclonidine is present at 0.08% (w / v) to 0.125% (w / v). In one preferred embodiment, apraclonidine is present at 0.06% (w / v). In another preferred embodiment, apraclonidine is present at 0.08% (w / v). In a most preferred embodiment, apraclonidine is present at 0.125% (w / v).

[0031] In some embodiments, the pharmaceutical composition is a liquid. In preferred embodiments, the liquid pharmaceutical composition is an aqueous liquid.

[0032] In one embodiment, the pharmaceutical composition containing apraclonidine contains an ophthalmologically acceptable preservative. Several ophthalmologically acceptable preservatives are known, such as benzalkonium chloride and polyquaternium-1. In a preferred embodiment, the pharmaceutical composition contains benzalkonium chloride. In one embodiment, the composition contains benzalkonium chloride in an amount of 0.003 to 0.02% (w / v). In a most preferred embodiment, the composition contains 0.005% (w / v) benzalkonium chloride.

[0033] In other embodiments, the pharmaceutical compositions comprising apraclonidine are preservative-free. In such embodiments, the compositions may be packaged in containers designed as unit-dose containers or multi-dose preservative-free (MDPF) containers. Unit-dose containers and multi-MDPF containers are known for topically administrable ophthalmic products, including prescription and over-the-counter (OTC) products.

[0034] Pharmaceutical compositions containing apraclonidine include a polymer as a comfort and / or thickening agent. In some embodiments, the polymer includes methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, xanthan gum, carbopol, hyaluronic acid, guar, or hydroxypropyl guar. Typical molecular weights of these polymers useful for viscosity enhancement range from 500,000 to 4,000,000. In a preferred embodiment, the composition includes hydroxypropyl methylcellulose as a comfort and / or thickening agent.

[0035] In some embodiments, the polymer is present at 0.05% to 0.5% (w / v). In some embodiments, the polymer is present at 0.2% to 0.4% (w / v). In some embodiments, the polymer is present at 0.3% (w / v). In a preferred embodiment, the composition comprises 0.3% (w / v) hydroxypropyl methylcellulose.

[0036] In some embodiments, the pharmaceutical composition is a liquid having a viscosity of 1 to 20 cP. In preferred embodiments, the composition has a viscosity of 5 to 15 cP. In most preferred embodiments, the composition has a viscosity of 6 to 8 cP.

[0037] In some embodiments, pharmaceutical compositions containing apraclonidine contain a polymeric gelling agent at a concentration effective to promote gelation upon contact with the eye or tear film, allowing the composition to remain in the eye for extended periods without being lost through tearing. Suitable gelling agents include, but are not limited to, thermosetting polymers such as tetrasubstituted ethylenediamine block copolymers of ethylene oxide and propylene oxide (e.g., poloxamine 1307); polycarbophil; and polysaccharides such as gellan, carrageenan (e.g., kappa-carrageenan and i-carrageenan), chitosan, and alginate gum. Alternatively, guar-based polymers may be utilized in the presence of borate for cross-linking in the eye, where the pH of the eye allows for cross-linking to form a guar gel.

[0038] In some embodiments, the pharmaceutical composition comprising apraclonidine includes a demulcent. Demulcents for use with the compositions disclosed herein include, but are not limited to, glycerin, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, propylene glycol, and polyacrylic acid. Preferred demulcents are propylene glycol and polyethylene glycol 400. In some embodiments, the polyethylene glycol is present at 0.4% (w / v).

[0039] Pharmaceutical compositions containing apraclonidine are preferably buffered and include an ophthalmically acceptable buffer. In some embodiments, the ophthalmically acceptable buffer includes a conjugate acid and a conjugate base. In some embodiments, the conjugate acid includes acetic acid, boric acid, propionic acid, maleic acid, fumaric acid, lactic acid, malonic acid, malic acid, mandelic acid, citric acid, tartric acid, succinic acid, or phosphoric acid. In some embodiments, the conjugate base includes acetate, propionate, malate, fumarate, lactate, malonate, malate, mandelate, citrate, tartrate, succinate, or phosphate. In a preferred embodiment, the composition includes a citrate buffer. In a most preferred embodiment, the composition includes citric acid and sodium citrate.

[0040] Pharmaceutical compositions containing apraclonidine may contain an ophthalmologically acceptable pH adjusting agent and are formulated at a pH in the range of 5.8 to 7.8. In a preferred embodiment, the composition has a pH of 6.3 to 7.3. In a more preferred embodiment, the composition has a pH of 6.5 to 7.0, most preferably 6.8. Several ophthalmologically acceptable pH adjusting agents are known, including, for example, NaOH and HCl.

[0041] In some embodiments, the pharmaceutical composition comprising apraclonidine is a liquid composition having an osmolality of 260 to 330 mOsm / kg, based on the total weight of the liquid pharmaceutical composition. In some embodiments, the liquid pharmaceutical composition has an osmolality of 270 to 320 mOsm / kg, based on the total weight of the liquid pharmaceutical composition. In some embodiments, the liquid pharmaceutical composition has an osmolality of 280 to 310 mOsm / kg, based on the total weight of the liquid pharmaceutical composition. In some embodiments, the liquid pharmaceutical composition has an osmolality of 290 to 300 mOsm / kg, based on the total weight of the liquid pharmaceutical composition. In some embodiments, the liquid pharmaceutical composition has an osmolality of 300 mOsm / kg, based on the total weight of the liquid pharmaceutical composition.

[0042] In some embodiments, the pharmaceutical composition containing apraclonidine includes a tonicity agent. Many ophthalmically acceptable tonicity agents are known, including both ionic and non-ionic agents. In some embodiments, the tonicity agent includes sodium chloride. In some embodiments, the tonicity agent includes sorbitol, propylene glycol, dextrose, glycerin, mannitol, or potassium chloride.

[0043] In some embodiments, the tonicity agent is present in an amount equivalent to 0.1% to 0.8% (w / v) sodium chloride, based on the total volume of the pharmaceutical composition. In a preferred embodiment, the pharmaceutical composition includes sodium chloride as the tonicity agent, and the sodium chloride is present in an amount of 0.6 to 0.8% (w / v). In a most preferred embodiment, the composition includes 0.7 to 0.8% (w / v) sodium chloride.

[0044] In some embodiments, pharmaceutical compositions containing apraclonidine may further comprise one or more antioxidants. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, and acetylcysteine.

[0045] In some embodiments, the pharmaceutical composition comprising apraclonidine may further comprise an anti-inflammatory agent. The anti-inflammatory agent may be steroidal or non-steroidal. Examples of suitable steroidal anti-inflammatory agents include, but are not limited to, dexamethasone, rimexolone, prednisolone, fluorometholone, and hydrocortisone. Examples of suitable nonsteroidal anti-inflammatory agents include, but are not limited to, prostaglandin H synthase inhibitors (Cox I or Cox II) such as diclofenac, flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indomethacin, naproxen, ibuprofen, bromfenac, ketoprofen, meclofenamic acid, piroxicam, sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetone, etodolac, phenylbutazone, aspirin, oxyphenbutazone, tenoxicam, and carprofen. II), also known as cyclooxygenase type I and type II inhibitors; cyclooxygenase type II selective inhibitors, such as celecoxib and etodolac; PAF antagonists, such as apafant, bepafant, minopafant, nupafant, and modipafant; PDEIV inhibitors, such as ariflo, torbafylline, rolipram, filaminast, piclamilast, sipamfilline, and roflumilast; and cytokine production inhibitors, such as NFkB transcription factor inhibitors.

[0046] In some embodiments, the pharmaceutical composition comprising apraclonidine may further comprise an anti-allergy agent. Examples of suitable anti-allergy agents include, but are not limited to, pemirolast, olopatadine, and corticosteroids (prednisolone, fluorometholone, loteprenol, and dexamethasone).

[0047] The pharmaceutical composition comprising apraclonidine may be in unit dosage form. In some embodiments, the unit dosage form is one or more containers filled with a composition described herein. In such form, the pharmaceutical composition may be divided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation. In some embodiments, the pharmaceutical composition comprising apraclonidine is a liquid composition dispensed in a multi-dose package that may support preservative-containing and preservative-free packaging. In some embodiments, the pharmaceutical composition comprising apraclonidine is a liquid composition dispensed in a disposable container. In some embodiments, the disposable container includes a headspace. In some embodiments, the headspace is substantially oxygen-free. In some embodiments, the pharmaceutical composition comprising apraclonidine is a liquid composition dispensed in a multi-use container. In some embodiments, the multi-use container includes an eye dropper bottle. In some embodiments, the multi-use container includes a bottle with a spout. In some embodiments, the pharmaceutical composition is packaged in a single-dose non-reclosable container. Alternatively, the pharmaceutical composition is packaged in a multi-dose reclosable container. In some embodiments, the desired dosage of the pharmaceutical composition comprising apraclonidine can be administered using a suitable dispenser to place a known number of drops in the eye. Numerous examples of suitable multi-dose eye dropper containers are known in the art, including, but not limited to, multi-dose eye dropper bottles such as the Droptainer® bottles first introduced by Alcon and the Novelia® multi-dose preservative-free eye droppers available from Nemera.

[0048] In some embodiments, the pharmaceutical composition comprising apraclonidine is stable after storage at 25° C. for at least one month. In some embodiments, the disclosed pharmaceutical compositions are stable after storage at 40° C. for at least one month. In some embodiments, the pharmaceutical composition comprising apraclonidine is stable after storage at 25° C. / 60% relative humidity (RH). In some embodiments, the pharmaceutical composition comprising apraclonidine is stable after storage at 40° C. / 75% RH. In some embodiments, stability can be measured by any one or more of appearance, container closure, pH, osmolality, viscosity, activity assay, absence of impurities, etc.

[0049] In some embodiments, when any of the pharmaceutical compositions described herein containing apraclonidine and free of preservatives is administered to the eye, the apraclonidine in such a pharmaceutical composition exhibits greater bioavailability to the cornea compared to another pharmaceutical composition containing brimonidine, in which brimonidine is present at 250 ppm.

[0050] In some embodiments, when any of the preservative-free pharmaceutical compositions described herein containing apraclonidine are administered to the eye, the apraclonidine in such a pharmaceutical composition exhibits greater bioavailability to the conjunctiva compared to another pharmaceutical composition containing brimonidine, in which brimonidine is present at 250 ppm.

[0051] In some embodiments, when any of the pharmaceutical compositions comprising apraclonidine described herein is administered to the eye, such pharmaceutical composition exhibits a higher apraclonidine bioavailability to the cornea compared to the brimonidine bioavailability to the cornea in another pharmaceutical composition comprising 250 ppm brimonidine.

[0052] In some embodiments, when any of the pharmaceutical compositions containing apraclonidine described herein is administered to the eye, such pharmaceutical compositions exhibit a higher apraclonidine bioavailability to the conjunctiva compared to the brimonidine bioavailability to the cornea in another pharmaceutical composition containing 250 ppm brimonidine.

[0053] In any of these embodiments, bioavailability may include corneal, conjunctival, or other ocular tissue bioavailability. In some embodiments, bioavailability is determined by pharmacokinetic methods. For example, dosing can occur on day 1, where one 40 pL drop of each test material can be administered to both eyes of each animal. Accurate administration can be achieved using a pipette. The timing of dose administration and notes regarding dose administration (e.g., if there was a successful dose, it gradually disappeared after administration) can be recorded in the study file. For example, sampling can be performed at 0.5, 2, 8, and 24 hours after dose administration. Animals can be euthanized (e.g., n=2 per group per time point). Eyes can be enucleated, and the bulbar conjunctiva and cornea can be abraded. For the bulbar conjunctiva, an approximately 3 x 3 mm sample can be obtained from the inferior / nasal aspect of each eye (e.g., from the 4-6 o'clock position for the right eye and the 6-8 o'clock position for the left eye). Between each new eye, instruments may be wiped clean and rinsed with saline and alcohol. After abrasion, the cornea and conjunctiva may be rinsed with saline, placed in a cryovial, and weighed. The cryovial may be weighed before and after placing the tissue therein, and the weight may be recorded. After recording the weight, the cryovial may be frozen on dry ice and kept on dry ice during sorting. Samples may be stored at -80°C until shipping.

[0054] In any of these embodiments, another pharmaceutical composition for comparison purposes may include a preservative-effective amount of a preservative. In any of these embodiments, another pharmaceutical composition for comparison purposes may include a preservative-effective amount of benzalkonium chloride. In some embodiments, the preservative-effective amount of preservative is 80 ppm to 120 ppm, or 100 ppm. In some embodiments, the preservative-effective amount of benzalkonium chloride is 80 ppm to 120 ppm, or 100 ppm. In any of these embodiments, another pharmaceutical composition for comparison purposes is LUMIFY® (see worldwide web at accessdata.fda.gov / drugsatfda_docs / nda / 2017 / 208144Origls000PharmR.pdf at 7). In some embodiments, 250 ppm brimonidine refers to 0.025% (w / w) brimonidine. In some embodiments, brimonidine includes brimonidine tartrate.

[0055] The present disclosure also provides a method for preparing a pharmaceutical composition comprising apraclonidine as described herein.In some embodiments, apraclonidine is formulated into a pharmaceutical composition suitable for administration to humans according to conventional procedures.Typically, the pharmaceutical composition is a sterile isotonic aqueous buffer solution.If necessary, the pharmaceutical composition may also contain a solubilizing agent.

[0056] In some embodiments, apraclonidine in any amount disclosed herein is contacted with a liquid, such as an aqueous liquid. In some embodiments, the liquid or aqueous liquid comprises sodium chloride in a citrate or phosphate buffer. In some embodiments, benzalkonium chloride ("BAK") is added. In some embodiments, hydroxypropyl methylcellulose is added. In some embodiments, BAK and hydroxypropyl methylcellulose are added.

[0057] Briefly, according to representative process steps, apraclonidine hydrochloride ophthalmic solutions containing a desired amount of apraclonidine hydrochloride can be prepared in the presence of citrate buffer, sodium chloride, hydroxypropylmethylcellulose (HPMC), and benzalkonium chloride (BAK). Apraclonidine hydrochloride ophthalmic formulations can be prepared by mixing together the following in the specified amounts: 6 mg / g HPMC stock; and 2) 4.1 mg / g apraclonidine hydrochloride with 43 mM sodium citrate and 0.9 mM citrate buffer, supplemented with sodium chloride as a tonicity agent and 0.14 mg / g BAK. For example, a 1.44 mg / g apraclonidine hydrochloride ophthalmic formulation can be prepared by steam sterilization of 6 mg / g HPMC stock, and apraclonidine hydrochloride buffer solution can be sterile filtered through a 0.2 μm PVDF filter and added to the HPMC stock. The resulting solution can be adjusted to the final pH and adjusted to the batch size with sterile purified water.

[0058] The present disclosure also provides a method of treating a subject having ocular redness, comprising administering to the subject any of the pharmaceutical compositions comprising apraclonidine described herein to the affected eye.

[0059] In some embodiments, the ocular condition is redness, eye redness, dry eye, or an allergic reaction. In some embodiments, the ocular condition is redness. In some embodiments, the ocular condition is eye redness, such as redness caused by minor irritation. In some embodiments, the ocular condition is dry eye. In some embodiments, the ocular condition is an allergic reaction.

[0060] In some embodiments, the administration is to one eye of the subject. In some embodiments, the administration is to both eyes of the subject.

[0061] The present disclosure also provides a method for reducing ocular redness in the eye of a subject, comprising ophthalmically administering to the subject any of the pharmaceutical compositions comprising apraclonidine described herein.

[0062] In any of the methods of treatment disclosed herein, when any of the pharmaceutical compositions comprising apraclonidine and a polymer described herein is administered to the eye, the apraclonidine in such a pharmaceutical composition exhibits increased bioavailability to the cornea compared to another pharmaceutical composition comprising brimonidine, in which the brimonidine is present at 250 ppm.

[0063] In any of the methods of treatment disclosed herein, when any of the pharmaceutical compositions comprising apraclonidine and a polymer described herein is administered to the eye, the apraclonidine in such a pharmaceutical composition exhibits increased bioavailability to the conjunctiva compared to another pharmaceutical composition comprising brimonidine, in which the brimonidine is present at 250 ppm.

[0064] In any of these embodiments, bioavailability may include corneal, conjunctival, or ocular bioavailability. In some embodiments, bioavailability is determined by the methodologies described herein.

[0065] In any of these embodiments, another pharmaceutical composition for comparison purposes may include a preservative-effective amount of a preservative. In any of these embodiments, another pharmaceutical composition for comparison purposes may include a preservative-effective amount of benzalkonium chloride. In some embodiments, the preservative-effective amount of preservative is 80 ppm to 120 ppm, or 100 ppm. In some embodiments, the preservative-effective amount of benzalkonium chloride is 80 ppm to 120 ppm, or 100 ppm. In any of these embodiments, another pharmaceutical composition for comparison purposes is LUMIFY® (see worldwide web at accessdata.fda.gov / drugsatfda_docs / nda / 2017 / 208144Origls000PharmR.pdf at 7). In some embodiments, 250 ppm brimonidine refers to 0.025% (w / w) brimonidine. In some embodiments, brimonidine includes brimonidine tartrate.

[0066] In any of the methods of treatment disclosed herein, the pharmaceutical composition containing apraclonidine can be administered to the eye in the form of eye drops.

[0067] In some embodiments, a pharmaceutical composition comprising apraclonidine is administered topically to one or more tissues of the eye. In one embodiment, the composition is administered topically to the eye 1 to 4 times daily. In a preferred embodiment, the composition is administered topically 1 to 2 times daily. In a more preferred embodiment, where the composition of the present invention comprises 0.125% (w / v) apraclonidine, the composition is effective to reduce redness within 1 minute of topical administration and to maintain the reduction in redness for 8 hours or more. In a most preferred embodiment, the composition is effective to reduce redness within 1 minute of topical administration and to maintain the reduction in redness for 10 hours or more.

[0068] The present disclosure also provides the use of any of the pharmaceutical compositions comprising apraclonidine described herein in the manufacture of a medicament for reducing ocular redness caused by minor irritation, in some embodiments, the ocular redness is redness or congestion caused by dry eye or an allergic reaction.

[0069] In order that the subject matter disclosed herein may be more effectively understood, the following examples are provided, it being understood that these examples are for illustrative purposes only and should not be construed as limiting the claimed subject matter in any way. [Example]

[0070] Example 1: Preparation of phosphate-buffered 0.08% (w / v) and 0.025% (w / v) apraclonidine compositions 800 ppm and 250 ppm formulations Representative 800 ppm and 250 ppm formulations are presented in Tables 1 and 2, respectively.

[0071] [Table 1]

[0072] [Table 2]

[0073] These formulations were prepared by mixing stock solutions as described below. The appropriate stock solutions can be added in the following order: 1) apraclonidine stock with sodium chloride, 2) HPMC stock, 3) sterile-filtered BAK stock, and 4) sterile-filtered WFI water, if needed.

[0074] [Table 3]

[0075] [Table 4]

[0076] The formulations were gently mixed in an overhead mixer equipped with a 1.5-inch stainless steel mixing paddle for 15-20 minutes to ensure homogeneity. In a laminar flow hood, the formulations containing apraclonidine stock with sodium chloride and HPMC stock were sterile filtered through a 0.2 μm PVDF membrane into appropriately sized sterile Nalgene bottles. After filtration, the required amount of sterile-filtered BAK stock was added and mixed by gently inverting the capped Nalgene bottle. Sterile-filtered WFI water was added to bring the formulation to the target volume.

[0077] Example 2: Stability of the 0.08% (w / v) apraclonidine composition of Example 1 Aqueous pharmaceutical compositions containing 0.08% (w / v) apraclonidine (free base), 7.66 mg / g sodium chloride in phosphate buffer were prepared. 0.10 mg / g benzalkonium chloride ("BAK") and / or 4.84 mg hydroxypropyl methylcellulose 2910 ("HPMC") were added. This resulted in the following pharmaceutical compositions: i) without BAK or HPMC ("-HPMC, -BAK"); ii) with BAK but without HPMC ("-HPMC, +BAK"); iii) with HPMC without BAK ("+HPMC, -BAK"); and iv) with BAK and HPMC ("+HPMC, +BAK"). Aliquots of compositions i) through iv) containing 0.08% (w / v) apraclonidine were incubated at 25°C for 4 weeks ("T4, 25C"), at 40°C for 4 weeks ("T4, 40C"), or not incubated ("T0"). Stability data for these four pharmaceutical compositions was then determined. It was found that the appearance, apraclonidine level, total impurity level, BAK level, pH value, osmolality value, and viscosity value were maintained for each of these four pharmaceutical compositions upon storage for 4 weeks at 25° C. or 40° C. The results are shown in Tables 5a-5d below.

[0078] [Table 5]

[0079] [Table 6]

[0080] [Table 7]

[0081] [Table 8]

[0082] Example 3: 0.08% (w / v) Apraclonidine Low Salt Formulation Composition A representative 800 ppm low salt formulation is provided in Table 6.

[0083] [Table 9]

[0084] Formulations were prepared by mixing stock solutions as described below. The appropriate stock solutions can be added in the following order: 1) apraclonidine stock, 2) 49.05 mM phosphate buffer, salts, glycerol stock, 3) HPMC stock, 4) sterile-filtered BAK stock, and 5) sterile-filtered WFI water, if needed.

[0085] [Table 10]

[0086] The formulation was gently mixed in an overhead mixer equipped with a 1.5-inch stainless steel mixing paddle for 15-20 minutes to ensure homogeneity. In a laminar flow hood, the formulation containing apraclonidine stock, 49.05 mM phosphate buffer with sodium chloride and glycerol, and HPMC stock was sterile filtered through a 0.2 μm PVDF membrane into an appropriately sized sterile Nalgene bottle. After filtration, the required amount of sterile-filtered BAK stock was added and mixed by gently inverting the capped Nalgene bottle. Sterile-filtered WFI water was added to bring the formulation to the target volume.

[0087] Example 4: Ocular bioavailability of the aqueous pharmaceutical composition of Example 1 LUMIFY® (a pharmaceutical composition containing 0.025% (w / w) brimonidine tartrate) was obtained. In addition, the -HPMC / -BAK, -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions containing 0.08% (w / v) apraclonidine of Example 1, and the -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions containing 0.025% (w / v) apraclonidine of Example 1 were obtained. The conjunctival and corneal bioavailability of pharmaceutical compositions containing brimonidine and apraclonidine was determined in rabbits. Specifically, ocular tissues were thawed and homogenized in HPLC-grade water. The homogenates were analyzed using HPLC and established bioanalytical methods for apraclonidine. Data were obtained from four eyes at 30 minutes or 2 hours post-dose.

[0088] The LUMIFY® pharmaceutical composition containing 0.025% (w / w) brimonidine was found to have negligible conjunctival bioavailability at 30 minutes and 2 hours after ocular application. In contrast, the -HPMC / -BAK, -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions containing 0.08% (w / v) apraclonidine were found to have good conjunctival bioavailability, with the pharmaceutical composition containing HPMC having superior conjunctival bioavailability (see Figure 1A). In Figure 1A, statistically higher levels of apraclonidine were observed in the conjunctiva compared to brimonidine for all formulations tested at 30 minutes (p<0.0001). A statistically significant improvement in bioavailability was observed for the +HPMC,-BAK apraclonidine formulation compared with the -HPMC,-BAK and -HPMC,+BAK-containing formulations (p<0.0001). The +HPMC,-BAK formulation demonstrated a statistically significant improvement in conjunctival bioavailability compared with the +HPMC,+BAK formulation (p≦0.05). Given that brimonidine and apraclonidine are both α2-selective adrenergic agonists, similar bioavailability would be expected. Thus, the results obtained for the -HPMC / -BAK, -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions containing 0.08% (w / v) apraclonidine were unexpected. The finding that the HPMC-containing pharmaceutical composition had good conjunctival bioavailability was equally unexpected. In contrast, BAK had no significant effect on conjunctival bioavailability.

[0089] Although the conjunctival bioavailability of the -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions containing 0.025% (w / v) apraclonidine was lower than that of the equivalent pharmaceutical composition containing 0.08% (w / v) apraclonidine, such bioavailability was unexpectedly higher than that of the LUMIFY® pharmaceutical composition (see Figure 1B). In Figure 1B, statistically higher levels of apraclonidine were observed in the conjunctiva for all formulations compared to LUMIFY at 30 minutes (p<0.0001). No differences in bioavailability were observed among the apraclonidine-containing formulations (ns). These data indicate that the increased conjunctival bioavailability for the 0.08% (w / v) apraclonidine pharmaceutical composition relative to the 0.025% (w / w) brimonidine LUMIFY® pharmaceutical composition is not simply due to a higher amount of alpha-2 selective adrenergic agonist. Thus, pharmaceutical compositions containing greater than 0.05% (w / v) and up to 0.2% (w / v) apraclonidine appear to unexpectedly exhibit good conjunctival bioavailability.

[0090] The corneal bioavailability of the LUMIFY® pharmaceutical composition containing 0.025% (w / w) brimonidine after 30 minutes and 2 hours was comparable to that of the -HPMC / -BAK and -HPMC / +BAK pharmaceutical compositions containing 0.08% (w / v) apraclonidine, whereas the corneal bioavailability of the +HPMC / -BAK and +HPMC / +BAK pharmaceutical compositions containing 0.08% (w / v) apraclonidine was associated with superior corneal bioavailability (see Figure 2A). In Figure 2A, at 30 minutes, the +HPMC,-BAK (p<0.0001) and +HPMC,+BAK (p<0.01) apraclonidine formulations demonstrated statistically higher levels of activity in the cornea compared to LUMIFY. The +HPMC,-BAK apraclonidine formulation also demonstrated statistically higher levels of apraclonidine in the cornea compared to -HPMC,+BAK and -HPMC,-BAK (p<0.0001). The +HPMC,-BAK formulation demonstrated statistically significant improvement in conjunctival bioavailability compared to the +HPMC,+BAK formulation (p≦0.05). Surprisingly, the corneal bioavailability of the LUMIFY® pharmaceutical composition containing 0.025% (w / w) brimonidine was found to be higher than any of the 0.025% (w / v) apraclonidine-containing pharmaceutical compositions tested (see Figure 2B). In Figure 2B, statistically higher levels of brimonidine were observed in the cornea at 30 minutes compared to all apraclonidine-containing formulations (p<0.0001). When comparing +HPMC,+BAK with +HPMC,-BAK, a difference in bioavailability was observed between them (p<0.01), but no difference in bioavailability was observed between +HPMC,+BAK and -HPMC+BAK (ns).

[0091] The aqueous humor bioavailability of the LUMIFY® pharmaceutical composition containing 0.025% (w / w) brimonidine at 30 minutes after administration was found to be higher than that of the pharmaceutical composition containing 0.08% (w / v) apraclonidine. Surprisingly, however, aqueous humor bioavailability was maintained for 2 hours after administration for the +HPMC / -BAK pharmaceutical composition, while it increased for the -HPMC / -BAK, -HPMC / +BAK, and +HPMC / +BAK pharmaceutical compositions 2 hours after administration. In contrast, the aqueous humor bioavailability of the LUMIFY® pharmaceutical composition decreased 2 hours after administration (see Figure 3). At 30 minutes, there was no statistically significant difference (ns) in aqueous humor levels of brimonidine compared to apraclonidine delivered in the +HPMC,-BAK formulation. The -HPMC,-BAK and -HPMC,+BAK formulations demonstrated statistically lower aqueous humor apraclonidine levels compared to the +HPMC,-BAK formulation (p<0.001). The +HPMC,-BAK formulation demonstrated improved aqueous humor bioavailability compared to the +HPMC,+BAK formulation (p<0.01).

[0092] Example 5: Efficacy of the apraclonidine composition of Example 1 Ocular efficacy was investigated in a mouse CAC model. On day 0, sensitization to short ragweed ("SRW") antigen was induced in mice by subcutaneous injection of SRW in Freund's adjuvant. On day 18, animals were challenged with topical SRW and then randomized based on their overall response to the challenge. On days 19-20, mice were administered the pharmaceutical formulation or phosphate-buffered saline. On day 21, mice were again administered the pharmaceutical formulation or phosphate-buffered saline. 20 minutes later, mice were evaluated as described below. 30-35 minutes after administration of the pharmaceutical formulation or phosphate-buffered saline, mice were administered topical SRW antigen. Mice were again evaluated 18 minutes after administration of topical SRW antigen ("Challenge 1"), followed by administration of topical SRW antigen on day 21. On days 22-24, mice received two doses of the pharmaceutical formulation or phosphate-buffered saline, followed by administration of topical SRW antigen as described for day 21. On days 22–24, before and after the second dosing round, mice were evaluated as described for day 21 ("Challenges 4, 6, and 8," respectively). Evaluations included scoring strabismus, redness, eye discharge, and eyelid swelling. Scoring was on a scale of "0" to "4," with "0" representing a "normal" eye and "4" representing "severe." Strabismus was assessed macroscopically, while redness, eye discharge, and eyelid swelling were assessed by blinded investigators using a Micron III imaging system. Only the right eye was evaluated. The scores for each criterion were added together and averaged to obtain a "clinical score" ranging from 0 to 4, with a clinical score of 0–1 representing the gold standard.

[0093] Eyes treated with phosphate-buffered saline prior to SRW antigen administration had higher clinical scores than eyes treated with pharmaceutical compositions containing 0.025% (w / v) apraclonidine, 0.08% (w / v) apraclonidine, 0.025% (w / v) brimonidine, or 1% (w / v) prednisone. Clinical scores for i) the +HPMC / +BAK pharmaceutical composition containing 0.08% (w / v) apraclonidine; ii) the +HPMC / +BAK pharmaceutical composition containing 0.025% (w / v) apraclonidine; iii) the -HPMC / -BAK pharmaceutical composition containing 0.08% (w / v) apraclonidine; and iv) the -HPMC / +BAK pharmaceutical composition containing 0.08% (w / v) apraclonidine were similar to those for the pharmaceutical composition containing 0.025% (w / w) brimonidine (see Figure 4).

[0094] Example 6: Preservative-containing citrate-buffered 0.06% (w / v), 0.08% (w / v), and 0.125% (w / v) apraclonidine compositions The compositions shown in Table 8 were prepared.

[0095] [Table 11]

[0096] Example 7: Stability of 0.06% and 0.2% Apraclonidine Compositions The compositions shown in Table 9 were prepared and subjected to stability testing.

[0097] [Table 12]

[0098] Compositions D, E, and vehicle were packaged in opaque white LDPE bottles and stored under one of three stability conditions: Long term: 5°C ± 3°C (simulates controlled refrigeration conditions) Long-term: 25°C ± 2°C / 40% RH ± 5% RH (simulates controlled ambient conditions) Accelerated: 40°C ± 2°C / 20% RH ± 5% RH (simulates stressed storage conditions)

[0099] The monthly test schedule for the specified storage conditions is given in Table 10.

[0100] [Table 13]

[0101] The results of the stability test are shown in Table 11.

[0102] [Table 14]

[0103] Stability testing results met the acceptance criteria when stored at 5°C and 25°C / 40% RH for up to 12 months and at 40°C / 20% RH for up to 6 months.

[0104] Example 8: Stability of 0.125% Apraclonidine Compositions Composition C of Example 6 was subjected to a one-month stability study, and the results are shown in Table 12.

[0105] [Table 15]

[0106] Example 9: Ocular bioavailability of 0.2% apraclonidine aqueous pharmaceutical composition The compositions shown in Table 13 were prepared.

[0107] [Table 16]

[0108] A single topical 40 μL dose of the composition shown in Table 13 was administered to both eyes (OU) of 30 rabbits using a graduated micropipette. Tissue samples were collected at 0.5, 1, 2, 4, and 8 hours after single-dose administration, and the amount of apraclonidine in each tissue sample was determined using HPLC. The following tissue samples were collected and analyzed: aqueous humor, bulbar conjunctiva, vitreous humor, lens, iris / ciliary body, and cornea. The results are shown in Figure 5. These results indicate that the majority of the administered drug rapidly distributes to the conjunctiva, the target tissue type for redness reduction.

[0109] Example 10: Determination of safety and efficacy through human clinical trials Preservative-free Compositions A, B, and C from Example 6 were prepared and their safety and efficacy were determined in a human clinical trial. These preservative-free versions simply omitted the benzalkonium chloride component but were otherwise identical to Compositions A, B, and C. The clinical trial was designed and conducted as a multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 112 subjects with a history of ocular redness. The study involved five clinic visits and two telephone safety checks over a period of approximately 5 to 6 weeks. Eligible subjects were randomized 1:1:1:1 to receive preservative-free Compositions A, B, C, or vehicle. Subjects received one drop of the assigned study medication in each eye on Day 1, followed by one drop in each eye four times daily (QID) from Days 2 to 28. The primary efficacy measure was investigator-assessed ocular redness 8 hours post-installation on Day 1. 112 subjects were randomized: 29 subjects received preservative-free Composition A, 28 subjects received preservative-free Composition B, 28 subjects received preservative-free Composition C, and 27 subjects received preservative-free vehicle. All treatment groups had similar baseline disease characteristics for both efficacy and safety assessments.

[0110] safety results Based on review of adverse events and ocular and systemic safety parameters, no safety issues were identified that could preclude further clinical development of the study drug compositions for redness relief. All three study drug compositions were well tolerated when administered QID for up to one month. Droplet comfort was graded as comfortable to wear across all eyes and treatment groups and remained relatively stable at visits and across study visits. All ocular TEAEs were reported as treatment-related and classified as mild in severity. No subjects experienced ocular TEAEs classified as moderate or severe. The most common ocular treatment-related TEAE reported was eye disorder (ocular irritation), reported in 1.8% of all subjects (one subject [3.4%] in the 0.06% group and one subject [3.6%] in the 0.08% group). No other ocular treatment-related TEAEs were reported in more than one subject.

[0111] Efficacy Results The primary efficacy endpoint, investigator-assessed ocular redness 8 hours (480 minutes) after instillation on Day 1, was met. Mean post-instillation ocular redness scores on Day 1 were significantly reduced for all three study drug compositions compared with the vehicle group (0.06%, 0.08%, and 0.125%): 0.06% vs. vehicle (least squares mean difference [SE] = -0.81 [0.120], 95% CI: [-1.05, -0.57], p<0.0001); 0.08% vs. vehicle (least squares mean difference [S E]=-0.61 [0.121], 95% CI: [-0.85, -0.37], p<0.0001); and 0.125% vs. vehicle: (least squares mean difference [SE]=-0.91 [0.121], 95% CI: [-1.15, -0.67], p<0.0001), thus demonstrating superiority in reducing eye redness due to minor eye irritation.

[0112] From the foregoing description, various modifications of the described subject matter will be apparent to those skilled in the art in addition to those described herein. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including, but not limited to, journal articles, U.S. and foreign patents, patent application publications, international patent application publications, gene bank accession numbers, etc.) is incorporated herein by reference in its entirety.

Claims

1. An aqueous topical ophthalmic pharmaceutical composition comprising apraclonidine and a polymer, wherein the apraclonidine is present at greater than 0.05% (w / v) and less than or equal to 0.2% (w / v).

2. 10. The pharmaceutical composition of claim 1, wherein the apraclonidine is present at 0.06% (w / v) to 0.2% (w / v).

3. 3. The pharmaceutical composition of claim 2, wherein the apraclonidine is present at 0.07% (w / v) to 0.15% (w / v).

4. 4. The pharmaceutical composition of claim 3, wherein the apraclonidine is present at 0.08% (w / v) to 0.125% (w / v).

5. 10. The pharmaceutical composition of claim 1, wherein the apraclonidine is present at 0.125% (w / v).

6. 10. The pharmaceutical composition of claim 1, which is a liquid having a viscosity of 1 to 20 cP.

7. 2. The pharmaceutical composition of claim 1, wherein the polymer is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, xanthan gum, carbopol, hyaluronic acid, and hydroxypropyl guar.

8. 8. The pharmaceutical composition of claim 7, wherein the polymer is hydroxypropyl methylcellulose.

9. 9. The pharmaceutical composition of claim 8, wherein the polymer is present at 0.3% (w / v).

10. 10. The pharmaceutical composition of claim 1, further comprising an ophthalmologically acceptable buffer.

11. 11. The pharmaceutical composition of claim 10, comprising citric acid and sodium citrate.

12. 10. The pharmaceutical composition of claim 1, further comprising a tonicity agent in an amount sufficient to result in the pharmaceutical composition having an osmolality of 260 to 330 mOsm / kg, based on the total weight of the pharmaceutical composition.

13. 13. The pharmaceutical composition of claim 12, wherein the tonicity agent is sodium chloride.

14. 2. The pharmaceutical composition of claim 1, having a pH value of 5.8 to 7.

8.

15. 10. The pharmaceutical composition of claim 1, further comprising benzalkonium chloride.

16. 16. The pharmaceutical composition of claim 15, comprising 0.005% (w / v) benzalkonium chloride.

17. 10. A method for reducing ocular redness in an eye of a subject, comprising administering to the eye of the subject the pharmaceutical composition of claim 1.

18. 18. The method of claim 17, wherein the pharmaceutical composition comprises apraclonidine in the form of apraclonidine hydrochloride, wherein the apraclonidine hydrochloride is present in an amount of 0.08 to 0.125% (w / v) apraclonidine free base equivalent, hydroxypropyl methylcellulose in an amount of 0.05 to 0.5% (w / v), and a tonicity agent in an amount sufficient to result in the pharmaceutical composition having an osmolality of 260 to 330 mOsm / kg, based on the total weight of the pharmaceutical composition, and wherein the pharmaceutical composition has a pH of 6.3 to 7.

3.

19. 19. The method of claim 18, wherein the pharmaceutical composition further comprises benzalkonium chloride in an amount of 0.005% (w / v).

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