Pharmaceutical composition for relieving eye redness comprising azalidine

Abstract

The present disclosure relates to pharmaceutical compositions comprising azaldine and a polymer, methods of making the pharmaceutical compositions, and methods of reducing ocular redness by administering the pharmaceutical compositions wherein the azaldine is present from greater than 0.05% (w / v) to no more than 0.2% (w / v) based on the total volume of the pharmaceutical composition.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 491,051, filed Mar. 18, 2023, titled “Drug Compositions Containing Apraclonidine for Alleviating Ocular Redness and Methods of Use Thereof,” which is hereby incorporated by reference in its entirety. Technical Field

[0003] This disclosure relates to pharmaceutical compositions containing apraclonidine and methods for reducing ocular redness of an eye by topically administering such a composition to the eye of a subject. Background Art

[0004] Ocular redness is a transient condition that can be caused by minor irritants such as fatigue, oversleeping, allergic reactions to environmental allergens, dry eye, or irritation caused by wearing contact lenses. Current over-the-counter ophthalmic vasoconstrictors are not effective in alleviating redness over the long term. Available products on the market generally belong to the class of compounds known as “adrenergic agonists.” Naphazoline hydrochloride (an α-1 / α-2 mixed adrenergic agonist) and tetrahydrozoline (an α-1 selective adrenergic agent) bind to adrenergic receptors on arterial blood vessels. Short-term vasoconstriction of the arteries seems to relieve redness. However, in the long run, such vasoconstriction produces several adverse side effects such as rebound redness and rapid tolerance. Selectively targeting blood vessels, particularly venules, may help relieve redness without producing adverse side effects and appears to be the specific mode of action of α-2 adrenergic agonists.

[0005] Both apraclonidine and brimonidine are α-2 selective adrenergic agonists and have the same mode of action. Apraclonidine binds to adrenergic receptors in venules, causing capillary constriction, thereby providing adequate tissue oxygenation during product use. With adequate oxygenation, the side effect of rebound redness can be prevented as the drug effect gradually wears off. Other α-2 adrenergic agonists are not as readily desensitized as α-1 adrenergic agonists, thus preventing rapid tolerance. Apraclonidine is a hydrophilic analogue of clonidine and reaches the target tissue (i.e., the conjunctiva) to directly relieve redness. In addition, apraclonidine and brimonidine have previously been used in anti-glaucoma management. Commercially available products (Apraclonidine Ophthalmic Solution) contains 0.5% or 1% apraclonidine. Given the use of apraclonidine in ophthalmology and its use at higher concentrations in glaucoma treatment regimens, it has an established safety profile. However, known high-concentration apraclonidine formulations are complex and have an intraocular pressure-lowering effect, and are thus not suitable for long-term use to relieve ocular redness. Although there are no apraclonidine products available for relieving redness, currently Bausch + Lomb has marketed a brimonidine product for this indication and sells it as brimonidine tartrate ophthalmic solution 0.025%. Brimonidine in currently available products does not reach significant tissue levels in the conjunctiva, which may be a key target tissue for reducing redness. Without being bound by any theory, a drug that can reach both the cornea and the conjunctiva is preferred because both the cornea and the conjunctiva are key target tissues for relieving redness. Thus, a drug that reaches both of these target tissues can have a faster onset of action and / or a longer duration of action.

[0006] U.S. Patent No. 9,259,425 ("Horn") reports a pharmaceutical composition containing a selective α-2 adrenergic receptor agonist at a concentration of from about 0.0001% to about 0.05%. In addition, Horn preferred brimonidine over apraclonidine and did not report experimental data on apraclonidine. Thus, there has long been a need for a pharmaceutical composition containing an α-2 selective adrenergic agonist, but this need has not been met, wherein the α-2 selective adrenergic agonist has significant bioavailability in both the cornea and the conjunctiva, and the composition can effectively and rapidly (e.g., within 1 minute) reduce ocular redness in a subject's eye and has a long duration of action (e.g., more than 6-8 hours). SUMMARY OF THE INVENTION

[0007] The present disclosure provides a pharmaceutical composition containing apraclonidine, wherein apraclonidine is present at greater than 0.05% (w / v) up to and including 0.2% (w / v).

[0008] The present disclosure also provides a pharmaceutical composition containing apraclonidine, wherein apraclonidine is present at greater than 0.05% (w / v) up to and including 0.2% (w / v), and wherein the pharmaceutical composition contains a polymer as a comfort and / or viscosity enhancer.

[0009] The present disclosure also provides a pharmaceutical composition containing apraclonidine, wherein apraclonidine is present at greater than 0.05% (w / v) up to and including 0.2% (w / v), wherein apraclonidine exhibits higher bioavailability in the cornea compared to another pharmaceutical composition containing brimonidine, wherein the brimonidine is present at 250 ppm in the other pharmaceutical composition.

[0010] The present disclosure also provides a pharmaceutical composition comprising apraclonidine, wherein apraclonidine is present in an amount greater than 0.05% (w / v) up to and including 0.2% (w / v), and wherein, after administration of the pharmaceutical composition to the eye, apraclonidine exhibits a higher bioavailability to the conjunctiva compared to another pharmaceutical composition comprising brimonidine, wherein brimonidine is present at 250 ppm in the other pharmaceutical composition.

[0011] The present disclosure also provides a method of producing a pharmaceutical composition comprising apraclonidine, wherein apraclonidine is present in an amount greater than 0.05% (w / v) up to and including 0.2% (w / v).

[0012] The present disclosure also provides methods of treating a subject having an ocular disorder (such as red eye or irritation caused by dry eye or allergy), the methods comprising administering a pharmaceutical composition comprising apraclonidine, wherein apraclonidine is present in an amount greater than 0.05% (w / v) up to and including 0.2% (w / v). The pharmaceutical composition comprises a polymer.

[0013] The present disclosure also provides methods of treating a subject having an ocular disorder, the methods comprising administering a pharmaceutical composition comprising apraclonidine, wherein the apraclonidine is present in an amount greater than 0.05% (w / v) up to and including 0.2% (w / v), and wherein, compared to another pharmaceutical composition comprising brimonidine, the apraclonidine exhibits a higher bioavailability to the cornea, wherein brimonidine is present at 250 ppm in the other pharmaceutical composition.

[0014] The present disclosure also provides methods of treating a subject having an ocular disorder or preventing a subject from developing an ocular disorder, the methods comprising administering a pharmaceutical composition comprising apraclonidine, wherein the apraclonidine is present in an amount greater than 0.05% (w / v) up to and including 0.2% (w / w), and wherein, compared to another pharmaceutical composition comprising brimonidine, the apraclonidine exhibits a higher bioavailability to the conjunctiva, wherein brimonidine is present at 250 ppm in the other pharmaceutical composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The drawings, which are incorporated in and constitute a part of this specification, illustrate several features of the present disclosure.

[0016] This 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 Patent Office upon request and payment of the necessary fee.

[0017] Figure 1A Conjunctival bioavailability data of pharmaceutical compositions comprising 0.025% (w / w) brimonidine or 0.08% (w / v) apraclonidine are shown 30 minutes and 2 hours after application to the eye.Figure 1B Shows the conjunctival bioavailability data of aqueous pharmaceutical compositions containing 0.025% (w / w) brimonidine or 0.025% (w / v) apraclonidine at 30 minutes and 2 hours after application to the eye. The ordinate represents the concentration of brimonidine or apraclonidine (in ng / g), and the abscissa represents the time after administration. The circles represent (brimonidine tartrate) data; 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 reference point.

[0018] Figure 2A Shows the corneal bioavailability data of pharmaceutical compositions containing 0.025% (w / w) brimonidine or 0.08% (w / v) apraclonidine at 30 minutes and 2 hours after application to the eye. Figure 2B Shows the corneal bioavailability data of aqueous pharmaceutical compositions containing 0.025% (w / w) brimonidine or 0.025% (w / v) apraclonidine at 30 minutes and 2 hours after application to the eye. The ordinate represents the concentration of brimonidine or apraclonidine (in ng / g), and the abscissa represents the time after administration. The circles represent (brimonidine tartrate) data; 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 reference point.

[0019] Figure 3 Shows the aqueous humor bioavailability data of pharmaceutical compositions containing 0.025% (w / w) brimonidine or 0.08% (w / v) apraclonidine at 30 minutes and 2 hours after application to the eye. The ordinate represents the concentration of brimonidine or apraclonidine (in ng / mL), and the abscissa represents the time after administration. The circles represent (brimonidine tartrate) data; 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 reference point.

[0020] Figure 4Shows the ocular efficacy in a murine conjunctival allergen challenge (“CAC”) model. The ordinate represents the clinical score, ranging from 0 to 4 units, while the abscissa represents the number of challenges. 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 at each reference point.

[0021] Figure 5 Shows the ocular tissue distribution in rabbit eyes of a single topical dose of 0.2% apraclonidine at 0.5, 1, 2, 4, and 8 hours. Detailed Description

[0022] 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.

[0023] As used herein, the term “a or an” means “at least one / at least one kind” or “one or more / one kind or more kinds” unless the context clearly indicates otherwise.

[0024] 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 being treated (e.g., a human) is “in need of treatment”. That is, the animal requires treatment.

[0025] As used herein, the terms “antagonize” and “antagonizing” mean to reduce or completely eliminate one or more effects.

[0026] As used herein, the term “carrier” means a diluent, adjuvant, or excipient administered with a compound in a composition.

[0027] As used herein, the term “compound” means all stereoisomers, tautomers, isotopes, and polymorphs of the compounds described herein.

[0028] As used herein, the term “comprising” (and “comprises”)

[0029] 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") is inclusive and open-ended, and includes the options after the term and does not exclude additional, unenumerated elements or method steps.

[0030] As used herein, the terms "individual", "subject", and "patient", which are used interchangeably, mean any animal described herein.

[0031] As used herein, the phrase "ophthalmologically acceptable" means that a compound, material, composition, and / or dosage form is within the scope of reasonable medical judgment and is suitable for contact with the eyes of humans and other animals.

[0032] As used herein, the term "treat", "treated", or "treating" refers to both therapeutic treatment and prophylactic measures, where the aim is to prevent or slow down (alleviate) an undesired physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical or veterinary outcome. For the purposes of this document, beneficial or desired clinical or veterinary outcomes include, but are not limited to, alleviation of symptoms; reduction in the degree of a condition, disorder, or disease; stabilization (i.e., non-worsening) of a condition, disorder, or disease; delay in the onset or slowdown of the progression of a condition, disorder, or disease; improvement or alleviation (whether partial or total) of a condition, disorder, or disease state, whether detectable or not; improvement in at least one measurable physical parameter, which at least one measurable physical parameter may not necessarily be distinguishable by the patient; or turn for the better or improvement of a condition, disorder, or disease. Treatment includes optionally eliciting a clinically or veterinarily significant response without undue side effects.

[0033] As used herein, the term "%(w / v)" means the amount (in grams) of a specific solute per 100 mL of solution.

[0034] As used herein, the term "%(w / w)" means the percentage obtained by dividing the mass of a specific solute by the mass of the solution (solute and solvent together) and multiplying by 100.

[0035] The present disclosure provides a pharmaceutical composition suitable for topical administration to the eye and containing apraclonidine, wherein the apraclonidine is present in an amount greater than 0.05% (w / v) up to and not exceeding 0.2% (w / v). In some embodiments, the apraclonidine is present in the form of an ophthalmically acceptable salt. In a preferred embodiment, the pharmaceutical composition contains apraclonidine hydrochloride in an amount equivalent to apraclonidine as the free base in a concentration greater than 0.05% (w / v) but not exceeding 0.2% (w / v). For example, if the apraclonidine is present in the form of apraclonidine hydrochloride, a composition containing 0.125% (w / v) of apraclonidine as the free base will contain 0.144% (w / w) apraclonidine hydrochloride.

[0036] Apraclonidine (as the free base) is present in the pharmaceutical composition in an amount greater than 0.05% (w / v) up to and not exceeding 0.2% (w / v). In some embodiments, the apraclonidine is present in an amount of 0.06% (w / v) to 0.2% (w / v). In some embodiments, the apraclonidine is present in an amount of 0.07% (w / v) to 0.15% (w / v). In some embodiments, the apraclonidine is present in an amount of 0.08% (w / v) to 0.125% (w / v). In a preferred embodiment, the apraclonidine is present in an amount of 0.06% (w / v). In another preferred embodiment, the apraclonidine is present in an amount of 0.08% (w / v). In a most preferred embodiment, the apraclonidine is present in an amount of 0.125% (w / v).

[0037] In some embodiments, the pharmaceutical composition is a liquid. In a preferred embodiment, the liquid pharmaceutical composition is an aqueous liquid.

[0038] In one embodiment, the pharmaceutical composition containing apraclonidine contains an ophthalmically acceptable preservative. Several ophthalmically acceptable preservatives are known and include, for example, 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.

[0039] In other embodiments, the pharmaceutical composition containing apraclonidine is preservative-free. In such embodiments, the composition can be packaged in a unit-dose container or a container designed as a multi-dose preservative-free (MDPF) container. Unit-dose containers and multiple MDPF containers are known for topically applicable ophthalmic products, including prescription and over-the-counter (OTC) products.

[0040] The pharmaceutical composition containing apraclonidine contains a polymer as a comfort agent and / or a viscosity agent. In some embodiments, the polymer includes methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, xanthan gum, carbomer, hyaluronic acid, guar gum or hydroxypropyl guar gum. The typical molecular weight range of these polymers that can be used to enhance viscosity is from 500K to 4 million. In a preferred embodiment, the composition contains hydroxypropyl methylcellulose as a comfort agent and / or a viscosity agent.

[0041] 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 contains 0.3% (w / v) hydroxypropyl methylcellulose.

[0042] In some embodiments, the pharmaceutical composition is a liquid with a viscosity of 1 - 20 cP. In a preferred embodiment, the composition has a viscosity of 5 to 15 cP. In a most preferred embodiment, the composition has a viscosity of 6 to 8 cP.

[0043] In some embodiments, the pharmaceutical composition containing apraclonidine contains a polymer as a gelling agent, the concentration of which can effectively promote gelling upon contact with the eye or the tear film, enabling it to stay in the eye for a longer time without loss due to tear drainage. Suitable gelling agents include but are not limited to thermosetting polymers, such as tetra-substituted ethylenediamine block copolymers of ethylene oxide and propylene oxide (e.g., poloxamer 1307); polycarbophil; and polysaccharides, such as gellan gum, carrageenan (e.g., κ-carrageenan and ι-carrageenan), chitosan and alginate gum. Alternatively, guar gum-based polymers can be used in the presence of borate for crosslinking in the eye, where the ocular pH allows the formation of a guar gum gel.

[0044] In some embodiments, the pharmaceutical composition containing apraclonidine contains a demulcent. Demulcents used in conjunction with the compositions disclosed herein include but are not limited to glycerol, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, propylene glycol and polyacrylic acid. Preferred demulcents are propylene glycol and polyethylene glycol 400. In some embodiments, polyethylene glycol is present at 0.4% (w / v).

[0045] The drug composition containing apraclonidine is preferably buffered and contains an ophthalmically acceptable buffer. In some embodiments, the ophthalmically acceptable buffer contains 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, tartaric 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 contains a citrate buffer. In a most preferred embodiment, the composition contains citric acid and sodium citrate.

[0046] The drug composition containing apraclonidine may contain an ophthalmically acceptable pH adjuster and is formulated within a pH range of 5.8 - 7.8. In a preferred embodiment, the pH of the composition is 6.3 - 7.3. In a more preferred embodiment, the pH of the composition is 6.5 - 7.0, and most preferably the pH is 6.8. Several ophthalmically acceptable pH adjusters are known and include, for example, NaOH and HCl.

[0047] In some embodiments, the drug composition containing apraclonidine is a liquid composition with an osmotic pressure of 260 to 330 mOsm / kg based on the total weight of the liquid drug composition. In some embodiments, the liquid drug composition has an osmotic pressure of 270 to 320 mOsm / kg based on the total weight of the liquid drug composition. In some embodiments, the liquid drug composition has an osmotic pressure of 280 to 310 mOsm / kg based on the total weight of the liquid drug composition. In some embodiments, the liquid drug composition has an osmotic pressure of 290 to 300 mOsm / kg based on the total weight of the liquid drug composition. In some embodiments, the liquid drug composition has an osmotic pressure of 300 mOsm / kg based on the total weight of the liquid drug composition.

[0048] In some embodiments, the drug composition containing apraclonidine contains a tonicity regulator. Many ophthalmically acceptable tonicity regulators are known and include ionic and non-ionic agents. In some embodiments, the tonicity regulator includes sodium chloride. In some embodiments, the tonicity regulator includes sorbitol, propylene glycol, glucose, glycerol, mannitol, or potassium chloride.

[0049] In some embodiments, the tonicity regulator is present at 0.1% - 0.8% (w / v) sodium chloride based on the total volume of the drug composition. In a preferred embodiment, the drug composition contains sodium chloride as the tonicity regulator and the sodium chloride is present in an amount of 0.6 - 0.8% (w / v). In a most preferred embodiment, the composition contains 0.7 - 0.8% (w / v) sodium chloride.

[0050] In some embodiments, the pharmaceutical composition comprising apraclonidine may further comprise one or more antioxidants. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, and acetylcysteine.

[0051] 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, limethason, prednisolone, fluorometholone, and hydrocortisone. Examples of suitable non-steroidal anti-inflammatory agents include, but are not limited to, prostaglandin H synthase inhibitors (Cox I or Cox II), also known as cyclooxygenase type I and type II inhibitors, such as diclofenac, flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indomethacin, naproxen, ibuprofen, bromfenac, ketoprofen, meclofenoxate, piroxicam, sulindac, mefenamic acid, diflunisal, oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetone, etodolac, phenylbutazone, aspirin, oxyphenbutazone, tenoxicam, and carprofen; cyclooxygenase type II selective inhibitors, such as celecoxib and etodolac; PAF antagonists, such as apafant, bepafant, minapafant, neopafant, and modipafant; PDEIV inhibitors, such as cilomilast, tobalophylline, rolipram, fevipiprant, pyrazinamide, cipamfylline, and roflumilast; and inhibitors of cytokine production, such as inhibitors of the NFkB transcription factor.

[0052] 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, loteprednol, and dexamethasone).

[0053] The pharmaceutical composition containing apraclonidine can be in unit dosage form. In some embodiments, the unit dosage form is one or more containers containing the composition described herein. In such a dosage form, the pharmaceutical composition can be divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation. In some embodiments, the pharmaceutical composition containing apraclonidine is a liquid composition, and these liquid compositions are placed in multi-dose packages that can support both preservative-containing and preservative-free packages. In some embodiments, the pharmaceutical composition containing apraclonidine is a liquid composition placed in a disposable container. In some embodiments, the disposable container includes a headspace. In some embodiments, the headspace is substantially free of oxygen. In some embodiments, the pharmaceutical composition containing apraclonidine is a liquid composition placed in a reusable container. In some embodiments, the reusable container includes a dropper bottle. In some embodiments, the reusable container includes a bottle with a neck. In some embodiments, the pharmaceutical composition is contained within a single-dose, non-resealable container. Alternatively, the pharmaceutical composition is contained within a multi-dose, resealable container. In some embodiments, the required dose of the pharmaceutical composition containing apraclonidine can be administered to the eye in a known number of drops through a suitable dispenser. Many examples of suitable multi-dose dropper bottle containers are known in the art and include, but are not limited to, the Droptainer first introduced by Alcon and the multi-dose preservative-free eye drop bottles provided by Nemera. TM bottles and those provided by Nemera such as multi-dose dropper bottles like multi-dose preservative-free eye drop bottles.

[0054] In some embodiments, the pharmaceutical composition containing apraclonidine is stable after storage at 25 °C for at least one month. In some embodiments, the disclosed pharmaceutical composition is stable after storage at 40 °C for at least one month. In some embodiments, the pharmaceutical composition containing apraclonidine is stable after storage at 25 °C / 60% relative humidity (RH). In some embodiments, the pharmaceutical composition containing apraclonidine is stable after storage at 40 °C / 75% RH. In some embodiments, the stability can be measured by any one or more of appearance, container seal integrity, pH, osmotic pressure, viscosity, assay value of the active ingredient, absence of impurities, etc.

[0055] In some embodiments, after administering any of the pharmaceutical compositions containing apraclonidine and free of preservatives described herein to the eye, compared with another pharmaceutical composition containing brimonidine, apraclonidine in such a pharmaceutical composition exhibits higher bioavailability to the cornea, wherein the brimonidine is present at 250 ppm in the other pharmaceutical composition.

[0056] In some embodiments, after administration of any of the drug compositions described herein that contain apraclonidine and are preservative-free to the eye, apraclonidine in such drug compositions exhibits higher bioavailability to the conjunctiva compared to another drug composition that contains brimonidine, wherein the brimonidine is present at 250 ppm in the other drug composition.

[0057] In some embodiments, after administration of any of the drug compositions described herein that contain apraclonidine to the eye, such drug compositions exhibit higher apraclonidine bioavailability to the cornea compared to the bioavailability of brimonidine to the cornea in another drug composition that contains 250 ppm brimonidine.

[0058] In some embodiments, after administration of any of the drug compositions described herein that contain apraclonidine to the eye, such drug compositions exhibit higher apraclonidine bioavailability to the conjunctiva compared to the bioavailability of brimonidine to the cornea in another drug composition that contains 250 ppm brimonidine.

[0059] In any of these embodiments, the bioavailability can include corneal, conjunctival, or other ocular tissue bioavailability. In some embodiments, the bioavailability is evaluated by pharmacokinetic methods. For example, the dose administration can be performed on day 1, wherein one drop (40 μL) of each test material can be administered to both eyes of each animal. A pipette can be used for precise administration. The time of dose administration and comments regarding the dose administration (e.g., appropriate dose, whether any liquid was blinked out of the eye after administration, etc.) can be recorded in the study document. Sample collection can be performed, for example, at 0.5, 2, 8, and 24 hours after dose administration. The animals can be euthanized (e.g., n = 2 per group at each time point). The eyeballs can be enucleated, and the bulbar conjunctiva and cornea can be removed. For the bulbar conjunctiva, a sample of approximately 3 x 3 mm can be obtained from the inferior / nasal side of each eye (e.g., from the 4 - 6 o'clock position of the right eye and the 6 - 8 o'clock position of the left eye). Between operations on each new eye, the equipment can be wiped and rinsed with saline and alcohol. After removal, the cornea and conjunctiva can be rinsed with saline, placed in a cryovial, and weighed. The tissue can be weighed before and after being placed in the cryovial, and the weights can be recorded. After recording the weights, the cryovial can be frozen on dry ice and kept on dry ice during sorting. The samples can be stored at -80 °C until shipment.

[0060] In any of these embodiments, another pharmaceutical composition for comparison purposes may comprise a preservative in a preservative-effective amount. In any of these embodiments, another pharmaceutical composition for comparison purposes may comprise benzalkonium chloride in a preservative-effective amount. In some embodiments, the preservative-effective amount of the preservative is from 80 ppm to 120 ppm, or 100 ppm. In some embodiments, the preservative-effective amount of benzalkonium chloride is from 80 ppm to 120 ppm, or 100 ppm. In any of these embodiments, another pharmaceutical composition for comparison purposes is (See page 7 of “accessdata.fda.gov / drugsatfda_docs / nda / 2017 / 208144Orig1s000PharmR.pdf” on the World Wide Web). In some embodiments, 250 ppm brimonidine refers to 0.025% (w / w) brimonidine. In some embodiments, brimonidine includes brimonidine tartrate.

[0061] 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. Generally, the pharmaceutical composition is a sterile, isotonic, buffered aqueous solution. If necessary, the pharmaceutical composition may further include a solubilizing agent.

[0062] In some embodiments, any amount of apraclonidine disclosed herein is contacted with a liquid (such as an aqueous liquid). In some embodiments, the liquid or aqueous liquid includes 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.

[0063] Briefly, through representative process steps, an apraclonidine ophthalmic solution containing the desired amount of apraclonidine hydrochloride can be prepared in the presence of a citrate buffer, sodium chloride, hydroxypropyl methylcellulose (HPMC), and benzalkonium chloride (BAK). The apraclonidine ophthalmic pharmaceutical product can be prepared by mixing the following substances in the specified amounts: 1) 6 mg / g HPMC stock solution; and 2) 4.1 mg / g apraclonidine hydrochloride, containing 43 mM sodium citrate, 0.9 mM citric acid buffer, sodium chloride added as a tonicity modifier, and 0.14 mg / g BAK. For example, a 1.44 mg / g apraclonidine hydrochloride ophthalmic pharmaceutical product can be prepared by steam sterilizing the 6 mg / g HPMC stock solution, and the apraclonidine buffer solution can be aseptically filtered through a 0.2 μm PVDF filter and added to the HPMC stock solution. The resulting solution can be adjusted to the final pH and adjusted to the batch size with sterile purified water.

[0064] The present disclosure also provides methods for treating a subject having ocular redness, the methods comprising administering to the affected eye of the subject any of the pharmaceutical compositions described herein that comprise apraclonidine.

[0065] In some embodiments, the ocular disorder is hyperemia, ocular redness, dry eye, or an allergic reaction. In some embodiments, the ocular disorder is hyperemia. In some embodiments, the ocular disorder is ocular redness, such as redness caused by mild irritation. In some embodiments, the ocular disorder is dry eye. In some embodiments, the ocular disorder is an allergic reaction.

[0066] In some embodiments, the administration is to a single eye of the subject. In some embodiments, the administration is to both eyes of the subject.

[0067] The present disclosure also provides methods for reducing ocular redness in the eyes of a subject, the methods comprising administering to the eyes of the subject any of the pharmaceutical compositions described herein that comprise apraclonidine.

[0068] In any of the treatment methods disclosed herein, after administering to the eye any of the pharmaceutical compositions described herein that comprise apraclonidine and a polymer, apraclonidine in such a pharmaceutical composition exhibits higher bioavailability to the cornea compared to another pharmaceutical composition that comprises brimonidine, wherein the brimonidine is present in the other pharmaceutical composition at 250 ppm.

[0069] In any of the treatment methods disclosed herein, after administering to the eye any of the pharmaceutical compositions described herein that comprise apraclonidine and a polymer, apraclonidine in such a pharmaceutical composition exhibits higher bioavailability to the conjunctiva compared to another pharmaceutical composition that comprises brimonidine, wherein the brimonidine is present in the other pharmaceutical composition at 250 ppm.

[0070] In any of these embodiments, the bioavailability can include corneal, conjunctival, or ocular bioavailability. In some embodiments, the bioavailability is evaluated by the methods described herein.

[0071] In any of these embodiments, another pharmaceutical composition for comparison purposes can comprise a preservative in a preservative-effective amount. In any of these embodiments, another pharmaceutical composition for comparison purposes can comprise benzalkonium chloride in a preservative-effective amount. In some embodiments, the preservative-effective amount of the 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 (See page 7 of “accessdata.fda.gov / drugsatfda_docs / nda / 2017 / 208144Orig1s000PharmR.pdf” on the World Wide Web). In some embodiments, 250 ppm brimonidine refers to 0.025% (w / w) brimonidine. In some embodiments, brimonidine includes brimonidine tartrate.

[0072] In any of the treatment methods disclosed herein, the pharmaceutical composition containing apraclonidine can be administered to the eye in the form of eye drops.

[0073] In some embodiments, the pharmaceutical composition containing apraclonidine is topically administered to one or more tissues of the eye. In one embodiment, the composition is topically administered to the eye one to four times a day. In a preferred embodiment, the composition is topically administered one to two times a day. In a more preferred embodiment in which the composition of the present invention contains 0.125% (w / v) of apraclonidine, these compositions are effective in reducing redness within 1 minute after topical administration and effectively maintaining the reduction of redness for 8 hours or longer. In the most preferred embodiment, the composition is effective in reducing redness within 1 minute after topical administration and effectively maintaining the reduction of redness for 10 hours or longer.

[0074] The present disclosure also provides the use of any of the pharmaceutical compositions containing apraclonidine described herein in the preparation of a medicament for reducing ocular redness caused by minor irritation. In some embodiments, the ocular redness is congestion or ocular redness caused by dry eye or allergic reaction.

[0075] To more effectively understand the subject matter disclosed herein, examples are provided below. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the claimed subject matter in any way.

[0076] Examples

[0077] Example 1: Preparation of Phosphate-Buffered 0.08% (w / v) and 0.025% (w / w) Apraclonidine Compositions

[0078] 800 ppm and 250 ppm Drug Product Formulations

[0079] Representative 800 ppm and 250 ppm drug product formulations are presented in Table 1 and Table 2, respectively.

[0080] Table 1: 800 ppm Apraclonidine

[0081] Ingredient Concentration (mg / g) Apraclonidine (free base) 0.8 Dihydrogen phosphate monohydrate 0.93 Disodium hydrogen phosphate heptahydrate 3.6 Sodium chloride 7.7 Hydroxypropyl methylcellulose 4.8 Benzalkonium chloride 0.1 WFI qs

[0082] Table 2: 250 ppm Apraclonidine

[0083] Ingredient Concentration (mg / g) Apraclonidine (free base) 0.25 Dihydrogen phosphate monohydrate 0.87 Disodium hydrogen phosphate heptahydrate 3.3 Sodium chloride 7.7 Hydroxypropyl methylcellulose 4.8 Benzalkonium chloride 0.1 WFI qs

[0084] A pharmaceutical product is prepared by mixing the stock solutions described below. If necessary, the appropriate stock solutions can be added in the following order: 1) Apraclonidine stock solution containing sodium chloride (sodium chloride), 2) HPMC stock solution, 3) Sterile filtered BAK stock solution, and 4) Sterile filtered WFI water.

[0085] Table 3: Preparation of 250 ppm pharmaceutical product with stock solutions

[0086]

[0087] Table 4: Preparation of 800 ppm pharmaceutical product with stock solutions

[0088]

[0089] The pharmaceutical product was gently mixed for 15 - 20 minutes using an overhead mixer with a 1.5 inch stainless steel mixing paddle to ensure uniformity. In a laminar flow hood, the pharmaceutical product containing Apraclonidine stock solution (sodium chloride) and HPMC stock solution was sterile filtered through a 0.2 μm PVDF membrane into a sterile Nalgene bottle of appropriate size. After filtration, the required amount of sterile filtered BAK stock solution was added and the capped Nalgene bottle was gently inverted for mixing. Sterile filtered WFI water was added to bring the formulation to the target volume.

[0090] Example 2: Stability of 0.08% (w / v) Apraclonidine Composition of Example 1

[0091] An aqueous pharmaceutical composition was prepared containing 0.08% (w / v) Apraclonidine (free base), 7.66 mg / g sodium chloride in phosphate buffer. 0.10 mg / g Benzalkonium Chloride (“BAK”) and / or 4.84 mg Hydroxypropyl Methylcellulose 2910 (“HPMC”) was added. This resulted in the following pharmaceutical compositions: i) without BAK or HPMC (“-HPMC, -BAK”); ii) with BAK but without HPMC (“-HPMC, +BAK”); iii) without BAK but with HPMC (“+HPMC, -BAK”); and iv) with BAK and HPMC (“+HPMC, +BAK”). Portions of compositions i) - 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 (“TO”). The stability data of the four pharmaceutical compositions were then determined. It was found that the appearance, Apraclonidine level, total impurity level, BAK level, pH value, osmotic pressure value, and viscosity value of each of the four pharmaceutical compositions remained unchanged after storage at 25 °C or 40 °C for 4 weeks. The results are shown in Tables 5a - 5d below.

[0092] Table 5a: -HPMC, -BAK

[0093]

[0094] Table 5b: -HPMC, +BAK

[0095]

[0096] Table 5c: +HPMC, -BAK

[0097]

[0098]

[0099] Table 5d: +HPMC, +BAK

[0100]

[0101] Example 3: 0.08% (w / v) Apraclonidine Low-Salt Pharmaceutical Product Composition Representative 800 ppm low-salt pharmaceutical product formulations are presented in Table 6.

[0102] Table 6: 800 ppm Low-Salt

[0103]

[0104]

[0105] The pharmaceutical product is prepared by mixing the stock solutions as described below. If necessary, the appropriate stock solutions may be added in the following order: 1) Apraclonidine stock solution, 2) 49.05 mM phosphate buffer, salt, glycerol stock solution, 3) HPMC stock solution, 4) sterile-filtered BAK stock solution, and 5) sterile-filtered WFI water.

[0106] Table 7: Preparation of 800 ppm Pharmaceutical Product with Stock Solutions

[0107]

[0108] The pharmaceutical product is gently mixed for 15 - 20 minutes using a overhead mixer with a 1.5-inch stainless steel mixing paddle to ensure uniformity. In a laminar flow hood, the pharmaceutical product containing Apraclonidine stock solution, 49.05 mM phosphate buffer (containing sodium chloride and glycerol), and HPMC stock solution is sterile filtered through a 0.2 μm PVDF membrane into a sterile Nalgene bottle of appropriate size. After filtration, the required amount of sterile-filtered BAK stock solution is added, and the capped Nalgene bottle is gently inverted to mix. Sterile-filtered WFI water is added to bring the formulation to the target volume.

[0109] Example 4: Ocular Bioavailability of the Aqueous Pharmaceutical Composition of Example 1

[0110] Obtained (a pharmaceutical composition comprising 0.025% (w / w) brimonidine tartrate). In addition, the -HPMC / -BAK, -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions of Example 1 comprising 0.08 (w / v) apraclonidine, and the -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions comprising 0.025% (w / v) apraclonidine were obtained. The conjunctival and corneal bioavailabilities of the pharmaceutical compositions comprising brimonidine and apraclonidine were determined in rabbits. Specifically, the ocular tissues were thawed and homogenized in HPLC-grade water. The homogenate was analyzed using HPLC and a pre-established apraclonidine bioanalytical method. Data for four eyes were obtained at 30 minutes or 2 hours after administration.

[0111] It was found that the conjunctival bioavailability of the pharmaceutical composition comprising 0.025% (w / w) brimonidine was negligible at 30 minutes and 2 hours after application to the eye. In contrast, it was found that the -HPMC / -BAK, -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions comprising 0.08% (w / v) apraclonidine had good conjunctival bioavailability, and the pharmaceutical compositions comprising HPMC had excellent conjunctival bioavailability (see Figure 1A ). At Figure 1A , at 30 minutes, for all the formulations tested, a statistically higher level of apraclonidine was observed in the conjunctiva compared to brimonidine (p < 0.0001). A statistically significant improvement in the bioavailability of the +HPMC, -BAK apraclonidine formulation was observed compared to the formulations containing -HPMC, -BAK and -HPMC, +BAK (p < 0.0001). The +HPMC, -BAK formulation showed a statistically significant improvement in conjunctival bioavailability compared to the +HPMC, +BAK formulation (p ≤ 0.05). Since both brimonidine and apraclonidine are α-2 selective adrenergic agonists, similar bioavailabilities might be expected. Thus, the results obtained for the -HPMC / -BAK, -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions comprising 0.08% (w / v) apraclonidine were unexpected. The finding that the pharmaceutical compositions comprising HPMC had better conjunctival bioavailability was likewise unexpected. In contrast, BAK had little effect on conjunctival bioavailability.

[0112] Although the conjunctival bioavailability of the -HPMC / +BAK, +HPMC / -BAK, and +HPMC / +BAK pharmaceutical compositions containing 0.025% (w / v) apraclonidine is lower than that of comparable pharmaceutical compositions containing 0.08% (w / v) apraclonidine, such bioavailability is unexpectedly higher than the pharmaceutical composition (see Figure 1B ). In Figure 1B , at 30 minutes, statistically higher levels of apraclonidine were observed in the conjunctiva for all formulations relative to LUMIFY (p < 0.0001). No differences in bioavailability (ns) were observed among the apraclonidine-containing formulations. These data indicate that the increased conjunctival bioavailability of the pharmaceutical composition containing 0.08% (w / v) apraclonidine does not stem solely from a greater amount of the α-2 selective adrenergic agonist relative to the pharmaceutical composition containing 0.025% (w / w) brimonidine. Accordingly, pharmaceutical compositions containing greater than 0.05% (w / v) to no more than 0.2% (w / v) apraclonidine will exhibit unexpectedly good conjunctival bioavailability.

[0113] Although the corneal bioavailability of the pharmaceutical composition containing 0.025% (w / w) brimonidine after 30 minutes and 2 hours is comparable to that of the -HPMC / -BAK and -HPMC / +BAK pharmaceutical compositions containing 0.08% (w / v) apraclonidine, the corneal bioavailability of the +HPMC / -BAK and +HPMC / +BAK pharmaceutical compositions containing 0.08% (w / v) apraclonidine is associated with excellent 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 exhibited statistically higher levels of the active agent in the cornea relative to LUMIFY. The +HPMC, -BAK apraclonidine formulation also showed statistically higher levels of apraclonidine in the cornea relative to -HPMC, +BAK and -HPMC, -BAK (p < 0.0001). The +HPMC, -BAK formulation showed a statistically significant improvement in conjunctival bioavailability relative to the +HPMC, +BAK formulation (p ≤ 0.05). Surprisingly, the corneal bioavailability of the pharmaceutical composition containing 0.025% (w / w) brimonidine was greater than that of any of the tested pharmaceutical compositions containing 0.025% (w / v) apraclonidine (see Figure 2B ). In Figure 2BIn the case of apraclonidine, at 30 minutes, statistically higher levels of brimonidine were observed in the cornea relative to all apraclonidine-containing formulations (p < 0.0001). A bioavailability difference was observed between +HPMC, +BAK and +HPMC, -BAK (p < 0.01), while no bioavailability difference was observed between +HPMC, +BAK and -HPMC, +BAK (ns).

[0114] It was found that at 30 minutes after administration, the aqueous humor bioavailability of a drug composition containing 0.025% (w / w) brimonidine was greater than that of a drug composition containing 0.08% (w / v) apraclonidine. However, surprisingly, the aqueous humor bioavailability of the +HPMC / -BAK drug composition remained constant at 2 hours after administration, while the aqueous humor bioavailability of the -HPMC / -BAK, -HPMC / +BAK and +HPMC / +BAK drug compositions increased at 2 hours after administration. In contrast, the aqueous humor bioavailability of the drug composition decreased at 2 hours after administration (see Figure 3 ). At 30 minutes, there was no statistically significant difference (ns) in the aqueous humor levels of brimonidine relative to apraclonidine delivered in the +HPMC, -BAK formulation. Relative to the +HPMC, -BAK formulation, the -HPMC, -BAK and -HPMC, +BAK formulations showed statistically lower aqueous humor levels of apraclonidine (p < 0.001). Relative to the +HPMC, +BAK formulation, the +HPMC, -BAK formulation showed an improvement in aqueous humor bioavailability (p < 0.01).

[0115] Example 5: Efficacy of the apraclonidine composition of Example 1

[0116] Ocular efficacy was examined in a murine CAC model. On day 0, mice were sensitized to SRW by subcutaneous injection of short ragweed ("SRW") antigen in Freund's adjuvant. On day 18, the animals were challenged with topical SRW and then randomly grouped according to their overall response to the challenge. On days 19 to 20, a pharmaceutical formulation or phosphate buffered saline was administered to the mice. On day 21, the pharmaceutical formulation or phosphate buffered saline was administered to the mice again. Twenty minutes later, the mice were evaluated as described below. Thirty to 35 minutes after administration of the pharmaceutical formulation or phosphate buffered saline, topical SRW antigen was administered to the mice. The mice were evaluated again 18 minutes after administration of the topical SRW antigen ("Challenge 1"). Topical SRW antigen was administered later on day 21. On days 22 to 24, the pharmaceutical formulation or phosphate buffered saline was administered twice, followed by topical SRW antigen as described on day 21. The mice were evaluated during and after the second round of administration on days 22 to 24 as described on day 21 ( "Challenges 4, 6, and 8", respectively). The evaluations included scoring for strabismus, congestion, secretions, and eyelid swelling. The scores ranged from "0" to "4", where a score of "0" represented a "normal" eye and a score of "4" represented "severe". Strabismus was evaluated roughly, while congestion, secretions, and eyelid swelling were evaluated by blinded examiners under a Micron III imaging system. Only the right eye was evaluated. The scores for each criterion were added and averaged to obtain a "clinical score" ranging from 0 to 4, where a clinical score of 0 to 1 represented the gold standard.

[0117] The clinical scores of eyes that received phosphate buffered saline before administration of SRW antigen were higher than those of eyes that received a pharmaceutical composition comprising 0.025% (w / v) apraclonidine, 0.08% (w / w) apraclonidine, 0.025% (w / w) brimonidine, or 1% (w / v) prednisone. The clinical scores of the following: i) the +HPMC / +BAK pharmaceutical composition comprising 0.08% (w / v) apraclonidine; ii) the +HPMC / +BAK pharmaceutical composition comprising 0.025% (w / v) apraclonidine; iii) the -HPMC / -BAK pharmaceutical composition comprising 0.08% (w / v) apraclonidine; and iv) the -HPMC / +BAK pharmaceutical composition comprising 0.08% (w / v) apraclonidine, were similar to the clinical scores of the pharmaceutical composition comprising 0.025% (w / w) brimonidine (see Figure 4 ).

[0118] Example 6: Preserved Citrate Buffered 0.06% (w / v), 0.08% (w / v), and 0.125% (w / v) Apraclonidine Compositions

[0119] Prepare the compositions shown in Table 8.

[0120] Table 8

[0121]

[0122] * Added as follows: 0.069% (w / v) apraclonidine hydrochloride (equivalent to 0.06% (w / v) apraclonidine as the free base)

[0123] 0.092% (w / v) apraclonidine hydrochloride (equivalent to 0.08% (w / v) apraclonidine as the free base)

[0124] 0.144% (w / v) apraclonidine hydrochloride (equivalent to 0.125% (w / v) apraclonidine as the free base)

[0125] Example 7: Stability of 0.06% and 0.2% apraclonidine compositions

[0126] Prepare the compositions shown in Table 9 and conduct stability tests.

[0127] Table 9

[0128]

[0129] * 0.069% (w / v) apraclonidine hydrochloride added as apraclonidine equivalent to 0.06% (w / v) as the free base; 0.23% (w / v) apraclonidine hydrochloride added as apraclonidine equivalent to 0.2% (w / v) as the free base

[0130] Package Compositions D, E, and the vehicle in opaque white LDPE bottles and store under one of the following three stability conditions:

[0131] Long - term: 5°C ± 3°C (simulating controlled refrigerated conditions)

[0132] Long - term: 25°C ± 2°C / 40% RH ± 5% RH (simulating controlled environmental conditions)

[0133] Accelerated: 40°C ± 2°C / 20% RH ± 5% RH (simulating stress storage conditions)

[0134] Table 10 gives the test schedule (in months) for the specified storage conditions.

[0135] Table 10

[0136]

[0137]

[0138] X: Chemical (assay, ID, and impurities) and physical (appearance, pH, viscosity, osmotic pressure, and weight change) tests Y: Sterility test

[0139] Z: Particulate matter determined by HIAC

[0140] NT: Stability not tested. The stability test results are shown in Table 11.

[0141] Table 11

[0142]

[0143]

[0144] LOQ: 0.05% of the HPLC working concentration

[0145] NT: Not tested

[0146] 1 Vehicle is negative

[0147] 2 Not applicable to vehicle

[0148] 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, the stability test results meet the acceptance criteria.

[0149] Example 8: Stability of 0.125% apraclonidine composition

[0150] A 1-month stability test was conducted on Composition C of Example 6. The results are shown in Table 12.

[0151] Table 12

[0152]

[0153]

[0154] LOQ: 0.05% NT: Not tested N / A: Not applicable

[0155] Example 9: Ocular bioavailability of 0.2% apraclonidine aqueous pharmaceutical composition

[0156] Prepare the compositions shown in Table 13.

[0157] Table 13

[0158] Ingredient %(w / v) Apraclonidine hydrochloride 0.23* Hypromellose 2910 (E4M) 0.3 Sodium citrate (dihydrate) 0.45 Citric acid (monohydrate) 0.0067 Sodium chloride 0.74 Benzalkonium chloride 0.005 Hydrochloric acid Adjusted to pH 6.8 Sodium hydroxide Adjusted to pH 6.8 Purified water q.s. to 100

[0159] * Equivalent to 0.2% (w / v) free base

[0160] A single topical ocular dose of 40 μL of the compositions shown in Table 13 was administered to the eyes of both eyes (OU) of 30 rabbits using a calibrated micropipette. Tissue samples were collected at 0.5, 1, 2, 4, and 8 hours after the single dose, 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, lens, iris-ciliary body, and cornea. The results are as Figure 5 shown. These results indicate that the drug administered in large amounts is rapidly distributed to the conjunctiva, which is the type of target tissue for reducing redness.

[0161] Example 10: Human clinical study to evaluate safety and efficacy

[0162] Preservative-free versions of Compositions A, B, and C from Example 6 were prepared and their safety and efficacy were evaluated 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 design and conduct of this clinical study was a multicenter, double-blind, randomized, vehicle-controlled, parallel-group study in 112 subjects with a history of ocular redness. The study involved 5 outpatient visits and 2 telephone safety checks over a period of approximately 5 to 6 weeks. Eligible subjects were randomly assigned in a 1:1:1:1 ratio to receive the preservative-free versions of Compositions A, B, C, or vehicle. Subjects received one drop of the assigned study medication in each eye on Day 1 (once), followed by four drops (QID) in each eye daily from Day 2 - Day 28. The primary efficacy measure was ocular redness evaluated by the investigator 8 hours after instillation on Day 1. Of the 112 randomized subjects, 29 subjects received the preservative-free version of Composition A, 28 subjects received the preservative-free version of Composition B, 28 subjects received the preservative-free version of Composition C, and 27 received the preservative-free vehicle. All treatment groups had similar baseline disease characteristics with respect to efficacy and safety assessments.

[0163] Safety results

[0164] Based on the review of adverse events and ocular and systemic safety parameters, no safety issues were observed that would preclude further clinical development of the test pharmaceutical compositions for the relief of redness. All three test pharmaceutical compositions were well tolerated after QID administration for up to 1 month. The comfort of instillation was rated as comfortable for all eyes and treatment groups and remained relatively stable across all visit time points and study visits. All ocular TEAEs were reported as treatment-related and were classified as mild in severity. No subject had an ocular TEAE classified as moderate or severe. The most common treatment-related ocular TEAE reported was eye disorder due to ocular irritation, which was reported in 1.8% of all subjects (1 subject [3.4%] in the 0.06% group and 1 subject [3.6%] in the 0.08% group). No other treatment-related ocular TEAEs were reported in more than 1 subject.

[0165] Efficacy Results

[0166] The primary efficacy endpoint, ocular redness as evaluated by the investigator 8 hours (480 minutes) after the study drug instillation on Day 1, was met. Compared to the vehicle group, the mean ocular redness scores were significantly reduced for all three test pharmaceutical compositions (0.06%, 0.08%, and 0.125%) after instillation on Day 1: 0.06% compared to vehicle: (LS mean difference [SE]= -0.81 [0.120], 95% CI: [-1.05, -0.57], p < 0.0001); 0.08% compared to vehicle: (LS mean difference [SE]= -0.61 [0.121], 95% CI: [-0.85, -0.37], p < 0.0001); and 0.125% compared to vehicle: (LS mean difference [SE]= -0.91 [0.121], 95% CI: [-1.15, -0.67], p < 0.0001), thus demonstrating superiority in the relief of ocular redness caused by mild ocular irritation.

[0167] In addition to those modifications described herein, various modifications of the subject matter will be apparent to those skilled in the art in light of the foregoing description. 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 non-U.S. patents, patent application publications, international patent application publications, GenBank accession numbers, etc.) is hereby incorporated 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) to no more than 0.2% (w / v).

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

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

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

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

6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a liquid with a viscosity of 1-20 cP.

7. 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, carbomer, hyaluronic acid and hydroxypropyl guar gum.

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

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

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

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition comprises citric acid and sodium citrate.

12. The pharmaceutical composition of claim 1, further comprising a tonicity adjuster in an amount sufficient to provide the pharmaceutical composition with an osmotic pressure of 260 to 330 mOsm / kg based on the total weight of the pharmaceutical composition.

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

14. The pharmaceutical composition of claim 1, wherein the pH value of the pharmaceutical composition is 5.8 to 7.

8.

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

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

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

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

3.

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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