Methods and compositions for the treatment of presbyopia, mydriasis, and other eye disorders

Abstract

The present invention provides methods, compositions, and kits containing alpha-adrenergic antagonists, such as phentolamine, for use in monotherapy or as part of a combination therapy to treat patients suffering from presbyopia, mydriasis, and / or other ocular disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 751,391, filed October 26, 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention provides methods, compositions, and kits containing alpha-adrenergic antagonists, such as phentolamine, for use in monotherapy or as part of a combination therapy to treat patients suffering from presbyopia, mydriasis, and / or other ocular disorders. [Background technology]

[0003] Presbyopia is an age-related eye disorder that results in the inability to focus on nearby objects. Presbyopia is typically caused by a hardening of the eye's lens, which reduces its ability to flex. People often first notice the effects of presbyopia at about age 40, and the effects become increasingly noticeable over the following two decades. The effects of presbyopia can have a significant negative impact on quality of life, for example, interfering with activities that involve reading.

[0004] Existing treatments for presbyopia are not effective for all patients and / or have undesirable properties. A common treatment for presbyopia is the use of corrective lenses (e.g., reading glasses or bifocals), which must be carried by the patient. In addition, bifocal or multifocal lenses, including contact lenses, can be difficult to use, especially when performing tasks that require frequent changes between viewing near and far objects. Monovision treatment approaches, in which one eye is optimized for distance vision and lenses or surgical methods compensate for presbyopia in the other eye, can result in impaired depth perception and disorientation. Surgical approaches such as LASIK and corneal inlays also present all the risks inherent in surgical procedures. Despite ongoing research, there are currently no non-invasive, pharmacological treatments for presbyopia approved as safe and effective by the U.S. Food and Drug Administration.

[0005] Mydriasis is an eye disorder characterized by abnormally dilated pupils, often caused by one or more of disease, trauma, or pharmacological agents. The pharmacological agent may be, for example, a drug administered to the eye to cause pupil dilation as part of an eye examination. Alternatively, the pharmacological agent may be a drug administered to the patient for other reasons, and may be a single or multiple doses of the drug administered to the patient. Adverse effects of mydriasis may include sensitivity to light or inability to focus, especially in bright environments. Existing treatments for mydriasis vary based on the cause of mydriasis, but are not effective for all patients and / or have undesirable properties. One treatment for mydriasis described in the literature is REV-EYES™ (dapiprazole hydrochloride ophthalmic solution). A typical administration protocol for REV-EYES™ is to administer two drops of ophthalmic solution to the patient's eye, followed by another two drops of ophthalmic solution five minutes later. Some drawbacks of REV-EYES™ are that it is reported to cause discomfort to patients, a noticeable burning sensation upon administration, and noticeable redness of the eye. There is a need for better treatments for pupil dilation.

[0006] The present invention addresses the aforementioned need for methods and compositions for treating patients suffering from presbyopia, mydriasis, and other ocular disorders while minimizing undesirable side effects, and the invention provides other related advantages. Summary of the Invention

[0007] The present invention provides methods, compositions, and kits containing an α-adrenergic antagonist such as phentolamine for use in monotherapy or as part of a combination therapy to treat patients suffering from presbyopia, mydriasis, and / or other eye disorders. The α-adrenergic antagonist such as phentolamine is preferably administered topically to the patient's eye in the form of a liquid aqueous ophthalmic formulation. Desirably, the α-adrenergic antagonist is administered to the patient once a day, alone or in combination with an additional agent, to reduce the patient's pupil diameter, e.g., to have a pupil diameter of less than 2 mm, 1.8 mm, or 1.6 mm, or to have a pupil diameter reduction of at least 1 mm, 2 mm, 3 mm, or more. In certain embodiments, the α-adrenergic antagonist is administered to the patient once a day, alone or in combination with an additional agent, to reduce the patient's pupil diameter, e.g., to have a pupil diameter of less than 3.0, 2.8, 2.6, 2.4, or 2.2 mm. Such reduction in pupil diameter by the α-adrenergic antagonist provides therapeutic benefit to patients suffering from presbyopia or mydriasis. The reduction in pupil diameter may be characterized according to the percentage reduction in pupil diameter by administering the α-adrenergic antagonist, such as when the reduction in pupil diameter is at least 5%, 10%, 15%, 20%, 30%, or 40%. One benefit of the therapeutic methods described herein is that the patient may experience improved visual performance, for example, an improvement in the patient's ability to see clearly and / or distinguish between an object and its background. The improved visual performance may include improved visual performance at near and far distances. Another benefit of the therapeutic methods described herein is that there are methods that provide a once-daily administration protocol, which is easier for the patient than administration protocols that require administration of the therapeutic agent(s) multiple times a day. Yet another benefit of the treatment methods described herein is that some methods provide rapid onset of treatment, e.g., therapeutic benefit can be observed as early as about 30 minutes after administration of an alpha-adrenergic antagonist, such as phentolamine, to a patient's eye.In certain embodiments, the therapeutic benefit can be observed within 30 to 60 minutes after administration of an alpha-adrenergic antagonist, such as, for example, phentolamine, to the patient's eye. In certain embodiments, the therapeutic benefit can be observed as early as 1 hour after administration of an alpha-adrenergic antagonist, such as, for example, phentolamine, to the patient's eye. Exemplary aspects and embodiments of the invention are described below.

[0008] One aspect of the present invention provides a method for treating presbyopia in a patient. The method includes administering a dosage of an α-adrenergic antagonist to an eye of a patient in need thereof in an amount effective to thereby treat presbyopia, the dosage being administered to the eye no more than once a day. The dosage may be administered at or near the patient's bedtime. One benefit of such an administration protocol is to minimize the ocular redness experienced by the patient during the patient's waking hours while achieving the reduction in pupil diameter desired for the treatment of presbyopia. In certain embodiments, the dosage contains phentolamine mesylate.

[0009] Another aspect of the present invention provides a method for treating presbyopia in a patient while minimizing ocular redness during the patient's waking hours. The method includes administering a dose of an alpha-adrenergic antagonist to an eye of a patient in need thereof only at or near the patient's bedtime, in an amount effective to thereby treat presbyopia. One benefit of the administration protocol is to minimize ocular redness experienced by the patient during the patient's waking hours, while achieving a reduction in pupil diameter desired for treating presbyopia. In certain embodiments, the dose contains phentolamine mesylate. In certain embodiments, the method further includes administering to said eye of the patient an additional agent that promotes the constriction of the patient's pupil or improves visual performance. In certain embodiments, the method further includes administering to said eye of the patient an additional agent that promotes the constriction of the patient's pupil. In certain embodiments, the method further includes administering to said eye of the patient an additional agent that improves visual performance. In other embodiments, the alpha-adrenergic antagonist is the only agent administered to treat presbyopia.

[0010] Another aspect of the present invention provides a method for treating presbyopia in a patient according to a monotherapy treatment regimen. The method comprises administering a dosage of a single therapeutic agent to an eye of a patient in need thereof in an amount effective for treating presbyopia, the single therapeutic agent being an α-adrenergic antagonist. The dosage may be administered to the eye of the patient according to a specific administration protocol, such as administration to the eye of the patient once a day, which may be, for example, at or near the patient's bedtime. Such an administration protocol may require, for example, that the dosage be administered to the eye of the patient for at least 3 or 7 consecutive days. In a specific embodiment, the single therapeutic agent is phentolamine mesylate.

[0011] Another aspect of the present invention provides a method of treating mydriasis in a patient. The method comprises administering to an eye of a patient in need thereof a dosage of an α-adrenergic antagonist in an amount effective to thereby treat mydriasis. In certain embodiments, the mydriasis is due to the patient receiving one or more of an adrenaline or a parasympatholytic agent. In certain embodiments, the mydriasis is due to the patient receiving one or more of an α agonist, a TAAR1 agonist, or an NSAID. In certain embodiments, the mydriasis is due to the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, phenylephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the mydriasis is due to the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, flurbiprofen, suprofen, hydroxyamphetamine, phenylephrine, cyclopentolate, ketorolac, or pharma- ceutically acceptable salts thereof. In certain embodiments, the single therapeutic agent is phentolamine mesylate.

[0012] The present invention also provides for reducing eye redness by administering an α-adrenergic antagonist.In certain embodiments, the method further comprises administering an agent that reduces eye redness.Exemplary agents that reduce eye redness include brimonidine, tetrahydrozoline, oxymetazoline, naphthazoline, or their pharma- ceutical acceptable salts, such as LUMIFY®, a commercially available ophthalmic solution that contains brimonidine tartrate (0.025% weight / weight).

[0013] Another aspect of the present invention provides a pharmaceutical composition comprising an alpha-adrenergic antagonist and a second therapeutic agent selected from the group consisting of muscarinic acetylcholine receptor agonists, alpha-2 adrenergic agonists, prostaglandins, and lipoic acid choline ester. Preferably, the pharmaceutical composition is formulated for ophthalmic administration. [Brief description of the drawings]

[0014] [Figure 1] 1 shows exemplary ocular redness measured according to (1) the CCLRU Redness Scale, and (2) the NYX-001 Redness Scale. [Diagram 2] 1 is a graph showing the observed changes in pupil diameter observed in the clinical trial described in Example 5. [Diagram 3] 1 is a graph showing observed ocular redness observed in the clinical trial described in Example 5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present invention provides methods, compositions, and kits containing an α-adrenergic antagonist such as phentolamine for use in monotherapy or as part of a combination therapy to treat patients suffering from presbyopia, mydriasis, and / or other eye disorders. The α-adrenergic antagonist such as phentolamine is preferably administered topically to the patient's eye in the form of a liquid aqueous ophthalmic formulation. Desirably, the α-adrenergic antagonist is administered to the patient once a day, alone or in combination with an additional agent, to reduce the patient's pupil diameter, e.g., to have a pupil diameter of less than 2 mm, 1.8 mm, or 1.6 mm, or to have a pupil diameter reduction of at least 1 mm, 2 mm, 3 mm, or more. In certain embodiments, the α-adrenergic antagonist is administered to the patient once a day, alone or in combination with an additional agent, to reduce the patient's pupil diameter, e.g., to have a pupil diameter of less than 3.0, 2.8, 2.6, 2.4, or 2.2 mm. The reduction in pupil diameter may be characterized according to the percent reduction in pupil diameter by administering the α-adrenergic antagonist, such as when the reduction in pupil diameter is at least 5%, 10%, 15%, 20%, 30%, or 40%. Such reduction in pupil diameter by the α-adrenergic antagonist provides a therapeutic benefit to patients suffering from presbyopia or mydriasis. One benefit of the therapeutic methods described herein is that the patient may experience improved visual performance, for example, an improvement in the patient's ability to see clearly and / or distinguish between an object and its background. The improved visual performance may include improved visual performance at near and far distances. Another benefit of the therapeutic methods described herein is that the methods provide a once-daily administration protocol, which is easier for the patient than administration protocols that require administration of the therapeutic agent(s) multiple times a day. Yet another benefit of the treatment methods described herein is that some methods provide rapid onset of treatment, e.g., therapeutic benefit can be observed as early as about 30 minutes after administration of an alpha-adrenergic antagonist, such as phentolamine, to a patient's eye.In certain embodiments, the therapeutic benefit can be observed within 30 to 60 minutes after administration of an alpha-adrenergic antagonist, such as, for example, phentolamine, to the patient's eye. In certain embodiments, the therapeutic benefit can be observed as early as 1 hour after administration of an alpha-adrenergic antagonist, such as, for example, phentolamine, to the patient's eye. Exemplary aspects and embodiments of the invention are described below. Various aspects of the invention are presented in the following sections, however, aspects of the invention described in one particular section are not limited to any particular section.

[0016] definition To facilitate the understanding of this invention, several terms and phrases are defined below.

[0017] As used herein, the terms "a," "an," and "the" mean "one or more" and include plurals unless the context is inappropriate.

[0018] As used herein, the term "patient" refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans.

[0019] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result. Unless otherwise specified, an effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treating" includes any effect that results in the improvement of, e.g., lowering, reducing, modulating, ameliorating, or eliminating, or ameliorating the symptoms of, a condition, disease, disorder, or the like.

[0020] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with a carrier, inert or active, that makes the composition particularly suitable for therapeutic use in vivo or ex vivo.

[0021] As used herein, the term "pharmaceutical acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline solution, water, emulsions (such as oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Martin in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0022] As used herein, the term "pharmaceutical acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of the compound of the present invention that can be administered to a subject to provide the compound of the present invention. As known to those skilled in the art, the "salt" of the compound of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, may be used in the preparation of salts that are not themselves pharmaceutically acceptable but are useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0023] Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and bases of the formula NW3, where W is C 1~4 The compounds include those in which the aryl group is an alkyl group.

[0024] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, etc. Other examples of salts include Na + , NH4 + , and NW4 + (Wherein, W is C 1~4 and the anion of a compound of the present invention complexed with a suitable cation, such as an alkyl group.

[0025] For therapeutic use, the salts of the compounds of the invention are contemplated to be pharma- ceutically acceptable. However, salts of acids and bases that are non-pharma-ceutically acceptable may also find use, for example, in the preparation or purification of a pharma- ceutically acceptable compound.

[0026] The term "alkanoate" is art-recognized and refers to an alkyl-C(O)O - Refers to...

[0027] The term "alkyl" is art-recognized and includes saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl group has about 30 or fewer alkyl groups in its backbone (e.g., C1-C4 for a straight chain). 30 , C3-C for branched chains 30), or up to about 20 carbon atoms. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, or about 5, 6 or 7 carbons in the ring structure.

[0028] As used herein, the term "EV06" refers to a compound having the following chemical structure: [ka] , optical isomers, or mixtures thereof, and Z is an anion. - can be any pharma- ceutically acceptable anion. Non-limiting examples of anions include chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof), succinate, benzoate, and anions of amino acids such as glutamic acid. In some embodiments, the anion is chloride. In some embodiments, the anion is tartrate.

[0029] Throughout the description, when compositions and kits are described as having, including, or comprising certain components, or processes and methods are described as having, including, or comprising certain steps, it is further contemplated that there are compositions and kits of the invention that consist essentially of, or consist of, the recited components, and there are processes and methods according to the invention that consist essentially of, or consist of, the recited processing steps.

[0030] As a general matter, compositions specifying percentages are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, it is controlled by the preceding definition of the variable.

[0031] I. Treatment method The present invention provides a method for treating a patient suffering from presbyopia, mydriasis, and / or other ocular disorders by administering an alpha-adrenergic antagonist, such as phentolamine, to the patient's eye. The alpha-adrenergic antagonist is preferably administered topically to the patient's eye in the form of a liquid aqueous ophthalmic formulation. Various aspects and embodiments of the treatment method are described in the following sections. The sections are arranged for convenience, and information in one section is not limited to that section and may be applied to the methods in other sections.

[0032] A. First Method One aspect of the invention provides a method of treating presbyopia in a patient, comprising administering to an eye of a patient in need thereof a dosage of an alpha adrenergic antagonist in an amount effective to thereby treat presbyopia, wherein the dosage is administered to the eye no more than once per day.

[0033] The method may be further characterized by additional features, such as the dosing regimen and the identity of the dose, as described in more detail below. The present invention encompasses all permutations and combinations of these features. For example, in certain embodiments, the dose is administered at or near the patient's bedtime. In certain embodiments, the dose is administered within one hour of the patient's bedtime.

[0034] In certain embodiments, the dosage comprises a pharma- ceutically acceptable salt of phentolamine.In certain embodiments, the dosage comprises phentolamine mesylate.

[0035] B. Second Method Another aspect of the invention provides a method of treating presbyopia in a patient while minimizing ocular redness during the patient's waking hours, comprising administering to the patient's eye in need thereof a dosage of an alpha adrenergic antagonist only at or near the patient's bedtime, in an amount effective to thereby treat presbyopia.

[0036] The method may be further characterized by additional features, such as the administration regimen and the administration, identity, and amount of the additional agent, as described in more detail below. The present invention encompasses all permutations and combinations of these features. For example, in certain embodiments, the dosage is administered to the eye no more than once a day. In certain embodiments, the dosage comprises a pharma- ceutically acceptable salt of phentolamine. In certain embodiments, the dosage comprises phentolamine mesylate.

[0037] C. The third method Another aspect of the invention provides a method of treating presbyopia in a patient, comprising administering to an eye of a patient in need thereof a dosage of an alpha adrenergic antagonist in an amount effective to thereby treat the presbyopia.

[0038] The methods may be further characterized by additional features, such as dosing regimens and the administration, identity, and amount of additional agents, as described in more detail below. The present invention encompasses all permutations and combinations of these features.

[0039] In certain embodiments, the dosage is administered to the patient daily. In certain embodiments, the dosage is administered to the patient twice a day. In certain embodiments, the dosage comprises a pharma- ceutically acceptable salt of phentolamine. In certain embodiments, the dosage comprises phentolamine mesylate.

[0040] In certain embodiments, the dosage of the alpha-adrenergic antagonist is a 1% w / w solution of phentolamine mesylate. In certain embodiments, the dosage of the alpha-adrenergic antagonist is a 1.5% w / w solution of phentolamine mesylate. In certain embodiments, the dosage of the alpha-adrenergic antagonist is a 2% w / w solution of phentolamine mesylate.

[0041] In certain embodiments, the dose is administered as a single eye drop. In certain embodiments, the dose is administered as two eye drops.

[0042] In certain embodiments, the dosage is administered to the patient as a fixed dose combination with an additional therapeutic agent, hi certain embodiments, the additional therapeutic agent is pilocarpine.

[0043] D. Additional Features of the First, Second, and Third Treatment Methods The first, second, and third methods of treatment may be further characterized according to additional features. One feature is whether an additional agent is administered (e.g., an agent that promotes pupil constriction or improves visual performance in a patient). Another feature is whether the dosage of α-adrenergic antagonist is administered sequentially or simultaneously with the additional agent.

[0044] In certain embodiments, the method further comprises administering to said eye of the patient an additional agent that promotes the constriction of the patient's pupil or improvement in visual performance. In certain embodiments, the method further comprises administering to said eye of the patient an additional agent that promotes the constriction of the patient's pupil. This desirably results in a further reduction in the patient's pupil diameter beyond that achieved when administering only an α-adrenergic antagonist. In certain embodiments, the method further comprises administering to said eye of the patient an additional agent that promotes the improvement in visual performance.

[0045] In certain embodiments, the additional agent is administered to the patient's eye simultaneously with the dose of the alpha adrenergic antagonist, hi certain embodiments, the additional agent is administered to the patient's eye sequentially, before or after the dose of the alpha adrenergic antagonist is administered to the patient's eye.

[0046] The method may be further characterized according to the amount of the additional agent administered to the patient's eye. For example, in certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.0001 mg to about 0.001 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.001 mg to about 0.01 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 0.5 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.5 mg to about 1.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 1.0 mg to about 1.5 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 1.5 mg to about 2.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 2.0 mg to about 2.5 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 2.5 mg to about 3.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 2.5 mg to about 3.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.001 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 1.0 mg to about 2.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 0.125 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.125 mg to about 0.25 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.25 mg to about 0.50 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.50 mg to about 0.75 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.75 mg to about 1.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 1.25 mg to about 1.5 mg.

[0047] The method may be further characterized according to the identity of the additional agent. In certain embodiments, the additional agent improves visual performance. In certain embodiments, the additional agent promotes the constriction of the patient's pupil. In certain embodiments, the additional agent is selected from the group consisting of a muscarinic acetylcholine receptor agonist, an alpha-2 adrenergic agonist, a prostaglandin, and a lipoic acid choline ester.

[0048] In certain embodiments, the additional agent is a muscarinic acetylcholine receptor agonist.

[0049] In certain embodiments, the additional agent is pilocarpine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is pilocarpine hydrochloride. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 0.3 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.2 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.3 mg to about 0.6 mg.

[0050] In certain embodiments, the additional agent is pilocarpine or a pharma- ceutically acceptable salt thereof, which is administered to the patient in the form of an ophthalmic solution. In certain embodiments, the ophthalmic solution contains pilocarpine or a pharma- ceutically acceptable salt thereof in an amount of about 0.1% w / w to about 3% w / w. In certain embodiments, the ophthalmic solution contains pilocarpine or a pharma- ceutically acceptable salt thereof in an amount of about 0.2% w / w to about 0.4% w / w. In certain embodiments, the ophthalmic solution contains pilocarpine or a pharma- ceutically acceptable salt thereof in an amount of about 1% w / w to about 2% w / w. In certain embodiments, a drop of the ophthalmic solution containing pilocarpine or a pharma- ceutically acceptable salt thereof is administered to the patient's eye.

[0051] In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising pilocarpine in an amount ranging from about 0.001% to about 0.1% weight / weight, about 0.001% to about 2% weight / weight, about 0.01% to about 2% weight / weight, or about 0.01% to about 4% weight / weight. In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising pilocarpine in an amount ranging from about 0.01%, 0.25%, 0.5%, 1%, 2%, or 4% weight / weight.

[0052] In certain embodiments, the additional agent is carbachol or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is carbachol. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.5 mg to about 2.5 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.5 mg to about 1.0 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 1.0 mg to about 1.5 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 1.2 mg.

[0053] In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising carbochol in an amount ranging from about 0.001% to about 0.1% weight / weight, about 0.001% to about 3% weight / weight, about 0.1% to about 1.5% weight / weight, or about 0.1% to about 2% weight / weight. In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising carbochol in an amount ranging from about 0.1%, 0.25%, 0.5%, 0.75%, 1.5%, 2%, 2.25%, or 3% weight / weight.

[0054] In certain embodiments, the additional agent is bethanechol or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is a bethanechol salt. In certain embodiments, the additional agent is bethanechol chloride. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 3 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 1 mg to about 2 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 1.2 mg.

[0055] In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising bethanechol chloride in an amount ranging from about 0.001% to about 0.1% weight / weight, about 0.001% to about 0.01% weight / weight, or about 0.01% to about 0.1% weight / weight. In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising bethanechol chloride in an amount ranging from about 0.001%, 0.01%, or 0.1% weight / weight.

[0056] In certain embodiments, the additional agent is aceclidine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is aceclidine hydrochloride. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 4 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 0.01 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1.5 mg.

[0057] In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising aceclidine hydrochloride in an amount ranging from about 0.001% to about 0.1% weight / weight, about 0.001% to about 1.5% weight / weight, about 0.001% to about 3% weight / weight, about 1.35% to about 1.65% weight / weight, or about 0.01% to about 2% weight / weight. In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising aceclidine hydrochloride in an amount ranging from about 0.01%, 0.1%, 0.25%, 0.5%, 1%, 1.5%, 2%, 3%, or 4% weight / weight.

[0058] In certain embodiments, the additional agent is oxotremorine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is oxotremorine. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 0.3 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.2 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.3 mg to about 0.6 mg.

[0059] In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising oxotremorine in an amount ranging from about 0.001% to about 0.1% weight / weight, about 0.001% to about 2% weight / weight, about 0.01% to about 2% weight / weight, or about 0.01% to about 4% weight / weight. In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising oxotremorine in an amount ranging from about 0.01%, 0.25%, 0.5%, 1%, 2%, or 4% weight / weight.

[0060] In certain embodiments, the additional agent is methacholine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is methacholine. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 0.3 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.2 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.3 mg to about 0.6 mg.

[0061] In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising methacholine in an amount ranging from about 0.001% to about 0.1% weight / weight, about 0.001% to about 2% weight / weight, about 0.01% to about 2% weight / weight, or about 0.01% to about 4% weight / weight. In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising methacholine in an amount ranging from about 0.01%, 0.25%, 0.5%, 1%, 2%, or 4% weight / weight.

[0062] In certain embodiments, the additional agent is muscarine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is muscarine. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1.0 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 0.3 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.2 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.3 mg to about 0.6 mg.

[0063] In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising muscarine in an amount ranging from about 0.001% to about 0.1% weight / weight, about 0.001% to about 2% weight / weight, about 0.01% to about 2% weight / weight, or about 0.01% to about 4% weight / weight. In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising muscarine in an amount ranging from about 0.01%, 0.25%, 0.5%, 1%, 2%, or 4% weight / weight.

[0064] In certain embodiments, the additional agent is an alpha-2 adrenergic agonist. In certain embodiments, the additional agent is brimonidine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is brimonidine tartrate. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 4 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 0.1 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1 mg.

[0065] In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising brimonidine tartrate in an amount ranging from about 0.01% to about 4% weight / weight, about 0.02% to about 4% weight / weight, about 0.02% to about 0.2% weight / weight, about 0.2% to about 3% weight / weight, or about 0.01% to about 2% weight / weight. In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising brimonidine tartrate in an amount ranging from about 0.01%, 0.02%, 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 3%, or 4% weight / weight.

[0066] In certain embodiments, the additional agent is carbamoylcholine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 4 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 0.1 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1 mg.

[0067] In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising carbamoylcholine or a pharma- ceutically acceptable salt thereof in an amount ranging from about 0.01% to about 4% weight / weight, about 0.02% to about 4% weight / weight, about 0.02% to about 0.2% weight / weight, about 0.2% to about 3% weight / weight, or about 0.01% to about 2% weight / weight. In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising carbamoylcholine or a pharma- ceutically acceptable salt thereof in an amount ranging from about 0.01%, 0.02%, 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 3%, or 4% weight / weight.

[0068] In certain embodiments, the additional agent is physostigmine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 4 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 0.1 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1 mg.

[0069] In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising physostigmine or a pharma- ceutically acceptable salt thereof in an amount ranging from about 0.01% to about 4% weight / weight, about 0.02% to about 4% weight / weight, about 0.02% to about 0.2% weight / weight, about 0.2% to about 3% weight / weight, or about 0.01% to about 2% weight / weight. In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising physostigmine or a pharma- ceutically acceptable salt thereof in an amount ranging from about 0.01%, 0.02%, 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 3%, or 4% weight / weight.

[0070] In certain embodiments, the additional agent is echothiophate or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 4 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 0.1 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1 mg.

[0071] In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising echothiophate or a pharma- ceutically acceptable salt thereof in an amount ranging from about 0.01% to about 4% weight / weight, about 0.02% to about 4% weight / weight, about 0.02% to about 0.2% weight / weight, about 0.2% to about 3% weight / weight, or about 0.01% to about 2% weight / weight. In certain embodiments, a drop of an ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising echothiophate or a pharma- ceutically acceptable salt thereof in an amount ranging from about 0.01%, 0.02%, 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 3%, or 4% weight / weight.

[0072] In certain embodiments, the additional agent is acetylcholine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 4 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.01 mg to about 0.1 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1 mg.

[0073] In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising acetylcholine or a pharma- ceutically acceptable salt thereof in an amount ranging from about 0.01% to about 4% weight / weight, about 0.02% to about 4% weight / weight, about 0.02% to about 0.2% weight / weight, about 0.2% to about 3% weight / weight, or about 0.01% to about 2% weight / weight. In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising acetylcholine or a pharma- ceutically acceptable salt thereof in an amount ranging from about 0.01%, 0.02%, 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 3%, or 4% weight / weight.

[0074] In certain embodiments, the additional agent is a prostaglandin. In certain embodiments, the additional agent is dinoprostone or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is dinoprostone. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 4 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.1 mg to about 1 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 1 mg to about 3 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.001 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.0025 mg to about 0.01 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 0.0025 mg. In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising dinoprostone in an amount of about 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, or 0.01% weight / weight.

[0075] In certain embodiments, the additional agent is latanaprost or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is latanaprost. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.001 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.0025 mg to about 0.01 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 0.0025 mg. In certain embodiments, one drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising latanaprost in an amount of about 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, or 0.01% weight / weight. In certain embodiments, the additional agent is latanaprost, which is administered to the patient's eye in an amount ranging from about 0.5 to about 1.0 micrograms, about 1.0 to about 1.5 micrograms, about 1.5 to about 2.0 micrograms of latanaoprost, or about 2.0 to about 5.0 micrograms of latanaoprost.

[0076] In certain embodiments, the additional agent is bimatoprost or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is bimatoprost. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.001 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.001 mg to about 0.003 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 0.002 mg. In certain embodiments, one drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising bimatoprost in an amount of about 0.001%, 0.005%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, or 0.05% weight / weight.

[0077] In certain embodiments, the additional agent is travoprost or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is travoprost. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.001 mg to about 0.1 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.001 mg to about 0.01 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount of about 0.005 mg. In certain embodiments, a drop of the ophthalmic formulation is administered to the patient's eye, the ophthalmic formulation comprising travoprost in an amount of about 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, or 0.01% weight / weight.

[0078] In certain embodiments, the additional agent is EV06 or a pharma- ceutically acceptable salt thereof. In certain embodiments, the additional agent is EV06 chloride. In certain embodiments, the additional agent is EV06 tartrate. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.25 mg to about 1.2 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.25 mg to about 0.5 mg. In certain other embodiments, the additional agent is administered to the patient's eye in an amount ranging from about 0.5 mg to about 0.75 mg. In certain embodiments, the additional agent is administered to the patient's eye in an amount of about 0.6 mg.

[0079] In certain embodiments, the additional agent is a cholinesterase inhibitor.

[0080] In certain embodiments, an additional therapeutic agent is administered to the patient's eye. In such embodiments, the method further comprises administering to the patient's eye an alpha adrenergic agonist, such as brimonidine or a pharma- ceutically acceptable salt thereof.

[0081] E. The fourth method Another aspect of the present invention provides a method of treating presbyopia in a patient according to a monotherapy treatment regimen, comprising administering to an eye of the patient in need thereof a dosage of a single therapeutic agent in an amount effective to treat presbyopia, wherein the single therapeutic agent is an alpha-adrenergic antagonist.

[0082] The methods may be further characterized by additional features, such as dosing regimens and dosage uniformity, as described in more detail below. The present invention encompasses all permutations and combinations of these features.

[0083] Thus, in certain embodiments, the dosage is administered at or near the patient's bedtime. In certain embodiments, the dosage is administered within one hour of the patient's bedtime. In certain embodiments, the dosage comprises a pharma- ceutically acceptable salt of phentolamine. In certain embodiments, the dosage comprises phentolamine mesylate.

[0084] In certain embodiments, the single therapeutic agent dose is a 1% w / w phentolamine mesylate solution. In certain embodiments, the single therapeutic agent dose is a 1.5% w / w phentolamine mesylate solution. In certain embodiments, the single therapeutic agent dose is a 2% w / w phentolamine mesylate solution.

[0085] In certain embodiments, the dose is administered as a single eye drop. In certain embodiments, the dose is administered as two eye drops.

[0086] F. Fifth Method Another aspect of the invention provides a method of treating mydriasis in a patient, comprising administering to an eye of a patient in need thereof a dosage of an alpha adrenergic antagonist in an amount effective to thereby treat mydriasis.

[0087] The method may be further characterized by additional features such as the cause of the pupil dilation and the amount of reduction in pupil diameter experienced by the patient. The present invention encompasses all permutations and combinations of these features.

[0088] Thus, in certain embodiments, the pupil dilation is due to the patient receiving a drug that causes pupil dilation. In certain embodiments, the pupil dilation is due to the patient receiving one or more of adrenaline or parasympatholytic agents. In certain embodiments, the pupil dilation is due to the patient receiving one or more of alpha agonists, TAAR1 agonists, or NSAIDs. In certain embodiments, the pupil dilation is due to the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, flurbiprofen, suprofen, hydroxyamphetamine, phenylephrine, cyclopentolate, ketorolac, or pharmaceutically acceptable salts thereof. In certain embodiments, the pupil dilation is due to the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, phenylephrine, or pharmaceutically acceptable salts thereof. In certain embodiments, the pupil dilation is due to the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving atropine, homatropine, scopolamine, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving cyclopentolate or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving tropicamide or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving phenylephrine or a pharma- ceutically acceptable salt thereof.

[0089] In certain embodiments, the pupil dilation is due to the patient receiving flurbiprofen or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving flurbiprofen sodium. In certain embodiments, the pupil dilation is due to the patient receiving suprofen or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving hydroxyamphetamine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving tropicamide or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving cyclopentolate or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving ketorolac or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pupil dilation is due to the patient receiving hydroxyamphetamine hydrobromide and tropicamide, sold as PAREMYD®. In certain embodiments, the pupil dilation occurs when the patient receives cyclopentolate hydrochloride and phenylephrine hydrochloride, sold as CYCLOMYDRIL®. In certain embodiments, the pupil dilation occurs when the patient receives scopolamine and phenylephrine. In certain embodiments, the pupil dilation occurs when the patient receives ketorolac and phenylephrine, sold as OMIDRIA®.

[0090] The method can be further characterized according to the administration regimen.For example, in certain embodiments, the dosage is administered to the eye no more than once a day.In certain embodiments, the dosage is administered to the eye no more than once every two days.In certain embodiments, the dosage is administered to the patient's eye after the patient completes an eye examination in which a pupil dilator is administered to the patient's eye.

[0091] The method may be further characterized according to the amount of reduction in pupil diameter. For example, in certain embodiments, the patient experiences at least 1 mm reduction in pupil diameter when measured under mesopic conditions, relative to the diameter of the pupil of a patient under the same mesopic conditions but not receiving the dose. In certain embodiments, the patient experiences at least 2 mm reduction in pupil diameter when measured under mesopic conditions, relative to the diameter of the pupil of a patient under the same mesopic conditions but not receiving the dose. In certain embodiments, the patient experiences at least 3 mm reduction in pupil diameter when measured under mesopic conditions, relative to the diameter of the pupil of a patient under the same mesopic conditions but not receiving the dose. In certain embodiments, the patient experiences at least 4 mm, 5 mm, or more reduction in pupil diameter when measured under mesopic conditions, relative to the diameter of the pupil of a patient under the same mesopic conditions but not receiving the dose. In certain other embodiments, the patient experiences a reduction in pupil diameter, when measured under mesopic conditions, ranging from about 0.5 mm to about 5 mm relative to the pupil diameter of a patient not receiving the dose, but under the same mesopic conditions.

[0092] In certain embodiments, the patient experiences a reduction in pupil diameter of at least 1 mm when measured under photopic conditions relative to the diameter of the pupil of a patient not receiving the dose, but under the same photopic conditions. In certain embodiments, the patient experiences a reduction in pupil diameter of at least 2 mm when measured under photopic conditions relative to the diameter of the pupil of a patient not receiving the dose, but under the same photopic conditions. In certain embodiments, the patient experiences a reduction in pupil diameter of at least 3 mm when measured under photopic conditions relative to the diameter of the pupil of a patient not receiving the dose, but under the same photopic conditions. In certain embodiments, the patient experiences a reduction in pupil diameter of at least 4 mm, 5 mm, or more when measured under photopic conditions relative to the diameter of the pupil of a patient not receiving the dose, but under the same photopic conditions. In certain other embodiments, the patient experiences a reduction in pupil diameter of about 0.5 mm to about 5 mm when measured under photopic conditions relative to the diameter of the pupil of a patient not receiving the dose, but under the same photopic conditions.

[0093] In certain embodiments, the patient experiences a reduction in pupil diameter of at least 1 mm relative to the diameter of the pupil of a patient under the same conditions (e.g., mesopic or photopic vision) but not receiving the dose. In certain embodiments, the patient experiences a reduction in pupil diameter of at least 2 mm relative to the diameter of the pupil of a patient under the same conditions (e.g., mesopic or photopic vision) but not receiving the dose. In certain embodiments, the patient experiences a reduction in pupil diameter of at least 3 mm relative to the diameter of the pupil of a patient under the same conditions (e.g., mesopic or photopic vision) but not receiving the dose. In certain embodiments, the patient experiences a reduction in pupil diameter of at least 4 mm, 5 mm, or more relative to the diameter of the pupil of a patient under the same conditions (e.g., mesopic or photopic vision) but not receiving the dose. In certain embodiments, the patient experiences a reduction in pupil diameter of at least 4 mm, 5 mm, or more relative to the diameter of the pupil of a patient under the same conditions (e.g., mesopic or photopic vision) but not receiving the dose. In certain other embodiments, the patient experiences a reduction in pupil diameter ranging from about 0.5 mm to about 5 mm relative to the diameter of the pupil of a patient under the same conditions (e.g., mesopic or photopic vision) but not receiving the dose.

[0094] G. 6th Method Another aspect of the invention provides a method of preventing progressive myopia in a patient, comprising administering to an eye of a patient in need thereof a dosage of an alpha adrenergic antagonist in an amount effective to thereby prevent progressive myopia.

[0095] The method can be further characterized by additional features. For example, in certain embodiments, the patient is an adult human. In certain other embodiments, the patient is a pediatric human. In certain embodiments, the method further comprises administering to the eye of the patient one or more additional agents as described herein. The present invention encompasses all permutations and combinations of these features.

[0096] H. Additional Features of the First, Second, Third, and Fourth Treatment Methods Additional features that may characterize the first, second, third, and fourth methods of treatment described herein (e.g., those described in Parts A-D above) are provided below and include, for example, the degree of ocular redness, the dosing regimen of the alpha-adrenergic antagonist, the duration of therapeutic effect on presbyopia, and the pupil diameter in the eye that received the dose. A more detailed description of such features is provided below. The present invention encompasses all permutations and combinations of these features.

[0097] Degree of eye redness The method may be further characterized according to the degree of eye redness experienced by the patient. The degree of eye redness may be evaluated and characterized using procedures described in the literature, such as the Cornea and Contact Lens Research Unit (CCLRU) Redness Scale developed by the School of Optometry, University of New South Wales. See, for example, Terry et al. in Optom.Vis.Sci. (1993) vol.70, pages 234-243, and Pult et al. in Ophthal.Physiol.Opt. (2008) vol.28, pages 13-20. The CCLRU Redness Scale evaluates eye redness on a four-point scale: (0) no eye redness, (1) very slight eye redness, (2) slight eye redness, (3) moderate eye redness, and (4) severe eye redness. See FIG. 1 for a diagram of the eye redness scale.

[0098] In certain embodiments, the patient experiences an increase in eye redness of no more than 2 grades as measured using the CCLRU Redness Rating Scale during the patient's waking hours compared to the level of eye redness in patients not receiving that dose of the α-adrenergic antagonist. In certain embodiments, the patient experiences an increase in eye redness of no more than 1 grade as measured using the CCLRU Redness Rating Scale during the patient's waking hours compared to the level of eye redness in patients not receiving that dose of the α-adrenergic antagonist. In certain embodiments, any increase in eye redness experienced by the patient is less than 1 grade as measured using the CCLRU Redness Rating Scale during the patient's waking hours compared to the level of eye redness in patients not receiving that dose of the α-adrenergic antagonist.

[0099] Alpha-adrenergic antagonist dosing regimens The methods may be further characterized according to the administration regimen of the alpha-adrenergic antagonist. For example, in certain embodiments, a dose of the alpha-adrenergic antagonist is administered daily.

[0100] In certain embodiments, the dose of the alpha adrenergic antagonist is administered for at least three consecutive days. In certain embodiments, the dose of the alpha adrenergic antagonist is administered for at least seven consecutive days. In certain embodiments, the dose of the alpha adrenergic antagonist is administered for at least fourteen consecutive days.

[0101] In certain embodiments, the dose is administered once daily. In certain embodiments, the dose is administered multiple times daily, such as two or three times daily.

[0102] In certain embodiments, the dose is administered as a single eye drop. In certain embodiments, the dose is administered as two eye drops.

[0103] Duration of therapeutic effect for presbyopia The method may be further characterized according to the duration of the therapeutic effect on presbyopia. For example, in certain embodiments, the method provides a therapeutic effect on presbyopia for a duration of at least 6 hours. In certain embodiments, the method provides a therapeutic effect on presbyopia for a duration of at least 12 hours. In certain embodiments, the method provides a therapeutic effect on presbyopia for a duration of at least 16 hours. In certain embodiments, the method provides a therapeutic effect on presbyopia for a duration of at least 18 hours. In certain embodiments, the method provides a therapeutic effect on presbyopia for a duration of at least 20 hours. In certain embodiments, the method provides a therapeutic effect on presbyopia for a duration of at least 24 hours. In certain embodiments, the method provides a therapeutic effect on presbyopia for a duration of at least 36 hours. In certain embodiments, the method provides a therapeutic effect on presbyopia for a duration of at least 48 hours.

[0104] Improved vision for patients The method may be further characterized according to the improvement in the patient's visual acuity. For example, in certain embodiments, the method provides an improvement in visual acuity characterized by at least one line improvement in the patient's visual acuity measured using an eye chart. In certain embodiments, the method results in an improvement in visual acuity characterized by at least two lines improvement in the patient's visual acuity measured using an eye chart. In certain embodiments, the method results in an improvement in visual acuity characterized by at least three lines improvement in the patient's visual acuity measured using an eye chart. In certain embodiments, the method results in an improvement in visual acuity characterized by four or more lines improvement in the patient's visual acuity measured using an eye chart. In certain embodiments, the eye chart is a Snellen chart. In certain other embodiments, the eye chart is a Jaeger chart. In certain other embodiments, the eye chart is a Rosenbaum chart or an ETDRS chart. In certain embodiments, the improvement in visual acuity is measured at a near distance (e.g., about 1, 2, or 3 feet). In certain embodiments, the improvement in visual acuity is measured at a far distance (e.g., about 20, 25, or 30 feet). In certain embodiments, the improvement in visual acuity is an improvement in near vision. In certain embodiments, the improved vision is improved distance vision. In certain embodiments, the improved vision is (i) improved near vision, and (ii) improved distance vision.

[0105] The method may be further characterized according to the duration of the improvement in the patient's vision. In certain embodiments, the patient experiences said improvement for a duration of at least 6 hours. In certain embodiments, the patient experiences said improvement for a duration of at least 12 hours. In certain embodiments, the patient experiences said improvement for a duration of at least 18 hours. In certain embodiments, the patient experiences said improvement for a duration of at least 20 hours. In certain embodiments, the patient experiences said improvement for a duration of at least 24 hours. In certain embodiments, the patient experiences said improvement for a duration of at least 30 hours. In certain embodiments, the patient experiences said improvement for a duration of at least 48 hours.

[0106] Pupil diameter in the dose-receiving eye The method may be further characterized according to the pupil diameter in the eye that has received the dose and the duration that the pupil diameter is maintained. For example, in certain embodiments, as a result of administration, the patient experiences an effect of having a pupil diameter of less than 3.0 in the eye that has received the dose when measured under photopic conditions. In certain embodiments, as a result of administration, the patient experiences an effect of having a pupil diameter of less than 2.8 in the eye that has received the dose when measured under photopic conditions. In certain embodiments, as a result of administration, the patient experiences an effect of having a pupil diameter of less than 2.6 mm in the eye that has received the dose when measured under photopic conditions. In certain embodiments, as a result of administration, the patient experiences an effect of having a pupil diameter of less than 2.4 mm in the eye that has received the dose when measured under photopic conditions. In certain embodiments, as a result of administration, the patient experiences an effect of having a pupil diameter of less than 2.2 mm in the eye that has received the dose when measured under photopic conditions. In certain embodiments, the patient experiences an effect of having a pupil diameter of less than 2 mm in the eye that has received the dose when measured under photopic conditions. In certain embodiments, as a result of administration, the patient experiences an effect of having a pupil diameter of less than 1.9 mm in the eye that has received the dose, when measured under photopic conditions. In certain embodiments, as a result of administration, the patient experiences an effect of having a pupil diameter of less than 1.8 mm in the eye that has received the dose, when measured under photopic conditions. In certain embodiments, as a result of administration, the patient experiences an effect of having a pupil diameter of less than 1.7 mm in the eye that has received the dose, when measured under photopic conditions. In certain embodiments, as a result of administration, the patient experiences an effect of having a pupil diameter of less than 1.6 mm in the eye that has received the dose, when measured under photopic conditions.

[0107] In certain embodiments, the patient experiences the effect for a duration of at least 6 hours. In certain embodiments, the patient experiences the effect for a duration of at least 12 hours. In certain embodiments, the patient experiences the effect for a duration of at least 18 hours. In certain embodiments, the patient experiences the effect for a duration of at least 20 hours. In certain embodiments, the patient experiences the effect for a duration of at least 24 hours. In certain embodiments, the patient experiences the effect for a duration of at least 30 hours. In certain embodiments, the patient experiences the effect for a duration of at least 48 hours.

[0108] Reducing intraocular pressure Another benefit that may be experienced by the patient is a reduction in intraocular pressure in the eye receiving the alpha-adrenergic antagonist.

[0109] I. General Considerations Regarding Treatment Methods General considerations that may be applied to the methods of treatment described herein (e.g., those described in Parts A-H above) are provided below, including, for example, the identity of the α-adrenergic antagonist, the dosage of the α-adrenergic antagonist, the formulation of the dosage, and the patient population that may derive particular benefit from the methods of treatment. A more detailed description of such features is provided below. The present invention encompasses all permutations and combinations of these features.

[0110] Identity of α-adrenergic antagonists The method can be further characterized according to the identity of the α-adrenergic antagonist. For example, in certain embodiments, the α-adrenergic antagonist is phentolamine, phenoxybenzamine, tolazoline, trazodone, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin, silodosin, atipamezole, idazoxan, mirtazapine, yohimbine, fenoldopam, thymoxamine, or a pharmaceutically acceptable salt of any of the above. In certain embodiments, the α-adrenergic antagonist is phentolamine or a pharmaceutically acceptable salt thereof. In certain embodiments, the α-adrenergic antagonist is a pharmaceutically acceptable salt of phentolamine. In certain embodiments, the α-adrenergic antagonist is phentolamine mesylate. In certain other embodiments, the α-adrenergic antagonist is fenoldopam or a pharmaceutically acceptable salt thereof. In certain embodiments, the alpha-adrenergic antagonist is fenoldopam mesylate.

[0111] In certain embodiments, the alpha-adrenergic antagonist is a non-selective alpha-adrenergic antagonist. In certain embodiments, the alpha-adrenergic antagonist is a reversible, non-selective alpha-adrenergic antagonist.

[0112] In certain embodiments, the α-adrenergic antagonist is characterized according to its activity against a particular α-adrenergic receptor. Thus, in certain embodiments, the α-adrenergic antagonist has antagonist activity against α-1 adrenergic receptor. The activity against α-1 adrenergic receptor may be further characterized according to whether it has activity against one or more of α-1 adrenergic receptor subtypes (e.g., α-1A, α-1B, and α-1D). Thus, in certain embodiments, the α-adrenergic antagonist has antagonist activity against α-1A adrenergic receptor. In certain embodiments, the α-adrenergic antagonist has antagonist activity against α-1B adrenergic receptor. In certain embodiments, the α-adrenergic antagonist has antagonist activity against α-1D adrenergic receptor. In certain embodiments, the alpha-adrenergic antagonist has antagonist activity for each of the alpha-1 adrenergic receptor subtypes.

[0113] In certain embodiments, the α-adrenergic antagonist has antagonist activity against the α-2 adrenergic receptor. The activity against the α-2 adrenergic receptor may be further characterized according to whether there is activity against one or more of the α-2 adrenergic receptor subtypes (e.g., α-2A, α-2B, and α-2C). Thus, in certain embodiments, the α-adrenergic antagonist has antagonist activity against the α-2A adrenergic receptor. In certain embodiments, the α-adrenergic antagonist has antagonist activity against the α-2B adrenergic receptor. In certain embodiments, the α-adrenergic antagonist has antagonist activity against the α-2C adrenergic receptor. In certain embodiments, the α-adrenergic antagonist has antagonist activity against each of the α-2 adrenergic receptor subtypes.

[0114] Alpha-adrenergic antagonists may be characterized according to their activity at (i) the alpha-1 adrenergic receptor versus (ii) the alpha-2 adrenergic receptor. In certain embodiments, the alpha-adrenergic antagonist has antagonist activity at both (i) the alpha-1 adrenergic receptor and (ii) the alpha-2 adrenergic receptor. In certain embodiments, the alpha-adrenergic antagonist has antagonist activity at (i) the alpha-1 adrenergic receptor but not at (ii) the alpha-2 adrenergic receptor. In certain embodiments, the alpha-adrenergic antagonist has antagonist activity at (i) the alpha-2 adrenergic receptor but not at (ii) the alpha-1 adrenergic receptor. In certain embodiments, the inhibitory activity (e.g., IC) of the alpha-adrenergic antagonist is characterized according to its activity at both (i) the alpha-1 adrenergic receptor and (ii) the alpha-2 adrenergic receptor. 50 In certain embodiments, the inhibitory activity of the alpha-adrenergic antagonist (e.g., as measured by IC value) is at least 10-fold greater for (i) the alpha-1 adrenergic receptor compared to (ii) the alpha-2 adrenergic receptor. 50 value) is at least 10-fold greater for (i) the alpha-2 adrenergic receptor compared to (ii) the alpha-1 adrenergic receptor.

[0115] Dosage of alpha-adrenergic antagonists The method can be further characterized according to the dosage of the α-adrenergic antagonist. For example, in certain embodiments, the dosage of the α-adrenergic antagonist is less than about 2 mg. In certain embodiments, the dosage of the α-adrenergic antagonist is less than about 1.5 mg. In certain embodiments, the dosage of the α-adrenergic antagonist is less than about 1 mg. In certain embodiments, the dosage of the α-adrenergic antagonist is less than about 0.5 mg.

[0116] Dosage of phentolamine or its pharma- ceutically acceptable salt When the α-adrenergic antagonist is phentolamine or a pharma- ceutically acceptable salt thereof, the method may be further characterized according to the amount of phentolamine or a pharma- ceutically acceptable salt thereof in the dosage. For example, in certain embodiments, the dosage contains about 0.1 mg to about 2.0 mg of phentolamine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the dosage contains about 0.5 mg to about 1.0 mg of phentolamine or a pharma- ceutically acceptable salt thereof.

[0117] In certain other embodiments, the dosage contains about 0.1 mg to about 2.0 mg of phentolamine mesylate. In certain embodiments, the dosage contains about 0.2 mg to about 0.7 mg of phentolamine mesylate. In certain embodiments, the dosage contains about 0.25 mg of phentolamine mesylate. In certain other embodiments, the dosage contains about 0.4 mg to about 0.6 mg of phentolamine mesylate. In certain other embodiments, the dosage contains about 0.5 mg of phentolamine mesylate. In certain other embodiments, the dosage contains about 0.8 mg to about 1.2 mg of phentolamine mesylate. In certain embodiments, the dosage contains about 1 mg of phentolamine mesylate.

[0118] The dosage of phentolamine or a pharma- ceutically acceptable salt thereof is desirably administered to the patient's eye in the form of an ophthalmic solution, which is delivered to the eye in the form of eye drops. In certain embodiments, the dosage is administered as one eye drop. A standard eye drop typically contains about 0.03 mL to about 0.05 mL of solution. Preferably, the eye drop contains about 0.05 mL of solution.

[0119] In certain embodiments, the dosage may be in the form of an ophthalmic solution.For example, in certain embodiments, the dosage is an ophthalmic solution containing a pharmaceutically acceptable aqueous carrier and phentolamine or a pharmaceutically acceptable salt thereof.In certain embodiments, the dosage is an ophthalmic solution containing water, a polyol, and phentolamine or a pharmaceutically acceptable salt thereof.In certain embodiments, the dosage is an ophthalmic solution containing water, a polyol, an alkali metal carboxylate, and phentolamine or a pharmaceutically acceptable salt thereof.

[0120] In certain other embodiments, the dosage is an ophthalmic solution containing a pharma- ceutically acceptable aqueous carrier and phentolamine mesylate. In certain embodiments, the dosage is an ophthalmic solution containing water, mannitol, and phentolamine mesylate. In certain embodiments, the dosage is an ophthalmic solution containing water, mannitol, sodium acetate, and phentolamine mesylate.

[0121] In certain other embodiments, the dosage is: (a) about 0.1% (weight / volume) to about 2% (weight / volume) of phentolamine mesylate; (b) about 1% (weight / volume) to about 6% (weight / volume) of at least one polyol compound selected from the group consisting of mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; (d) water; and a chelating agent-free aqueous ophthalmic solution comprising: The solution has a pH in the range of 4 to 6 and does not contain a chelating agent.

[0122] In certain embodiments, the dosage is: (a) about 0.5% (weight / volume) to about 2% (weight / volume) of phentolamine mesylate; (b) about 1% (weight / volume) to about 6% (weight / volume) of at least one polyol compound selected from the group consisting of mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; (d) water; and a chelating agent-free aqueous ophthalmic solution comprising: The solution has a pH in the range of 4.5 to 5.5 and does not contain a chelating agent.

[0123] In certain embodiments, the at least one polyol is mannitol. In certain embodiments, the solution contains 4% (weight / volume) mannitol. In certain embodiments, the alkali metal acetate is sodium acetate. In certain embodiments, the solution contains 3 mM sodium acetate.

[0124] In certain embodiments, the dosage is: (a) about 0.25% (weight / volume) to about 2% (weight / volume) of phentolamine mesylate; (b) about 3% (weight / volume) to about 5% (weight / volume) mannitol; (c) about 2 mM to about 4 mM sodium acetate; (d) water; and a chelating agent-free aqueous ophthalmic solution comprising: The solution has a pH in the range of 4.5 to 5.2 and does not contain a chelating agent.

[0125] In certain embodiments, the dosage is: (a) about 0.5% (weight / volume) to about 2% (weight / volume) of phentolamine mesylate; (b) about 3% (weight / volume) to about 5% (weight / volume) mannitol; (c) about 2 mM to about 4 mM sodium acetate; (d) water; and a chelating agent-free aqueous ophthalmic solution comprising: The solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0126] In certain embodiments, the dosage is: (a) about 0.5% (weight / volume) to about 1% (weight / volume) of phentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodium acetate; (d) water; and a chelating agent-free aqueous ophthalmic solution comprising: The solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0127] In certain embodiments, the dosage is: (a) about 0.25% (weight / volume) to about 2% (weight / volume) of phentolamine mesylate; (b) about 3% (weight / volume) to about 5% (weight / volume) mannitol; (c) about 1 mM to about 6 mM sodium acetate; (d) water, The solution has a pH in the range of 4.5 to 5.2 and does not contain any additional components that are chelating agents.

[0128] In certain embodiments, the dosage is: (a) about 1% (weight / volume) of phentolamine mesylate; (b) about 3% (weight / volume) to about 5% (weight / volume) mannitol; (c) a buffer solution containing about 2 mM to about 4 mM sodium acetate; (d) water, The solution has a pH in the range of 4.5 to 5.2 and does not contain any additional components that are chelating agents.

[0129] In certain embodiments, the dosage is: (a) about 0.25% (weight / volume) to about 2% (weight / volume) of phentolamine mesylate; (b) about 3% (weight / volume) to about 5% (weight / volume) mannitol; (c) about 2 mM to about 4 mM sodium acetate; (d) water, The solution has a pH in the range of 4.5 to 5.2 and does not contain any additional components that are chelating agents.

[0130] In certain embodiments, the dosage is: (a) about 0.5% (weight / volume) to about 2% (weight / volume) of phentolamine mesylate; (b) about 3% (weight / volume) to about 5% (weight / volume) mannitol; (c) a buffer solution containing about 2 mM to about 4 mM sodium acetate; (d) water, The solution has a pH in the range of 4.6 to 5.2 and does not contain any additional components that are chelating agents.

[0131] In certain embodiments, the dosage is: (a) about 0.5% (weight / volume) to about 1% (weight / volume) of phentolamine mesylate; (b) about 4% mannitol; (c) a buffer containing about 3 mM sodium acetate; (d) water, The solution has a pH in the range of 4.6 to 5.2 and does not contain any additional components that are chelating agents.

[0132] In certain embodiments, the dosage is an aqueous ophthalmic solution comprising: (a) about 1% (weight / volume) phentolamine mesylate; (b) about 4% (weight / volume) mannitol; (c) a buffer comprising about 3 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.5 to 5.5 and does not contain any additional components that are chelating agents.

[0133] In certain embodiments, the dosage is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 1% (weight / volume) phentolamine mesylate; (b) about 4% (weight / volume) mannitol; (c) a buffer comprising about 3 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.0 to 7.5 and does not contain a chelating agent.

[0134] Combination Therapy Administration Considerations In embodiments in which two or more therapeutic agents are administered, the amount of each therapeutic agent and the relative timing of administration of each therapeutic agent may be selected to achieve a desired combined therapeutic effect. For example, when administering a combination therapy to a patient in need of such administration, the therapeutic agents of the combination, or pharmaceutical composition(s) comprising the therapeutic agents, may be administered in any order, e.g., sequentially, concurrently, together, simultaneously, etc.

[0135] In certain embodiments, therapeutic agents may act additively or synergistically.Synergistic combinations may allow the use of lower doses of one or more agents of combination therapy and / or less frequent administration of one or more agents.Lower doses or less frequent administration of one or more agents may reduce the toxicity of therapy without reducing the efficacy of therapy.

[0136] Patient populations who may derive particular benefit from a treatment approach The methods may be further characterized according to patient populations that may derive particular benefit from the therapeutic method. For example, in certain embodiments, the patient is a human. In certain embodiments, the patient is an adult human. In certain embodiments, the patient is a geriatric human. In certain embodiments, the patient is a pediatric human.

[0137] Time of administration The above-mentioned various methods require administration of dosage at or near the time when the patient goes to bed.Thus, in certain embodiments, the dosage is administered within 2 hours, 1.5 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes of the time when the patient goes to bed.In certain embodiments, the dosage is administered within 1 hour of the time when the patient goes to bed.

[0138] Medication to reduce eye redness The method may be further characterized according to whether an ocular redness reducing agent is administered to the patient's eye. In certain embodiments, the method further comprises administering an effective amount of an ocular redness reducing agent to the patient's eye. Exemplary ocular redness reducing agents are brimonidine, tetrahydrozoline, oxymetazoline, naphthazoline, or pharma- ceutically acceptable salts thereof. These agents are not expected to alter pupil diameter. In certain embodiments, the ocular redness reducing agent is brimonidine or a pharma- ceutically acceptable salt thereof (e.g., brimonidine tartrate). Brimonidine tartrate is sold as LUMIFY®, an ophthalmic solution containing brimonidine tartrate (0.025% w / w). In certain embodiments, the ocular redness reducing agent is oxymetazoline or a pharma- ceutically acceptable salt thereof. An ophthalmic solution containing oxymetazoline is commercially available as VISINE LR®. In certain embodiments, the agent that reduces eye redness is naphthazoline or a pharma- ceutically acceptable salt thereof, such as naphthazoline hydrochloride, commercially available as CLEAR EYES®.

[0139] Visual performance improvements One benefit of the treatment methods is that the patient may experience an improvement in visual performance, which relates to the patient's overall visual quality and includes the patient's ability to see clearly and distinguish objects from their background.

[0140] One aspect of visual performance is visual acuity. Visual acuity is a measure of a patient's ability to see clearly. Visual acuity can be measured, for example, using a Snellen chart. Furthermore, visual acuity measurements can be performed under scotopic, mesopic, and / or photopic conditions.

[0141] Another aspect of visual performance is contrast sensitivity. Contrast sensitivity is a measure of a patient's ability to distinguish between an object and its background. Contrast sensitivity can be measured, for example, using the Holladay Automated Contrast Sensitivity System. Contrast sensitivity can be measured, for example, under various light conditions, including photopic, mesopic, and scotopic conditions, each with or without glare. In certain embodiments, contrast sensitivity is measured under mesopic conditions, with or without glare.

[0142] In certain embodiments, the improvement in visual performance provided by the method is improved visual acuity. In certain embodiments, the improvement in visual performance provided by the method is improved visual acuity under scotopic conditions. In certain embodiments, the improvement in visual performance provided by the method is improved visual acuity under mesopic conditions. In certain embodiments, the improvement in visual performance provided by the method is improved visual acuity under photopic conditions. In certain embodiments, the improvement in visual acuity is a three line improvement in the patient's visual acuity measured using an eye chart. In certain embodiments, the improvement in visual acuity is a two line improvement in the patient's visual acuity measured using an eye chart. In certain other embodiments, the improvement in visual acuity is a one line improvement in the patient's visual acuity measured using an eye chart. In certain embodiments, the eye chart is a Snellen optotype. In certain other embodiments, the eye chart is a Jaeger chart. In certain other embodiments, the eye chart is a Rosenbaum chart or an ETDRS chart. In certain embodiments, the improvement in visual acuity is measured at close distances (e.g., about 1, 2, or 3 feet). In certain embodiments, the improved vision is measured at a distance (e.g., about 20, 25, or 30 feet). In certain embodiments, the improved vision is improved near vision. In certain embodiments, the improved vision is improved distance vision. In certain embodiments, the improved vision is (i) improved near vision, and (ii) improved distance vision.

[0143] In certain embodiments, the visual performance improvement provided by the method is improved contrast sensitivity. The improved contrast sensitivity can be measured under various light conditions, such as photopic, mesopic, and scotopic conditions. In certain embodiments, the visual performance improvement provided by the method is improved contrast sensitivity under photopic conditions. In certain embodiments, the visual performance improvement provided by the method is improved contrast sensitivity under mesopic conditions. In certain embodiments, the visual performance improvement provided by the method is improved contrast sensitivity under scotopic conditions. Furthermore, contrast sensitivity can be measured in the presence or absence of glare. All combinations of light conditions and glare are contemplated.

[0144] The benefit provided by the treatment method can be characterized according to the patient's improvement in contrast sensitivity. For example, in certain embodiments, the improvement in contrast sensitivity is at least 10% (or 20%, 30%, 50%, 60%, or 70%) improvement measured under mesopic conditions using a Holladay automatic contrast sensitivity system. In certain embodiments, the improvement in contrast sensitivity is at least 10% (or 20%, 30%, 50%, 60%, or 70%) improvement measured under photopic conditions using a Holladay automatic contrast sensitivity system. In certain other embodiments, the improvement in contrast sensitivity is at least 10% (or 20%, 30%, 50%, 60%, or 70%) improvement measured under mesopic or scotopic conditions using a Holladay automatic contrast sensitivity system. In certain other embodiments, the improvement in contrast sensitivity is measured using a Pelli-Robson contrast sensitivity chart.

[0145] In certain other embodiments, the improved visual performance provided by the method is both (i) improved visual acuity (e.g., under scotopic, mesopic, and / or photopic conditions) and (ii) improved contrast sensitivity (e.g., under scotopic, mesopic, and / or photopic conditions).

[0146] In certain other embodiments, the improvement in visual performance is characterized according to one or more of the following: Assessment of uncorrected near visual acuity (e.g. binocular assessment of uncorrected near visual acuity), Mean change from baseline in uncorrected near visual acuity (UNVA), or The proportion of subjects with an improvement of at least 3 lines (e.g., 15 letters) in the study eye in post-treatment monocular best corrected distance visual acuity at 45 cm compared to baseline monocular best corrected distance visual acuity at 45 cm after treatment.

[0147] In certain other embodiments, the improvement in visual performance is characterized according to one or more of the following: Assessment of uncorrected near visual acuity (e.g. binocular assessment of uncorrected near visual acuity), Mean change from baseline in uncorrected near visual acuity (UNVA, both eyes), or The proportion of subjects with an improvement of at least 3 lines (e.g., 15 letters) in the study eye in post-treatment monocular best corrected distance visual acuity at 35 cm compared to baseline monocular best corrected distance visual acuity at 35 cm after treatment.

[0148] Reduction of pupil diameter One benefit of the treatment method is that the patient may experience a reduction in pupil diameter, which can result in improved visual performance.

[0149] The reduction in pupil diameter may be characterized according to the percent reduction in pupil diameter by administering the α-adrenergic antagonist, such as when the reduction in pupil diameter is at least 5%, 10%, 15%, 20%, 30%, or 40%. In certain embodiments, the reduction in pupil diameter is in the range of about 10% to about 40% as compared to the pupil diameter of a patient under the same conditions but not receiving a therapy defined by the method. In certain embodiments, the reduction in pupil diameter is in the range of about 20% to about 30% as compared to the pupil diameter of a patient under the same conditions but not receiving a therapy defined by the method. In certain embodiments, the reduction in pupil diameter is in the range of about 20% to about 40% as compared to the pupil diameter of a patient under the same conditions but not receiving a therapy defined by the method. In certain embodiments, the reduction in pupil diameter is measured under photopic conditions.

[0150] In more specific embodiments, the reduction in pupil diameter can be characterized according to the percentage reduction in pupil diameter and size measured under specific light conditions, for example. Thus, in certain embodiments, the reduction in pupil diameter under mesopic conditions is at least 5% compared to the pupil diameter of a patient under the same mesopic conditions but not receiving the therapy defined by the method. In certain other embodiments, the reduction in pupil diameter under mesopic conditions is at least 10% compared to the pupil diameter of a patient under the same mesopic conditions but not receiving the therapy defined by the method. In certain other embodiments, the reduction in pupil diameter under mesopic conditions is at least 20% compared to the pupil diameter of a patient under the same mesopic conditions but not receiving the therapy defined by the method. In certain other embodiments, the reduction in pupil diameter under mesopic conditions is at least 30% compared to the pupil diameter of a patient under the same mesopic conditions but not receiving the therapy defined by the method. In certain other embodiments, the patient experiences a reduction in pupil diameter of at least 0.5 mm when measured under mesopic conditions relative to the diameter of the pupil of a patient under the same mesopic conditions but not receiving a therapy defined by the method. In certain other embodiments, the patient experiences a reduction in pupil diameter of about 0.6 mm to about 3 mm, about 0.6 mm to about 2.5 mm, or about 0.6 mm to about 2 mm when measured under mesopic conditions relative to the diameter of the pupil of a patient under the same mesopic conditions but not receiving a therapy defined by the method. In certain other embodiments, the patient experiences a reduction in pupil diameter of about 0.6 mm to about 1.2 mm when measured under mesopic conditions relative to the diameter of the pupil of a patient under the same mesopic conditions but not receiving a therapy defined by the method. In still other embodiments, the patient's pupil is constricted to a diameter of about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, or about 4 mm to about 7 mm under mesopic conditions for a therapy defined by the method. In certain embodiments, the patient's pupil is constricted to a diameter of about 4 mm to about 6 mm under mesopic conditions for a therapy defined by the method.

[0151] In certain embodiments, the reduction in pupil diameter under photopic conditions is at least 5% compared to the pupil diameter of a patient under the same photopic conditions but not receiving the therapy defined by the method. In certain other embodiments, the reduction in pupil diameter under photopic conditions is at least 10% compared to the pupil diameter of a patient under the same photopic conditions but not receiving the therapy defined by the method. In certain other embodiments, the reduction in pupil diameter under photopic conditions is at least 20% compared to the pupil diameter of a patient under the same photopic conditions but not receiving the therapy defined by the method. In certain other embodiments, the reduction in pupil diameter under photopic conditions is at least 30% compared to the pupil diameter of a patient under the same photopic conditions but not receiving the therapy defined by the method. In certain other embodiments, the patient experiences a reduction in pupil diameter of at least 0.5 mm when measured under photopic conditions relative to the pupil diameter of a patient under the same photopic conditions but not receiving the therapy defined by the method. In certain other embodiments, the patient experiences a reduction in pupil diameter, when measured under photopic conditions, in the range of about 0.6 mm to about 3 mm, about 0.6 mm to about 2.5 mm, or about 0.6 mm to about 2 mm, relative to the diameter of the patient's pupil under the same photopic conditions but not receiving a therapy defined by the method. In certain other embodiments, the patient experiences a reduction in pupil diameter, when measured under photopic conditions, in the range of about 0.6 mm to about 1.2 mm, relative to the diameter of the patient's pupil under the same photopic conditions but not receiving a therapy defined by the method. In still other embodiments, the patient's pupil is reduced to a diameter of about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, or about 4 mm to about 7 mm, under photopic conditions, due to the therapy defined by the method. In certain embodiments, the patient's pupil is reduced to a diameter of about 4 mm to about 6 mm, under photopic conditions, due to the therapy defined by the method.

[0152] The reduction in pupil diameter can be analyzed and characterized using procedures such as those described below, in which a phentolamine mesylate solution was administered to the patient's eye and the change in pupil diameter was measured and characterized. This was performed in the context of a clinical trial using patients who were at least 18 years of age and had a clinical record of a pupil size of at least 7 mm in diameter under dim light conditions. The phentolamine mesylate solutions contained either 0.2% (weight / volume) phentolamine mesylate, 0.4% (weight / volume) phentolamine mesylate, or 0.8% (weight / volume) phentolamine mesylate.

[0153] Part I - Experimental Procedure Sixteen patients were randomized into four groups (four subjects each). Each group was treated with one drop of ophthalmic oxymetazoline solution (Visine LR®) in each eye followed by one drop of the test article in each eye at three consecutive study visits at least four days apart. The test articles were 0.2% (w / v) phentolamine mesylate solution, 0.4% (w / v) phentolamine mesylate solution, 0.8% (w / v) phentolamine mesylate solution, or placebo. The test article contained a designed amount of phentolamine mesylate in a solution of Tears Naturale II® (manufactured by Alcon Labs). The placebo was Tears Naturale II® (manufactured by Alcon Labs). Tears Naturale II® (Alcon Labs) contains dextran 70 (0.1% by weight), hydroxypropyl methylcellulose 2910 (0.3% by weight), polyquaternium-1 (0.001% by weight), potassium chloride, water (purified), sodium borate, sodium chloride, and hydrochloric acid and / or sodium hydroxide to adjust pH as needed. The patient's pupil diameter was recorded at baseline (i.e., before administration of treatment), and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after administration of the test article. The total study duration was approximately 9 hours. The treatment group randomization schedule is provided in Table 1 below. [Table 1]

[0154] Patients were eligible for enrollment if they (a) were at least 18 years of age and (b) had a pupil size recorded in dim light of greater than 7 mm. Patients were ineligible for enrollment in the study if they met any of the following criteria: (a) had moderate to severe hypertension, (b) had a history of heart rate abnormalities, (c) had received any investigational medication within 14 days of screening, (d) had known local or systemic hypersensitivity to adrenergic antagonists, or (e) had central corneal pathology.

[0155] Pupil diameter was measured to within 0.1 mm for each eye at baseline and each subsequent time point using a NeuroOpticsTM pupillometer. Comparisons of changes in mean values ​​within treatment groups were tested for significance using two-tailed paired sample t-tests with the threshold of significance set at p<0.01 (Bonferroni correction for multiple paired t-tests). Differences between treatment groups in mean values ​​of pupil size over the course of the study were tested for significance using repeated measures analysis of variance (discarding data from subjects missing any data points). Differences in means between treatment groups at individual time points were tested for significance using one-way analysis of variance. If one-way analysis of variance indicated significance at a given time point, an ad hoc Fisher test was performed to identify significant differences between individual group means.

[0156] Part II - Results Fifteen of the 16 patients completed the study. One patient randomized to group 3 completed only two of the three clinic visits and did not receive the 0.8% (wt / vol) phentolamine mesylate dose. Pupillometry results are described below.

[0157] One criterion for participation in the study was documentation of a pupil size >7 mm as measured under dim light conditions. Table 2 provides the mean pupil diameter, standard deviation of pupil diameter, and range of diameters observed recorded immediately prior to administration of each treatment. [Table 2]

[0158] Mean baseline pupil diameters were comparable across all four treatment groups, and the observed mean differences (Table 2) were not statistically significant (P=0.766). Of the 94 baseline pupil diameters collected during the study, there were 12 cases (representing 3 subjects, Table 3) in which the baseline pupil diameter was less than the inclusion criterion of 7 mm. Baseline pupil diameters less than 7 mm were evenly distributed across treatment groups (2, 3, 4, and 3 pupils in the placebo, 0.2%, 0.4%, and 0.8% (weight / volume) phentolamine mesylate treatment groups, respectively). [Table 3]

[0159] For all study groups, mean pupil diameter remained relatively unchanged at 30 minutes after treatment. By 1 hour after treatment, mean pupil diameter was lower for subjects receiving phentolamine treatment (P=0.47). Mean pupil diameter for subjects receiving placebo remained relatively constant for the 8 hour post-treatment observation. [Table 4]

[0160] Repeated measures analysis of variance showed significant (p<0.001) differences between treatment groups with respect to pupil diameter over the course of the study. Significant differences in mean pupil diameter between treatments were identified by one-way analysis of variance at 2 hours (p=0.0006), 4 hours (p=0.0027), and 8 hours (p=0.0016) after treatment. Ad hoc Fisher tests of significance between individual group means showed significant differences in mean pupil diameter for subjects treated with any concentration of phentolamine mesylate when compared to placebo at 2, 4, and 8 hours (Table 5). In contrast, there were no statistically significant differences in mean pupil diameter observed between different doses of phentolamine at any time point. [Table 5]

[0161] For all treatment groups, mean pupil diameter remained relatively unchanged from baseline at 30 minutes post-treatment (Table 6). By 1 hour post-treatment, the change from baseline in mean pupil diameter was significant (p<0.01) for subjects treated with 0.2% (wt / vol), 0.4% (wt / vol), and 0.8% (wt / vol) phentolamine mesylate. Mean pupil diameter did not change significantly from baseline for subjects receiving placebo over the 8 hour post-treatment observation period.

[0162] The differences in mean pupil diameter between treatment groups are expressed as the mean change in diameter from baseline in Table 6. When the mean change in pupil diameter from baseline is assessed as a function of time, it is apparent that subjects receiving phentolamine mesylate experienced a significant reduction in pupil size over the course of the study. [Table 6]

[0163] Effect on distance vision in the patient's eye The methods may be further characterized according to whether the method adversely affects the distance vision in the patient's eye. In certain embodiments, the patient's distance vision is not reduced.

[0164] Administering a dose to one or both of the patient's eyes The method may be further characterized according to whether the alpha-adrenergic antagonist is administered to one or both eyes of the patient. In certain embodiments, the dosage is administered to only one eye of the patient. In certain embodiments, the dosage is administered to both eyes of the patient.

[0165] Reducing abnormal focusing of scattered light rays in a patient's eye One benefit of the treatment method is that the patient may experience a reduction in the abnormal focusing of scattered light in the patient's eye. This can provide an improvement in the patient's visual performance. In certain embodiments, the treatment method provides a reduction in the abnormal focusing of scattered light in the patient's eye for at least 20 hours. In certain embodiments, the treatment method provides a reduction in the abnormal focusing of scattered light in the patient's eye for at least 24 hours. In still other embodiments, the treatment method provides a reduction in the abnormal focusing of scattered light in the patient's eye for at least 36 hours, 48 ​​hours, 60 hours, or 72 hours.

[0166] Implantable Ocular Devices The compositions described herein can be administered to the patient's eye via an implantable ocular device that dispenses the composition.The implantable ocular device can be configured to dispense the composition at a desired rate and / or frequency.In certain embodiments, the implantable ocular device is a sustained release insert.

[0167] III. Ophthalmic solution The therapeutically active agent is desirably administered to the patient's eye in the form of an ophthalmic solution. Such an ophthalmic solution comprises one or more therapeutically active agents and a pharma- ceutically acceptable carrier. Desirably, the ophthalmic solution exhibits good storage stability to allow distribution of the ophthalmic solution through normal distribution channels of pharmaceuticals. In certain embodiments, the pharma- ceutically acceptable carrier is water. Additional components may be added to the ophthalmic solution to optimize the performance characteristics of the ophthalmic solution. Exemplary additional components include, for example, chelating agents (e.g., EDTA), polyol compounds, poly(C 2-4 These include, for example, alkylene glycol polymers, dextrans, cellulosics, buffers, tonicity adjusting agents, preservatives, antioxidants, viscosity adjusting agents, corneal permeation enhancers, solubilizing agents, stabilizers, surfactants, demulcent polymers, humectants, and other materials.

[0168] Ophthalmic solutions may contain chelating agents (e.g., EDTA), polyol compounds, poly(C 2-4 The ophthalmic solution may be further characterized according to the presence or absence of one or more of: alkylene glycol polymers, dextran, cellulose agents, buffers, tonicity modifiers, preservatives, antioxidants, viscosity modifiers, corneal permeation enhancers, solubilizers, stabilizers, surfactants, demulcent polymers, wetting agents, and other materials. In certain embodiments, the ophthalmic solution does not contain a chelating agent (e.g., EDTA). In certain embodiments, the ophthalmic solution does not contain a preservative. In certain embodiments, the ophthalmic solution contains a preservative.

[0169] The various treatment methods described above include administering a dose of phentolamine or a pharma- ceutically acceptable salt thereof to a patient. The dose of phentolamine or a pharma- ceutically acceptable salt thereof is preferably in the form of an ophthalmic solution. The ophthalmic solution is formulated to be suitable for administration to the patient's eye and preferably provides an immediate release of phentolamine, i.e., the ophthalmic solution is not a sustained release formulation that delivers phentolamine over an extended period of time, such as hours, days, or weeks.

[0170] The ophthalmic solution desirably comprises a pharmaceutically acceptable aqueous carrier and phentolamine or a pharmaceutically acceptable salt thereof. The ophthalmic solution may contain excipient(s) suitable for administration to the eye. Various pharmaceutically acceptable salts are described in the literature. The preferred salt form of phentolamine is phentolamine mesylate. Thus, the method may use an ophthalmic solution comprising a pharmaceutically acceptable aqueous carrier and phentolamine mesylate.

[0171] Thus, in certain embodiments, the dosage utilized in the method is an ophthalmic solution comprising a pharma- ceutically acceptable aqueous carrier and phentolamine or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the dosage is an ophthalmic solution comprising a pharma- ceutically acceptable aqueous carrier and phentolamine mesylate. In certain other embodiments, the dosage is an ophthalmic solution comprising water, a polyol, and phentolamine, or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the dosage is an ophthalmic solution comprising water, mannitol, and phentolamine mesylate. In certain other embodiments, the dosage is an ophthalmic solution comprising water, a polyol, an alkali metal carboxylate, and phentolamine, or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the dosage is an ophthalmic solution comprising water, mannitol, sodium acetate, and phentolamine mesylate.

[0172] Other ophthalmic solutions contemplated for use in the present invention include, for example, (i) chelating agent-free aqueous ophthalmic solutions, and (ii) polyvinylpyrrolidone artificial tear formulations, each of which is described in more detail below.

[0173] The ophthalmic solution may be further characterized according to the viscosity of the solution. In certain embodiments, the ophthalmic solution at a temperature of about 25° C. has a viscosity in the range of 0.9 cP to about 1.1 cP. In certain embodiments, the ophthalmic solution at a temperature of about 25° C. has a viscosity of about 1 cP.

[0174] In certain embodiments, the ophthalmic solution comprises an alpha-adrenergic antagonist (eg, phentolamine or a pharma- ceutically acceptable salt thereof) and one or more additional agents described herein (eg, pilocarpine).

[0175] Chelating agent-free aqueous ophthalmic solution In certain embodiments, the dosage utilized in the method is a chelating agent-free aqueous ophthalmic solution comprising: (a) phentolamine or a pharma- ceutically acceptable salt thereof; (b) at least one polyol compound, such as a polyol compound having a molecular weight of less than 250 g / mol; (c) at least one buffer; and (d) water, wherein the solution does not contain a chelating agent. The amounts of components in the aqueous ophthalmic solution may be selected to achieve particular performance characteristics, such as stability on storage, to minimize irritation to the patient's eye, and to facilitate penetration of phentolamine into the patient's eye.

[0176] One exemplary preferred solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 4% (w / v) of phentolamine or a pharma- ceutically acceptable salt thereof; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound having a molecular weight less than 250 g / mol; (c) about 0.1 mM to about 10 mM of at least one buffer; and (d) water, wherein the solution has a pH in the range of 4.0 to 7.5 and does not contain a chelating agent.

[0177] Exemplary components and characteristics of aqueous ophthalmic solutions are described in more detail below.

[0178] Phentolamine and Pharmacologically Acceptable Salts The aqueous ophthalmic solution comprises phentolamine or a pharma- ceutically acceptable salt of phentolamine. Exemplary pharma- ceutically acceptable salts include, for example, hydrochloride and mesylate. Thus, in certain embodiments, the solution comprises phentolamine (i.e., as the free base). In certain other embodiments, the solution comprises phentolamine hydrochloride. In certain yet other embodiments, the solution comprises phentolamine mesylate.

[0179] The amount of phentolamine or its pharmaceutically acceptable salt in the aqueous ophthalmic solution can be adjusted to achieve desired performance characteristics.For example, if it is desired to provide a higher amount of phentolamine (or its pharmaceutically acceptable salt) to the patient with a single administration of the aqueous ophthalmic solution, the concentration of phentolamine (or its pharmaceutically acceptable salt) is increased in the aqueous ophthalmic solution.A single administration of the aqueous ophthalmic solution having a higher concentration of phentolamine (or its pharmaceutically acceptable salt) can provide the patient with reduced intraocular pressure for a longer period of time, since more phentolamine (or its pharmaceutically acceptable salt) is administered to the patient.

[0180] Thus, in certain embodiments, the aqueous ophthalmic solution comprises about 0.1% (wt / vol) to about 5% (wt / vol) phentolamine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the aqueous ophthalmic solution comprises about 0.1% (wt / vol) to about 1% (wt / vol) phentolamine or a pharma- ceutically acceptable salt thereof, about 1% (wt / vol) to about 2% (wt / vol) phentolamine or a pharma- ceutically acceptable salt thereof, about 2% (wt / vol) to about 3% (wt / vol) phentolamine or a pharma- ceutically acceptable salt thereof, about 3% (wt / vol) to about 4% (wt / vol) phentolamine or a pharma- ceutically acceptable salt thereof, about 4% (wt / vol) to about 5% (wt / vol) phentolamine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the aqueous ophthalmic solution comprises about 0.1% (wt / vol) to about 2% (wt / vol) phentolamine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the aqueous ophthalmic solution comprises about 0.25% (w / v) to about 2% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the aqueous ophthalmic solution comprises about 0.5% (w / v) to about 2% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the aqueous ophthalmic solution comprises about 0.25% (w / v) to about 1% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the aqueous ophthalmic solution comprises about 1% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the aqueous ophthalmic solution comprises about 0.1% (w / v) to about 4% (w / v) phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises about 0.1% (w / v) to about 2% (w / v) phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.25% (w / v) to about 2% (w / v) phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.5% (w / v) to about 2% (w / v) phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate.In certain other embodiments, the aqueous ophthalmic solution comprises about 1% (w / v) phentolamine mesylate, hi certain other embodiments, the aqueous ophthalmic solution comprises about 0.25% (w / v) or about 0.5% (w / v) phentolamine mesylate.

[0181] Polyol Compounds The aqueous ophthalmic solution includes one or more polyol compounds. A polyol compound is an organic compound having at least two hydroxyl groups (e.g., 2 to about 6 hydroxyl groups). Polyol compounds are beneficial to aqueous ophthalmic solutions because they can, for example, increase the stability of the aqueous ophthalmic solution upon storage and / or adjust the tonicity of the aqueous ophthalmic solution. Exemplary polyol compounds include, for example, mannitol, glycerol, propylene glycol, ethylene glycol, sorbitol, and xylitol.

[0182] The aqueous ophthalmic solution may contain a single polyol compound or a mixture of one or more polyol compounds. In other words, the aqueous ophthalmic solution comprises at least one polyol compound. In certain embodiments, the aqueous ophthalmic solution comprises at least one polyol compound that is mannitol, glycerol, propylene glycol, ethylene glycol, sorbitol, or xylitol. In certain other embodiments, the at least one polyol compound is mannitol. In certain other embodiments, the at least one polyol compound is glycerol. In certain other embodiments, the at least one polyol compound is propylene glycol. In certain other embodiments, the at least one polyol compound is mannitol and the solution further comprises glycerol. In certain other embodiments, the at least one polyol compound is mannitol and the solution further comprises propylene glycol. In certain other embodiments, the at least one polyol compound is glycerol and the solution further comprises propylene glycol. In certain other embodiments, the mannitol described in the above embodiment is D-mannitol.

[0183] The amount of at least one polyol compound in the aqueous ophthalmic solution may be selected to achieve desired performance characteristics for the solution. The polyol compound may, for example, increase the stability of the solution on storage and / or adjust the tonicity of the solution to make it more suitable for administration to the patient's eye. In certain embodiments, the aqueous ophthalmic solution comprises about 2% (wt / vol) to about 5% (wt / vol) of at least one polyol compound. In certain other embodiments, the aqueous ophthalmic solution comprises about 3.5% (wt / vol) to about 4.5% (wt / vol) of at least one polyol compound. In certain other embodiments, the aqueous ophthalmic solution comprises about 4% (wt / vol) of at least one polyol compound. In certain other embodiments, the aqueous ophthalmic solution comprises about 2% (wt / vol) to about 3% (wt / vol) of mannitol, and about 0.5% (wt / vol) to about 1.5% (wt / vol) of glycerin. In certain other embodiments, the mannitol described in the above embodiments is D-mannitol.

[0184] In certain embodiments, the amount of polyol may be selected based on the amount of phentolamine (or its pharma- ceutically acceptable salt), and there is an inverse relationship between the amount of phentolamine (or its pharma- ceutically acceptable salt) and the amount of polyol to achieve isotonicity with the eye. For example, in an embodiment in which the aqueous ophthalmic solution contains about 2% (weight / volume) phentolamine, mannitol is present in the solution at a concentration of about 3% (weight / volume). In an embodiment in which the aqueous ophthalmic solution contains about 1% (weight / volume) phentolamine, mannitol is present in the solution at a concentration of about 4% (weight / volume). To further illustrate this principle, in an embodiment in which the aqueous ophthalmic solution contains about 0.5% (weight / volume) phentolamine, mannitol may be present in the solution at a concentration of about 4.5% (weight / volume). In certain embodiments, the mannitol described in the above embodiment is D-mannitol.

[0185] It is understood that the aqueous ophthalmic solution can contain additional components as described herein, such as various polymeric materials. One such embodiment is an aqueous ophthalmic solution that includes at least one polyol compound, for example, propylene glycol, and further includes polypropylene glycol, for example, polypropylene glycol having a weight average molecular weight in the range of about 5,000 g / mol to about 100,000 g / mol.

[0186] Poly(C 2-4 (alkylene) glycol polymer The aqueous ophthalmic solution optionally contains poly(C 2-4 Exemplary poly(C 2-4 The alkylene) glycol polymer is a polypropylene glycol, for example, having a weight average molecular weight in the range of about 5,000 g / mol to about 100,000 g / mol, about 10,000 g / mol to about 50,000 g / mol, or about 50,000 g / mol to about 100,000 g / mol.

[0187] Dextran The aqueous ophthalmic solution may optionally include dextran. Dextran is a commercially available branched polysaccharide that contains glucose molecules. The amount of dextran in the aqueous ophthalmic solution may be selected to achieve particular performance characteristics. In certain embodiments, the aqueous ophthalmic solution includes from about 0.01% (weight / volume) to about 2% (weight / volume) dextran. In certain other embodiments, the aqueous ophthalmic solution includes from about 0.01% (weight / volume) to about 1% (weight / volume) dextran.

[0188] Dextran may be further characterized according to its weight average molecular weight. In certain embodiments, dextran has a weight average molecular weight ranging from about 65,000 g / mol to about 75,000 g / mol. In certain other embodiments, dextran has a weight average molecular weight of about 70,000 g / mol. In still other embodiments, dextran has a weight average molecular weight ranging from about 5,000 g / mol to about 100,000 g / mol, from about 10,000 g / mol to about 50,000 g / mol, or from about 50,000 g / mol to about 100,000 g / mol.

[0189] Cellulose Agent The aqueous ophthalmic solution may optionally include a cellulose agent. Exemplary cellulose agents include, for example, cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. In certain embodiments, the cellulose agent is hydroxypropylmethylcellulose. In certain other embodiments, the cellulose agent is cellulose, carboxymethylcellulose, hydroxyethylcellulose, or hydroxypropylcellulose. The amount of the cellulose agent in the aqueous ophthalmic solution may be selected to achieve desired performance characteristics. For example, in certain embodiments, the aqueous ophthalmic solution includes about 0.01% (weight / volume) to about 2% (weight / volume) of the cellulose agent.

[0190] The cellulose agent may be further characterized according to its weight average molecular weight. In certain embodiments, the cellulose agent has a weight average molecular weight in the range of about 5,000 g / mol to about 100,000 g / mol, about 10,000 g / mol to about 50,000 g / mol, or about 50,000 g / mol to about 100,000 g / mol.

[0191] buffer solution The aqueous ophthalmic solution includes at least one buffer. The buffer provides the solution with buffering capacity, i.e., the ability to neutralize, within limits, either acids or bases (alkali), with relatively or no change in the original pH. The buffer can be an acid, a base, or a combination of an acid and a base. The buffer can be an organic, inorganic, or a combination of organic and inorganic components. It should be understood that the buffer will at least partially dissociate in the aqueous solution to form, for example, a mixture of an acid and a conjugate base or a base and a conjugate acid. For example, the buffer can be a combination of a carboxylic acid and its carboxylate salt (e.g., a combination of acetic acid and sodium acetate). In another embodiment, the buffer can be a combination of an acid and a base, but the acid and the base are not conjugates. For example, the acid can be boric acid and the base can be tris(hydroxymethyl)aminomethane (TRIS).

[0192] Exemplary buffers include organic acids (e.g., acetic acid, sorbic acid, and oxalic acid), borate, bicarbonate, carbonate, gluconate, lactate, phosphate, propionate, perborate, tris-(hydroxymethyl)aminomethane (TRIS), bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)aminoalcohol (bis-tris), N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricene), N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine, 3-(N-morpholino)propanesulfonic acid, N-(carbamoylmethyl)taurine (ACES), amino acids, their salts, and combinations thereof. It should be understood that the salt form of the buffer can include any suitable counterion. For example, the salt form of the acid can include an alkali or alkaline earth metal counterion.

[0193] Buffers can be characterized according to their strength, i.e., buffering capacity. Buffering capacity can be tested, for example, by determining the millimoles (mM) of strong acid or base (or hydrogen or hydroxide ions, respectively) required when added to 1 liter (standard unit) of buffer solution to change the pH of the buffer solution by 1 unit. Buffering capacity generally depends on the type and concentration of the buffer components and can be greater at certain pH ranges. For example, a buffer can be characterized according to the pK of the buffer. a pH ranges around, e.g., the pK of a buffer a The optimal buffering capacity may be within about 1 pH unit or within about 2 pH units of 0.05 to 0.15 ...

[0194] In certain embodiments, the buffer is a weak acid buffer having one or more of the following characteristics: (a) a pKa of about 4.0 to about 6.0, more preferably about 4.5 to about 5.5, and (b) a lipophilicity value LogP of about -0.50 to about 1.5, more preferably about -0.25 to about 1.35.

[0195] The amount of buffer can be adjusted to achieve the desired performance characteristics for the aqueous ophthalmic solution. For example, in certain embodiments, the buffer can be present at a concentration of less than about 10 mM, less than about 7 mM, less than about 5 mM, less than about 3 mM, or less than about 2 mM. In some embodiments, the buffer can be present at a concentration of about 1 mM to about 10 mM, about 1 mM to about 7 mM, about 1 mM to about 5 mM, about 1 mM to about 3 mM, about 1 mM to about 2 mM, about 2 mM to about 5 mM, or about 2 mM to about 3 mM. In still other embodiments, the buffer is present at a concentration of about 3 mM.

[0196] The amount and identity of the buffer may be selected to achieve certain performance characteristics of the aqueous ophthalmic solution. For example, the amount of buffer may affect the amount of acid that can be neutralized before there is a substantial change in the pH of the aqueous ophthalmic solution. The amount of buffer may also affect the tonicity of the aqueous ophthalmic solution. Desirably, the amount and identity of the buffer should be selected to minimize any irritation that may be caused by administration of the aqueous ophthalmic solution to the patient's eye. Thus, in certain embodiments, the buffer is present at a concentration ranging from about 2 mM to about 4 mM. In yet other embodiments, the buffer is present at a concentration of about 3 mM. In certain embodiments, the buffer comprises an alkali metal alkyl carboxylate. In certain other embodiments, the buffer comprises an alkali metal acetate. In still other embodiments, the buffer comprises sodium acetate.

[0197] solution pH Aqueous ophthalmic solutions may be characterized according to the pH of the solution. Desirably, the aqueous ophthalmic solution has a pH in the range of 4.0 to 7.5. In certain embodiments, the aqueous ophthalmic solution has a pH in the range of 4.5 to 7.5. In certain other embodiments, the solution has a pH in the range of 4.5 to 6.0. In certain other embodiments, the solution has a pH in the range of 4.5 to 5.5. In still other embodiments, the solution has a pH in the range of 4.7 to 5.1.

[0198] Additional ingredients for aqueous ophthalmic solutions The aqueous ophthalmic solution may contain additional materials to make the composition more suitable for administration to a patient's eye. Exemplary additional materials are described below and include, for example, tonicity adjusting agents, preservatives, antioxidants, viscosity adjusting agents, stabilizers, corneal permeation enhancers, and surfactants.

[0199] A. Tonicity Adjusting Agents The aqueous ophthalmic solution may optionally include one or more tonicity adjusting agents. The tonicity adjusting agent may be ionic or non-ionic. In certain embodiments, the tonicity adjusting agent may be a salt, a carbohydrate, or a polyol. Exemplary tonicity adjusting agents include alkali metal or alkaline earth metal halides (such as LiBr, LiCl, LiI, KBr, KCl, KI, NaBr, NaCl, NaI, CaCl2, and MgCl2), boric acid, dextran (e.g., dextran 70), cyclodextrin, dextrose, mannitol, glycerin, urea, sorbitol, propylene glycol, or combinations thereof.

[0200] It is understood that a tonicity adjusting agent may be added to the aqueous ophthalmic solution in an amount sufficient to provide a desired osmolality. In certain embodiments, a tonicity adjusting agent is present in the aqueous ophthalmic solution in an amount sufficient such that the aqueous ophthalmic solution has an osmolality in the range of about 50 to about 1000 mOsm / kg, about 100 to about 400 mOsm / kg, about 200 to about 400 mOsm / kg, or about 280 to about 380 mOsm / kg. In certain embodiments, the tonicity adjusting agent may be present in an amount ranging from about 0.01% (wt / vol) to about 7% (wt / vol), from about 0.01% (wt / vol) to about 5% (wt / vol), from about 0.01% (wt / vol) to about 1% (wt / vol), from about 0.1% (wt / vol) to about 1% (wt / vol), from about 0.05% (wt / vol) to about 5% (wt / vol), from about 0.05% (wt / vol) to about 0.5% (wt / vol), from about 1% (wt / vol) to about 3% (wt / vol), or from about 2% (wt / vol) to about 4% (wt / vol) of the aqueous ophthalmic solution.

[0201] B. Preservatives Aqueous ophthalmic solution may optionally contain one or more preservatives, for example, to reduce or prevent microbial contamination.Exemplary preservatives include quaternary ammonium salts such as polyquaternium-1, cetrimide, benzalkonium chloride, or benzoxonium chloride; alkylmercury salts of thiosalicylic acid such as thiomersal, phenylmercuric nitrate, phenylmercuric acetate, or phenylmercuric borate; parabens such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethanol, cyclohexanol, 3-pentanol, or resorcinol; peroxides; chlorine dioxide or PURITE; guanidine derivatives such as chlorhexidine gluconate or polyaminopropyl biguanide; and combinations thereof.

[0202] The amount of preservative can be adjusted to achieve the desired performance characteristics for the aqueous ophthalmic solution. In certain embodiments, the preservative is present in an amount less than about 5% (w / v), 3% (w / v), 1% (w / v), or 0.1% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the preservative is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), from about 0.01% (w / v) to about 1% (w / v), from about 0.1% (w / v) to about 1% (w / v), from about 0.05% (w / v) to about 5% (w / v), or from about 0.05% (w / v) to about 0.5% (w / v) of the aqueous ophthalmic solution.

[0203] C. Antioxidants Aqueous ophthalmic solutions may optionally contain one or more antioxidants.Exemplary antioxidants for use in the aqueous ophthalmic solutions described herein include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium bisulfite, sodium sulfite, etc.; and oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.

[0204] The amount of antioxidant can be adjusted to achieve the desired performance characteristics for the aqueous ophthalmic solution. In certain embodiments, the antioxidant is present in an amount less than about 5% (w / v), 3% (w / v), 1% (w / v), or 0.1% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the antioxidant is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), from about 0.01% (w / v) to about 1% (w / v), from about 0.1% (w / v) to about 1% (w / v), from about 0.05% (w / v) to about 5% (w / v), or from about 0.05% (w / v) to about 0.5% (w / v) of the aqueous ophthalmic solution.

[0205] D. Viscosity modifier Aqueous ophthalmic solution may optionally contain one or more viscosity adjusting agents. Viscosity adjusting agents may be used, for example, to increase the absorption of active agent or increase the retention time of aqueous ophthalmic solution in eye.Exemplary viscosity adjusting agents include polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose (CMC) and its salts (e.g., CMC sodium salt), gelatin, cellulose glycolate, sorbitol, niacinamide, α-cyclodextran, polyvinyl alcohol, polyethylene glycol, hyaluronic acid, polysaccharides, monosaccharides, and combinations thereof.

[0206] The amount of the viscosity modifier can be adjusted to achieve the desired performance characteristics for the aqueous ophthalmic solution. In certain embodiments, the viscosity modifier is present in an amount less than about 10% (w / v), 5% (w / v), 3% (w / v), 1% (w / v), or 0.1% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the viscosity modifier is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), from about 0.01% (w / v) to about 1% (w / v), from about 0.1% (w / v) to about 1% (w / v), from about 0.05% (w / v) to about 5% (w / v), or from about 0.05% (w / v) to about 0.5% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the viscosity modifier is present in an amount sufficient to provide an aqueous ophthalmic solution having a viscosity in the range of about 30 centipoise to about 100 centipoise.

[0207] The viscosity modifier may be a polymer that provides a delayed release of one or more therapeutic agents in solution. The identity of the polymer may be selected to achieve a desired sustained release profile of the one or more therapeutic agents.

[0208] E. Corneal permeation enhancers The aqueous ophthalmic solution may optionally include one or more agents to facilitate corneal penetration of phentolamine (or a pharma- ceutically acceptable salt thereof). Exemplary agents for facilitating corneal penetration include polymers, organic acids, esters of organic acids (e.g., monoglycerides of fatty acids having 8 to 12 carbon atoms), cyclodextrin, benzalkonium chloride (BAK), EDTA, caprylic acid, citric acid, boric acid, sorbic acid, polyoxyethylene-20-stearyl ether (PSE), polyethoxylated castor oil (PCO), deoxycholic acid sodium salt (DC), cetylpyridinium chloride (CPC), laurocapram, hexamethylene lauramide, hexamethylene octanamide, decyl methyl sulfoxide, methyl sulfone, dimethyl sulfoxide, and combinations thereof.

[0209] The amount of corneal permeation enhancer can be adjusted to achieve the desired performance characteristics for the aqueous ophthalmic solution. In certain embodiments, the corneal permeation enhancer is present in an amount less than about 10% (w / v), 5% (w / v), 1% (w / v), or 0.1% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the corneal permeation enhancer is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), from about 0.01% (w / v) to about 1% (w / v), from about 0.1% (w / v) to about 1% (w / v), from about 0.05% (w / v) to about 5% (w / v), from about 0.05% (w / v) to about 0.5% (w / v), from about 1% (w / v) to about 3% (w / v), or from about 2% (w / v) to about 4% (w / v) of the aqueous ophthalmic solution.

[0210] F. Solubilizers The aqueous ophthalmic solution may optionally include one or more solubilizing agents to improve the solubility of phentolamine (or a pharma- ceutically acceptable salt thereof) in the aqueous ophthalmic solution. Exemplary solubilizing agents include, for example, fatty acid glycerol poly-low alkylene (i.e., C1-C7, linear or branched) glycol esters, fatty acid poly-low alkylene glycol esters, polyalkylene glycols (e.g., polyethylene glycol), glycerol ethers of vitamin E, tocopherol polyethylene glycol 1000 succinate (TPGS), tyloxapol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyethylene / polyoxypropylene surfactants (e.g., Pluronic F-68, F-84, and P-103), cyclodextrins, modified cyclodextrins, and combinations thereof. In certain embodiments, the solubilizing agent is a modified cyclodextrin, such as that sold under the brand name CAPTISOL®.

[0211] The amount of solubilizing agent can be adjusted to achieve the desired performance characteristics for the aqueous ophthalmic solution. In certain embodiments, the solubilizing agent is present in an amount less than about 10% (w / v), 5% (w / v), 3% (w / v), 1% (w / v), or 0.1% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the solubilizing agent is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), from about 0.01% (w / v) to about 1% (w / v), from about 0.1% (w / v) to about 1% (w / v), from about 0.05% (w / v) to about 5% (w / v), or from about 0.05% (w / v) to about 0.5% (w / v) of the aqueous ophthalmic solution.

[0212] G. Stabilizers The aqueous ophthalmic solution may optionally include one or more stabilizers to improve the stability of the aqueous ophthalmic solution, such as during storage. Stabilizers described in the pharmaceutical literature are contemplated as suitable for use in the aqueous ophthalmic solutions described herein. Exemplary stabilizers include alcohols (e.g., polyols such as mannitol, glycerol, propylene glycol, sorbitol, and xylitol), polyalkylene glycols, such as polyethylene glycol, polypropylene glycol, polyethylene glycol-nonphenolic ether, polyethylene glycol sorbitan monolaurate, polyethylene glycol sorbitan monooleate, polyethylene glycol sorbitan monooleate, polyethylene glycol stearate, polyethylene glycol polypropylene glycol ether, polyvinyl alcohol, polyvinylpyrrolidine, ascorbic acid, vitamin E, N-acetylcarnosine (NAC), sorbic acid, and combinations thereof. In certain embodiments, the stabilizer is a polymer, such as one of the polymers described above.

[0213] The amount of stabilizer can be adjusted to achieve the desired performance characteristics for the aqueous ophthalmic solution. In certain embodiments, the stabilizer is present in an amount less than about 10% (w / v), 5% (w / v), or 1% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the stabilizer is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), from about 0.01% (w / v) to about 1% (w / v), or from about 0.01% (w / v) to about 0.1% (w / v) of the aqueous ophthalmic solution.

[0214] H. Surfactants The aqueous ophthalmic solution may optionally include one or more surfactants. Exemplary surfactants include polysorbate 20 (i.e., polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (i.e., polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (i.e., polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (i.e., polyoxyethylene (20) sorbitan monooleate), glyceryl stearate, isopropyl stearate, polyoxyl stearate, propylene glycol stearate, stearate, glyceryl stearate, glyceryl stearate, isopropyl stearate, polyoxyl stearate, propylene glycol stearate, glyceryl stearate, glyceryl stearate, isopropyl stearate, polyoxyl stearate, propylene glycol stearate, glyceryl stearate, isopropyl stearate, polyoxyl ... isopropyl stea Included are sucrose phosphate, polyethylene glycol, polypropylene oxide, polypropylene oxide copolymer, Pluronic F68, Pluronic F-84, Pluronic P-103, alcohol ethoxylates, alkylphenol ethoxylates, alkyl glycosides, alkyl polyglycosides, fatty alcohols, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), cyclodextrin, polyacrylic acid, phosphatidyl chlorine, phosphatidyl serine, and combinations thereof.

[0215] The amount of surfactant can be adjusted to achieve the desired performance characteristics for the aqueous ophthalmic solution. In certain embodiments, the surfactant is present in an amount less than about 10% (w / v), 5% (w / v), 3% (w / v), 1% (w / v), or 0.1% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the surfactant is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), from about 0.01% (w / v) to about 1% (w / v), from about 0.1% (w / v) to about 1% (w / v), from about 0.05% (w / v) to about 5% (w / v), or from about 0.05% (w / v) to about 0.5% (w / v) of the aqueous ophthalmic solution.

[0216] I. Demulcent Polymers Aqueous ophthalmic solutions may optionally contain one or more demulcent polymers. Due to their ability to hold large amounts of water, demulcent polymers are useful for coating and moisturizing the cornea of ​​the eye. Exemplary demulcent polymers include cellulose derivatives, dextran 40, dextran 70, gelatin, and liquid polyols.

[0217] J. Wetting Agents The aqueous ophthalmic solution may optionally include one or more wetting agents. Wetting agents can be used to wet the ocular surface. Exemplary wetting agents include polysorbates, poloxamers, tyloxapol, and lecithin.

[0218] K. Additional Materials The aqueous ophthalmic solution may optionally contain one or more additional ingredients such as acetylcysteine, cysteine, sodium bisulfite, butyl-hydroxyanisole, butyl-hydroxytoluene, α-tocopherol acetate, thiourea, thiosorbitol, sodium dioctyl sulfosuccinate, monothioglycerol, sorbitol laurate, triethanolamine oleate, or palmitate.

[0219] Additionally, the aqueous ophthalmic solution may include a carrier, for example, one or more of the exemplary carriers described, for example, in Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] . The carrier may be, for example, a mixture of water and a water-miscible solvent (e.g., an alcohol such as glycerin, a vegetable oil, or a mineral oil). Other exemplary carriers include a mixture of water and one or more of the following materials: hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, alkali metal salts of carboxymethyl cellulose, hydroxymethyl cellulose, methylhydroxypropyl cellulose, hydroxypropyl cellulose, ethyl oleate, polyvinylpyrrolidone, acrylate polymers, methacrylate polymers, polyacrylamide, gelatin, alginate, pectin, tragacanth, karaya gum, xanthan gum, carrageenan, agar, acacia, starch (such as starch acetate or hydroxypropyl starch), polyvinyl alcohol, polyvinyl methyl ether, polyethylene oxide, or cross-linked polyacrylic acid.

[0220] Exemplary Aqueous Ophthalmic Solutions The aqueous ophthalmic solutions generally described above will now be more particularly described by reference to the following more specific examples, which are merely illustrative and are not intended to limit the scope of the invention in any way.

[0221] One such exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound selected from the group consisting of mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; and (d) water, wherein the solution has a pH in the range of 4 to 6 and does not contain a chelating agent.

[0222] The aqueous ophthalmic solution may be more specifically defined according to the following embodiments. For example, in certain embodiments, the aqueous ophthalmic solution comprises about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate. In certain embodiments, the aqueous ophthalmic solution comprises about 1% (w / v) to about 4% (w / v) mannitol. In certain other embodiments, the aqueous ophthalmic solution comprises 4% (w / v) mannitol. In certain embodiments, the alkali metal acetate is sodium acetate. In certain other embodiments, the aqueous ophthalmic solution comprises 3 mM sodium acetate. In yet another embodiment, the aqueous ophthalmic solution comprises: (i) about 0.25% (wt / vol) to about 1% (wt / vol) of phentolamine mesylate; (ii) about 1% (wt / vol) to about 6% (wt / vol) of one or more polyol compounds selected from the group consisting of mannitol, glycerol, and propylene glycol; (iii) about 1 mM to about 6 mM of an alkali metal acetate; (iv) acetic acid; and (v) water, wherein the solution has a pH in the range of 4 to 6.

[0223] Another such exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound selected from the group consisting of mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; and (d) water, wherein the solution has a pH in the range of 4.5 to 5.5 and does not contain a chelating agent.

[0224] The aqueous ophthalmic solution may be more specifically defined according to the following embodiments. For example, in certain embodiments, the at least one polyol is mannitol. In certain embodiments, the aqueous ophthalmic solution comprises about 1% (weight / volume) to about 4% (weight / volume) mannitol. In certain other embodiments, the aqueous ophthalmic solution comprises 4% (weight / volume) mannitol. In certain embodiments, the alkali metal acetate is sodium acetate. In certain other embodiments, the aqueous ophthalmic solution comprises 3 mM sodium acetate. In yet another embodiment, the aqueous ophthalmic solution comprises: (i) about 0.5% (wt / vol) to about 2% (wt / vol) of phentolamine mesylate; (ii) about 1% (wt / vol) to about 6% (wt / vol) of one or more polyol compounds selected from the group consisting of mannitol, glycerol, and propylene glycol; (iii) about 1 mM to about 6 mM of an alkali metal acetate; (iv) acetic acid; and (v) water, wherein the solution has a pH in the range of 4.5 to 5.5.

[0225] Another such exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.25% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound selected from the group consisting of mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; and (d) water, wherein the solution has a pH in the range of 4.5 to 5.5 and does not contain a chelating agent.

[0226] The aqueous ophthalmic solution may be more specifically defined according to the following embodiments. For example, in certain embodiments, the aqueous ophthalmic solution comprises about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises about 1% (w / v) to about 4% (w / v) mannitol. In certain other embodiments, the aqueous ophthalmic solution comprises 4% (w / v) mannitol. In certain embodiments, the alkali metal acetate is sodium acetate. In certain other embodiments, the aqueous ophthalmic solution comprises 3 mM sodium acetate. In yet another embodiment, the aqueous ophthalmic solution comprises: (i) about 0.5% (wt / vol) to about 1% (wt / vol) of phentolamine mesylate; (ii) about 1% (wt / vol) to about 6% (wt / vol) of one or more polyol compounds selected from the group consisting of mannitol, glycerol, and propylene glycol; (iii) about 1 mM to about 6 mM of an alkali metal acetate; (iv) acetic acid; and (v) water, wherein the solution has a pH in the range of 4.5 to 5.5.

[0227] Further exemplary aqueous ophthalmic solutions are provided below in Tables 1-3, in each case the solutions have a pH in the range of 4.7 to 5.1. [Table 7] [Table 8] [Table 9]

[0228] Another exemplary aqueous ophthalmic solution comprises phentolamine mesylate (e.g., 1% weight / volume), mannitol (e.g., 4% weight / volume), dextran having a weight average molecular weight of about 70,000 g / mol (e.g., 0.1% weight / volume), hydroxypropyl methylcellulose (e.g., 0.3% weight / volume), potassium chloride, purified water, sodium borate, and sodium chloride, and the solution has a pH in the range of about 4 to about 6. In certain embodiments, the solution has a pH in the range of 4.5 to 5.1. In certain embodiments, the aqueous ophthalmic solution consists essentially of phentolamine mesylate (e.g., 1% weight / volume), mannitol (e.g., 4% weight / volume), dextran having a weight average molecular weight of about 70,000 g / mol (e.g., 0.1% weight / volume), hydroxypropyl methylcellulose (e.g., 0.3% weight / volume), potassium chloride, purified water, sodium borate, and sodium chloride, and the solution has a pH in the range of 4 to 6. In certain other embodiments, the aqueous ophthalmic solution consists of phentolamine mesylate (e.g., 1% weight / volume), mannitol (e.g., 4% weight / volume), dextran having a weight average molecular weight of about 70,000 g / mol (e.g., 0.1% weight / volume), hydroxypropyl methylcellulose (e.g., 0.3% weight / volume), potassium chloride, purified water, sodium borate, and sodium chloride, and the solution has a pH in the range of 4.5 to 5.1.

[0229] Another exemplary aqueous ophthalmic solution comprises phentolamine mesylate (e.g., 1% weight / volume), mannitol (e.g., 4% weight / volume), sodium acetate (e.g., 3 mM), and water, and the solution has a pH in the range of about 4 to about 6. In certain embodiments, the solution has a pH in the range of 4.5 to 5.1. In certain embodiments, the aqueous ophthalmic solution consists essentially of phentolamine mesylate (e.g., 1% weight / volume), mannitol (e.g., 4% weight / volume), sodium acetate (e.g., 3 mM), and water, and the solution has a pH in the range of 4 to 6. In certain embodiments, the aqueous ophthalmic solution comprises phentolamine mesylate 1% weight / volume, mannitol 4% weight / volume, sodium acetate 3 mM, and water, and the solution has a pH in the range of 4.5 to 5.1. In certain other embodiments, the aqueous ophthalmic solution consists essentially of phentolamine mesylate (e.g., 1% weight / volume), mannitol (e.g., 4% weight / volume), sodium acetate (e.g., 3 mM), and water, and the solution has a pH in the range of 4.5 to 5.1. In certain embodiments, the aqueous ophthalmic solution consists essentially of phentolamine mesylate 1% weight / volume, mannitol 4% weight / volume, sodium acetate 3 mM, and water, and the solution has a pH in the range of 4.5 to 5.1.

[0230] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound selected from the group consisting of mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; and (d) water, wherein the solution has a pH in the range of 4 to 6 and does not contain a chelating agent.

[0231] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.25% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) about 2 mM to about 4 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0232] Yet another exemplary solution is a chelator-free aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) about 2 mM to about 4 mM sodium acetate; and (d) water, the solution having a pH in the range of 4.6 to 5.2 and containing no chelator. In certain embodiments, the chelator-free aqueous ophthalmic solution comprises about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate.

[0233] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.25% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) about 2 mM to about 4 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.5 to 5.2 and does not contain a chelating agent.

[0234] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) about 2 mM to about 4 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0235] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) about 1 mM to about 4 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0236] Yet another exemplary solution is a chelator-free aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodium acetate; and (d) water, the solution having a pH in the range of 4.6 to 5.2 and containing no chelator. In certain embodiments, the chelator-free aqueous ophthalmic solution comprises about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate.

[0237] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0238] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.25% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) a buffer comprising about 2 mM to about 4 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.5 to 5.2 and does not contain a chelating agent.

[0239] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) a buffer comprising about 2 mM to about 4 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0240] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) a buffer comprising about 1 mM to about 4 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0241] Yet another exemplary solution is a chelator-free aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 4% mannitol; (c) a buffer comprising about 3 mM sodium acetate; and (d) water, the solution having a pH in the range of 4.6 to 5.2 and containing no chelator. In certain embodiments, the chelator-free aqueous ophthalmic solution comprises about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate.

[0242] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 4% mannitol; (c) a buffer comprising about 3 mM sodium acetate; and (d) water, wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0243] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.25% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) a buffer containing about 2 mM to about 4 mM sodium acetate; (d) water; and (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine), wherein the solution has a pH in the range of 4.5 to 6.0 and does not contain a chelating agent.

[0244] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) a buffer containing about 2 mM to about 4 mM sodium acetate; (d) water; and (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine), wherein the solution has a pH in the range of 4.6 to 6.0 and does not contain a chelating agent.

[0245] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) a buffer containing about 1 mM to about 4 mM sodium acetate; (d) water; and (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine), wherein the solution has a pH in the range of 4.6 to 6.0 and does not contain a chelating agent.

[0246] Yet another exemplary solution is a chelator-free aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 4% mannitol; (c) a buffer solution comprising about 3 mM sodium acetate; (d) water; and (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine), the solution having a pH in the range of 4.6 to 6.0 and containing no chelator. In certain embodiments, the chelator-free aqueous ophthalmic solution comprises about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate.

[0247] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 4% mannitol; (c) a buffer containing about 3 mM sodium acetate; (d) water; and (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine), wherein the solution has a pH in the range of 4.6 to 6.0 and does not contain a chelating agent.

[0248] Yet another exemplary solution is an aqueous ophthalmic solution comprising: (a) about 0.25% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) a buffer comprising about 2 mM to about 4 mM sodium acetate; (d) water; and (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine), the solution having a pH in the range of 4.5 to 6.0.

[0249] Yet another exemplary solution is an aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 2% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) a buffer comprising about 2 mM to about 4 mM sodium acetate; (d) water; and (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine), the solution having a pH in the range of 4.6 to 6.0.

[0250] Yet another exemplary solution is an aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) mannitol; (c) a buffer comprising about 1 mM to about 4 mM sodium acetate; (d) water; (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine); and (f) glycerol, wherein the solution has a pH in the range of 4.6 to 6.0.

[0251] Yet another exemplary solution is an aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 4% mannitol; (c) a buffer comprising about 3 mM sodium acetate; (d) water; (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine); and (f) glycerol, the solution having a pH in the range of 4.6 to 6.0. In certain embodiments, the chelating agent-free aqueous ophthalmic solution comprises about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate.

[0252] Yet another exemplary solution is an aqueous ophthalmic solution comprising: (a) about 0.5% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 4% mannitol; (c) a buffer comprising about 3 mM sodium acetate; (d) water; (e) pilocarpine (e.g., about 0.1% w / v to about 1% w / v pilocarpine); and (f) glycerol, wherein the solution has a pH in the range of 4.6 to 6.0.

[0253] Stability characteristics of aqueous ophthalmic solutions. The aqueous ophthalmic solutions described herein can be further characterized according to their stability characteristics, such as the percentage of phentolamine (or its pharma- ceutically acceptable salt) present in the aqueous ophthalmic solution after storage for a particular length of time.As explained above, one of the benefits of the present aqueous ophthalmic solutions is that they have good stability over long periods of time, even though they do not have a chelating agent.

[0254] Thus, in certain embodiments, the aqueous ophthalmic solution is characterized in that less than 2% by weight of phentolamine or a pharma- ceutically acceptable salt thereof degrades after storage of the solution for 12 weeks at 25°C. In certain other embodiments, the aqueous ophthalmic solution is characterized in that less than 2% by weight of phentolamine or a pharma- ceutically acceptable salt thereof degrades after storage for 24 weeks (or 36 weeks or 48 weeks) at 25°C. In still other embodiments, less than 7% by weight of phentolamine or a pharma- ceutically acceptable salt thereof degrades after storage for 12 weeks (or 24, 36, or 48 weeks) at 40°C. In still other embodiments, the aqueous ophthalmic solution is characterized in that less than 10% by weight of phentolamine or a pharma- ceutically acceptable salt thereof degrades after storage for 18 months, 24 months, or 36 months at 25°C. In still other embodiments, the aqueous ophthalmic solution is characterized in that less than 10% by weight of phentolamine or a pharma- ceutically acceptable salt thereof degrades after storage for 18 months, 24 months, or 36 months at a temperature in the range of 2-8°C. In yet other embodiments, the aqueous ophthalmic solution is characterized in that less than 4% by weight (or preferably less than 3% by weight) of the phentolamine or pharma- ceutically acceptable salt thereof degrades after 18, 24, or 36 months of storage at 25° C. In yet other embodiments, less than 10% by weight of the phentolamine or pharma- ceutically acceptable salt thereof degrades after 4, 5, or 6 months of storage at 40° C.

[0255] Polyvinylpyrrolidone artificial tears Another ophthalmic solution contemplated for use in the present invention is an ophthalmic solution comprising a therapeutic agent (e.g., an α-adrenergic antagonist such as phentolamine or a pharma- ceutically acceptable salt thereof) and a polyvinylpyrrolidone artificial tear composition. Exemplary polyvinylpyrrolidone artificial tear compositions are described, for example, in U.S. Pat. Nos. 5,895,654, 5,627,611, and 5,591,426, and U.S. Patent Application Publication No. 2002 / 0082288, all of which are incorporated herein by reference. It is understood that the artificial tear composition promotes wetting and spreading, has good retention and stability in the eye, and desirably does not cause any significant discomfort to the user. Thus, an exemplary polyvinylpyrrolidone artificial tear composition includes: (1) polyvinylpyrrolidone, preferably in an amount of about 0.1-5% by weight of the solution; (2) benzalkonium chloride, preferably in an amount of about 0.01-0.10% by weight of the solution; (3) hydroxypropyl methylcellulose, preferably in an amount of about 0.2-1.5% by weight of the solution; (4) glycerin, preferably in an amount of about 0.2-1.0% by weight of the solution; and (5) water, wherein the composition is an isotonic aqueous solution.

[0256] Sustained Release Delivery Systems When it is desirable to have a sustained release of one or more therapeutic agents to the patient, the therapeutic agent(s) can be administered to the patient in the form of a sustained release delivery system. Sustained release delivery systems are described in published literature. Exemplary sustained release delivery systems include intracanalicular inserts, sustained release contact lenses, bioerodible IVT inserts, and intracameral inserts. The inserts can be biodegradable or non-biodegradable. Exemplary materials described in the literature for use in sustained release delivery systems include mixtures of EVA and PVA polymers, mixtures of silicone and PVA polymers, mixtures of polyimide and PVA polymers, mixtures of PMMA and EVA polymers, PLGA polymers, and liposomes. In certain embodiments, the ophthalmic solution can contain an oil, such as an oil with a viscosity high enough to prevent removal of the active ingredient from the ocular surface when an aliquot of the ophthalmic solution is applied to the ocular surface.

[0257] IV. Medical Kit Another aspect of the invention provides medical kits that include, for example, (i) a therapeutic agent described herein and (ii) instructions for treating presbyopia, mydriasis, and / or other ocular disorders according to the methods described herein. EXAMPLES

[0258] The invention having been generally described herein will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0259] Example 1 - Treatment of Presbyopia with Phentolamine Mesylate in Human Subjects The ability of phentolamine mesylate to treat human subjects suffering from presbyopia can be evaluated according to a clinical trial in which an aqueous ophthalmic solution containing phentolamine mesylate is administered to the patient's eye, and the patient is then evaluated for improvement in visual performance, including near visual performance. The experimental procedure and results are described below.

[0260] Part I - Experimental Procedure Human subjects are screened for potential enrollment and, if eligible, enrolled in the study. Exemplary inclusion and exclusion criteria for the study are provided below. If a subject does not meet the inclusion / exclusion criteria but the study investigator believes the subject should participate in the study, deviations may be allowed after discussion between the study director and the study sponsor. Inclusion criteria 45~55 years old. · Distance-corrected near vision worse than 20 / 40. ·Best corrected distance visual acuity of 20 / 20 or better in each eye. ·Able and willing to give informed consent and comply with all protocol-mandated procedures. Exclusion criteria Certain pupil conditions. ·Significant astigmatism, glaucoma, diabetes, cataracts, eye surgery, eye trauma, or accommodation problems. -Wearing contact lenses within 3 days prior to and for the duration of the study. Use of prohibited medicines. · Participation in any research study within the past 30 days.

[0261] Human subjects enrolled in the study will be randomized in a 1:1 randomization into two (or more) treatment arms. Treatment arms will receive a single dose of either: Placebo ophthalmic solution, 1% w / w phentolamine mesylate ophthalmic solution, or · 2% w / w phentolamine mesylate ophthalmic solution. A description of the study medications is provided in Table 1. [Table 10]

[0262] Doses of study medication are given once daily for one or more weeks. Visual performance is assessed, which may include analysis of near visual acuity, best corrected distance visual acuity (BCDVA), distance corrected near visual acuity (DCNVA), and / or visual acuity questionnaires.

[0263] Example 2 - Treatment of Presbyopia with Phentolamine Mesylate in Human Subjects The ability of phentolamine mesylate to treat human subjects suffering from presbyopia can be evaluated according to a clinical trial in which an aqueous ophthalmic solution containing phentolamine mesylate is administered to the patient's eye, and the patient is then evaluated for improvement in visual performance, including near visual performance. The experimental procedure and results are described below.

[0264] Part I - Experimental Procedure Human subjects are screened for potential enrollment and, if eligible, enrolled in the study. Exemplary inclusion and exclusion criteria for the study are provided below. If a subject does not meet the inclusion / exclusion criteria but the study investigator believes the subject should participate in the study, deviations may be allowed after discussion between the study director and the study sponsor. Inclusion criteria ·Able and willing to provide written informed consent and sign a Health Information Portability and Accountability Act (HIPAA) form before any study procedures are performed. ·Able and willing to follow all instructions and attend study visits. · Be 48-64 years of age at Visit 1, of any gender and any race or ethnicity. Early to moderate presbyopia as determined by screening monocular best corrected distance visual acuity (VA) at 45 cm. · It is possible and willing to avoid all unauthorized medicinal products over appropriate washout periods and during the study without significant risk to the subject. Exclusion criteria - Women of childbearing potential who are currently pregnant, breastfeeding, or planning to become pregnant. Have a known contraindication or sensitivity to the use of the study medicinal product(s) or any of its components. Have an active ocular infection (bacterial, viral, or fungal) at Visit 1 in either eye, a positive history of ocular herpes infection, preauricular lymphadenopathy, or ongoing, active ocular inflammation (e.g., moderate to severe blepharitis, allergic conjunctivitis, peripheral ulcerative keratitis, scleritis, uveitis). Have moderate or severe dry eyes. Have clinically significant abnormal lens findings (e.g., cataract) including any evidence of premature lens exchange and / or optic opacification in either eye. Have a dark-adapted pupil measurement of <4.0mm in either eye. Have intraocular pressure (IOP) less than 5 millimeters of mercury (mmHg) or greater than 22 mmHg in either eye recorded at Visit 1, or have a prior diagnosis of ocular hypertension or glaucoma, or are currently being treated with any type of topical IOP-lowering (glaucoma) medication at Visit 1. Have an abnormal dilated fundus examination in either eye recorded within 3 months of Visit 1, or a known history of retinal detachment or clinically significant retinal disease in either eye. ·Having a known previous history or diagnosis of iritis, scleritis, or uveitis, whether active or inactive. Having undergone a surgical intervention (ocular or systemic) within 6 months prior to Visit 1 or planned for a surgical intervention within 30 days after Visit 4. · Have undergone refractive eye surgery (open keratoplasty, photorefractive keratectomy [PRK], laser in situ keratomileusis [LASIK], laser-assisted subepithelial keratectomy [LASEK]), corneal inlay procedure, cataract extraction, or intraocular lens placement. Use artificial tears or a lubricating eye ointment regularly. · Unable or refusing to discontinue soft contact lens wear 7 days prior to study Visit 1 and rigid gas permeable (RGP) contact lens wear 14 days prior to Visit 1 and during the study. - The following unauthorized medications during the 2 weeks (14 days) prior to Visit 1 and during the study: (1) narcotic (opiate class) pain medications (e.g., codeine, OxyContin®, Vicodin®, Tramadol®), (2) bladder medications (e.g., Urecholine®, bethanechol), (3) antipsychotics, (4) antidepressants, (5) attention-deficit / hyperactivity disorder (ADHD) medications, (6) alpha-blockers (e.g., tamsulosin, Flomax®, Jayln®, Uroxatral®, Rapaflo®, (7) anticholinergics (e.g., atropine, belladonna, benztropine, dicyclomine, donepezil, hyoscyamine, propantheline, scopolamine, trihexyphenidyl), (8) muscarinic receptor agonists or cholinergic agonists (e.g., Salagen®, Evoxac®), (9) over-the-counter (OTC) or prescription antihistamines or decongestants, (10) prescribed topical ophthalmic medications, or (11) recreational drug use (e.g., marijuana, methadone, heroin, cocaine). - Have a diagnosis of diabetes or a history of hyperglycemia. · Has a condition or situation that, in the opinion of the Investigator, places the subject at increased risk, confounds the study data, or may significantly interfere with the subject's participation in the study, including, but not limited to, unstable: cardiovascular, hepatic, renal, respiratory, gastrointestinal, endocrine, immune, dermatological, hematological, neurological, or psychiatric disorders.

[0265] Human subjects enrolled in the study will be randomized in a 1:1 randomization into two (or more) treatment arms. Treatment arms will receive a single dose of either: Placebo ophthalmic solution, 1% w / w phentolamine mesylate ophthalmic solution, or · 2% w / w phentolamine mesylate ophthalmic solution. A description of the study medications is provided in Table 1. [Table 11]

[0266] Doses of study medication are given once daily for one or more weeks. Visual performance is assessed, which may include analysis of near visual acuity, best corrected distance visual acuity (BCDVA), distance corrected near visual acuity (DCNVA), and / or visual acuity questionnaires.

[0267] One measure of performance is the percentage of subjects with an improvement of at least 3 lines (15 letters) in the study eye in post-treatment monocular best corrected distance visual acuity at 45 cm compared to baseline monocular best corrected distance visual acuity at 45 cm up to 7 hours after treatment.

[0268] Another measure of performance is the percentage of subjects with an improvement of at least 3 lines (15 letters) in the test eye in a post-treatment near visual acuity measurement compared to baseline, such as by 7 hours after treatment.

[0269] Example 3 - Improvement of mydriasis in human subjects using phentolamine mesylate The ability of phentolamine mesylate to reverse pharmacologically induced mydriasis in the eyes of normal, healthy human subjects was evaluated according to a randomized, crossover, double-blind, placebo-controlled clinical trial. Approximately 32 subjects were enrolled and randomized 1:1 to one of two treatment sequences. All subjects were first administered a mydriatic agent (phenylephrine (2.5% wt / wt) or tropicamide (1% wt / wt)) by delivery of eye drops containing the mydriatic agent to the subjects' eyes. Then, approximately 1 hour after receiving the mydriatic agent, subjects were administered the study medication according to treatment protocol 1 or treatment protocol 2.

[0270] In treatment protocol 1, subjects received a placebo on the first treatment day (Visit 1 / Day 1) and a 1% wt / wt phentolamine mesylate ophthalmic solution on the second treatment day (Visit 2 / Day 8+2). In treatment protocol 2, subjects received a 1% wt / wt phentolamine mesylate ophthalmic solution on the first treatment day (Visit 1 / Day 1) and a placebo on the second treatment day (Visit 2 / Day 8+2). The study eye was defined as the eye with the larger pupil diameter at maximum (1 hour after instillation of mydriatic agent) at Visit 1. If both eyes had the same pupil diameter at maximum, the study eye was the right eye. This was the study eye for both Visit 1 and Visit 2 evaluations.

[0271] All treatments were administered to both eyes of the subjects. At each visit, pupil diameter, accommodation, near and far visual acuity (VA), and redness in each eye were measured before (-1 hour / baseline) and 1 hour (0 minutes / max) mydriatic drops in each eye (i.e., immediately before the study treatment was administered), and 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after treatment administration. Efficacy and safety were evaluated, including analysis of pupil diameter reduction. Further aspects of the experimental procedures and results are described below.

[0272] Part I - Experimental Procedure Human subjects were screened for potential enrollment and, if eligible, enrolled in the study. The inclusion and exclusion criteria for the study are listed below. Subjects enrolled in the study were randomized in a 1:1 ratio to one of two treatment sequences (the first treatment sequence involved subjects receiving a placebo on the first treatment day and a 1% wt / wt phentolamine mesylate ophthalmic solution on the second treatment day, and the second treatment sequence involved subjects receiving a 1% wt / wt phentolamine mesylate ophthalmic solution on the first treatment day and a placebo on the second treatment day). Randomization was stratified by mydriatic agent (phenylephrine or tropicamide), with randomization to each stratum capped at approximately 16 subjects (approximately half of the randomized subjects received phenylephrine and half received tropicamide). Subjects received their mydriatic agent 1 hour prior to treatment. Treatment Visit 1 was the first day that subjects received the first treatment in the treatment sequence. Treatment Visit 2 was Day 8+2 when subjects received the second treatment in their treatment sequence. Each subject received the same mydriatic agent throughout the study. Efficacy and safety were evaluated as described below. Study medications are listed in Table 1. [Table 12] Inclusion criteria 1. Only men or women aged ≥18~≤45 years with brown irises. 2. Subjects who are otherwise healthy and well-maintained. 3. Ability to adhere to all protocol mandated procedures and attend all scheduled office visits. 4. Willing to give written informed consent to participate in this study. Exclusion criteria 1. Clinically significant ocular disease judged by the investigator to be likely to interfere with the study (e.g., cataract, glaucoma, corneal edema, uveitis, severe keratoconjunctivitis sicca). 2. Unwilling or unable to discontinue contact lens wear during treatment visits. 3. Ocular trauma, ocular surgery, or non-refractive laser treatment within 6 months prior to screening. 4. Ophthalmic medications of any kind within 30 days of screening, except a) lid scrubs (which may have been used before screening, but not after screening); or b) lubricating drops for dry eyes (preservative-free artificial tears), which were permitted to be used during the study treatment days. 5. Recent or current evidence at screening of ocular infection or inflammation. Current evidence of clinically significant blepharitis, conjunctivitis, or a history of herpes simplex or herpes zoster keratitis at screening. 6. History of diabetic retinopathy. 7. Closed or very narrow angle that, in the opinion of the investigator, was potentially occlusive when the subject's pupil was dilated. 8. History of any traumatic (surgical or non-surgical) or non-traumatic condition affecting the pupil or iris (e.g., irregular pupil, neurogenic pupillary disorder, iris atrophy, iridotomy). 9. Known allergy or contraindication to any component of the mydriatic or vehicle formulation. 10. Known hypersensitivity or contraindication to α- and / or β-adrenergic receptor antagonists (e.g., chronic obstructive pulmonary disease or bronchial asthma, abnormally low blood pressure (BP) or heart rate (HR), second or third degree heart block or congestive heart failure (CHF), severe diabetes mellitus). 11. Clinically significant systemic disease that may have interfered with the study (e.g., poorly controlled diabetes mellitus, myasthenia gravis, cancer, hepatic, renal, endocrine, or cardiovascular disorders). 12. Initiation of treatment with any local or systemic adrenergic or cholinergic medication, or any change to its current dose, medication, or regimen, up to 7 days prior to screening or during the study. 13. Participation in any research study within 30 days prior to screening. 14. Women of childbearing potential who are pregnant, lactating, planning to become pregnant, or not using a medically acceptable form of contraception. Acceptable methods include use of at least one of the following: intrauterine device (IUD), hormonal (oral, injection, patch, implant, ring), barrier with spermicide (condom, diaphragm), or abstinence. Adult women were considered of childbearing potential unless they were 1 year postmenopausal or 3 months poststerilization. All women of childbearing potential must have had negative urine pregnancy test results at Visit 1 screening and Visit 2 testing and intended not to become pregnant during the study. 15. Resting HR outside the normal range (50-110 beats per minute) at the screening visit. HR was allowed to be repeated only once if outside the normal range after a resting period of at least 5 minutes in a sitting position. 16. Hypertension with resting diastolic BP > 105mmHg or systolic BP > 160mmHg at the screening visit. BP was allowed to be repeated only once if outside the specified range after a rest period of at least 5 minutes in the sitting position.

[0273] As stated in the exclusion criteria, the following were prohibited during the study: Use of any ophthalmic medications within 30 days of the screening visit, or anticipated use during the study, except for lubricating drops for dry eye (preservative-free artificial tears), which were permitted for use throughout the study. Initiation of treatment with any topical or systemic adrenergic or cholinergic medication, or any change to the dose, medication, or regimen, up to 7 days prior to screening or during the study. Many medications, both prescription and over-the-counter (OTC), contain active ingredients that can affect pupil diameter. This includes many eye drops, such as Visine, used to reduce redness, most cold and flu medications, antihistamines and bronchodilators, most nasal sprays, most blood pressure medications, many medications used for migraines, and many other products.

[0274] Intermittent use of OTC lubricating drops (preservative-free artificial tears) for dry eye was permitted between treatment visits; however, no other ophthalmic medications (OTC or prescription) were permitted within 30 days of the screening visit or during the study.

[0275] Efficacy analysis The primary efficacy endpoint was the change in pharmacologically induced mydriatic (maximal) pupil diameter (0 min) at 2 hours post-treatment in the study eye. The study eye was defined as the eye with the larger pupil diameter at maximum (1 hour after instillation of mydriatic agent) at Visit 1. If both eyes had the same pupil diameter at maximum, the study eye was the right eye. This was the study eye for both Visit 1 and Visit 2 evaluations.

[0276] Secondary efficacy endpoints (study eye, non-study eye, and both eyes) included: Change (mm) from maximum pupil diameter (0 min) at each remaining time point (30 min, 1 h, 4 h, 6 h). The percentage of subjects who achieved pre-specified reductions of ≥ 2mm, ≥ 3mm, and ≥ 4mm from maximum pupil diameter at each time point (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours). Percentage of subjects who achieved a pupil diameter ≤0.5 mm above baseline (-1 hour) at each time point (0 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours). Change from baseline (-1 hour) in accommodation at each time point (0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours). Percentage of subjects with unchanged adjustment from baseline (-1 hour) at each time point (0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours). Change from baseline (-1 hour) in BCDVA at each time point (0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours). Percentage of subjects who returned to baseline (-1 hour) BCDVA at each time point (0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours). Change from baseline (-1 hour) in DCNVA at each time point (0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours). Percentage of subjects returning to baseline (-1 hour) DCNVA at each time point (0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours). The change from baseline (-1 hour) in conjunctival hyperemia at each time point (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours) for the study eye and non-study eye in all subjects, in subjects using LUMIFY® (an ophthalmic solution containing brimonidine tartrate (0.025% weight / weight) sold by Bausch & Lomb, Inc.), and in subjects not using LUMIFY®.

[0277] Each efficacy endpoint was analyzed overall and by mydriatic agent.

[0278] Evaluating, recording, and analyzing efficacy parameters Pupil diameter, accommodation, near and distance visual acuity were measured at the screening visit (which was also the same day as treatment visit 1) and treatment visit 2. Pupil diameter was measured with a Neuroptics pupillometer (mm). Accommodation was measured by the Near Point Rule (diopters). Deterioration of accommodation was defined as a decrease in amplitude of >1 diopter compared to baseline. No change also included improvement in accommodation. DCNVA reading / near was measured by standard reading cards (Original Series Sloan Letter Early Treatment Diabetic Retinopathy Study (ETDRS) cards, LogMAR units). BCDVA distances are measured using standard ETDRS charts (letters). Redness was assessed visually using the CCLRU ocular redness scale (0–3).

[0279] All assessments were performed under photopic conditions. Photopic lighting conditions were kept the same during the two treatment visits. Every effort was made to have the same person perform the measurements at all time points and all visits.

[0280] Screening / Day 1 Potential subjects were contacted by the study center to schedule a screening visit, which took place on the same day as Treatment Visit 1, when the first dose of study treatment was administered.

[0281] Upon the subject's arrival at the study center, a member of the study center staff questioned the individual regarding eligibility for study participation and, if the subject wished to continue, signed an informed consent form and was assigned a screening number. Screening included an explanation of the study, medical and ophthalmic history, HR and BP, and a review of previous / concomitant medications. The second step in screening included procedures such as a urine pregnancy test (for women of childbearing potential), IOP assessment, and an ophthalmic examination, including biomicroscopy and direct or indirect ophthalmoscopy without dilation.

[0282] Treatment Visit 1 / Day 1 Treatment Visit 1 was on the same day as Screening. Once the subject completed the Screening assessment portion of the visit and it was determined that he / she met all inclusion criteria but none of the exclusion criteria, the visit then transitioned to the Treatment Visit 1 assessment. As part of Treatment Visit 1, the subject will: Patients were randomized to one of two treatment sequences, and randomization was stratified by mydriatic agent. Received one of two approved mydriatic agents (1% wt / w tropicamide or 2.5% wt / w phenylephrine) at -1 hour / baseline. The mydriatic agent was administered as a single drop to each eye. If the instillation failed, the investigator was to reinstill the eye. Received the first of two study treatments based on his / her randomized treatment sequence at 0±5 min / max. -Ocular tolerability was evaluated at 0±5 minutes / max after instillation of the study drug. The following were assessed compared to study treatment: pupil diameter, BCDVA, DCNVA, accommodation, and conjunctival redness, and any adverse events (AEs) at -1 h / baseline, 0 ± 5 min / max, 30 ± 5 min, 1 h ± 5 min, 2 h ± 10 min, 4 h ± 15 min, and 6 h ± 15 min. · Underwent IOP assessment at 6 hours ±15 minutes. HR and BP were assessed at screening, -1 hour / baseline, 2 hours ± 10 minutes, and 6 hours ± 15 minutes compared with study treatment.

[0283] The study eye was defined as the eye with the larger pupil diameter at maximum (1 hour after instillation of mydriatic agent) at Visit 1. If both eyes had the same pupil diameter at maximum, the study eye was the right eye. This was the study eye for both Visit 1 and Visit 2 evaluations.

[0284] If necessary, 2 hours after treatment, subjects were allowed to request administration of LUMIFY®, an ophthalmic solution containing brimonidine tartrate (0.025% weight / weight) sold by Bausch & Lomb, Inc., in the non-study eye (the facility was to record such use).

[0285] Treatment visit 2 / day 8+2 On Study Day 8+2, subjects returned to the clinic for Treatment Visit 2. As part of Treatment Visit 2, subjects: · Concomitant medications were reviewed, and women of childbearing potential underwent a urine pregnancy test. Received the same approved mydriatic agent (1% tropicamide or 2.5% phenylephrine) at -1 hour / baseline as received at Treatment Visit 1. The mydriatic agent was administered as a single drop in each eye. If the instillation failed, the investigator would reinstill the eye. Received the second of the two study treatments based on his / her randomized treatment sequence at 0±5 min / max. -Ocular tolerability was evaluated at 0±5 minutes / max after instillation of the study drug. The following: pupil diameter, BDCVA, DCNVA, accommodation, and conjunctival redness, and any AEs were assessed compared to study treatment at -1 h / baseline, 0 ± 5 min / max, 30 min ± 5 min, 1 h ± 5 min, 2 h ± 10 min, 4 h ± 15 min, and 6 h ± 15 min. · Underwent IOP assessment at 6 hours ±15 minutes. HR and BP were assessed at -1 h / baseline, 2 h ± 10 min, and 6 h ± 15 min compared with study treatment.

[0286] If necessary, two hours after treatment, subjects will be allowed to request administration of LUMIFY® (an ophthalmic solution containing brimonidine tartrate (0.025% weight / weight) sold by Bausch & Lomb, Inc.) in the non-test eye, and such use will be recorded.

[0287] Unplanned visit Unscheduled visits were any visits to the investigator other than the specific visits required in the protocol that may be required for the subject's ophthalmic condition. The investigator was to perform all procedures necessary to evaluate the study participant at these visits and to record any AEs on the Case Report Form (CRF).

[0288] Visit Variations The eighth day visit may be delayed by up to two days.

[0289] Efficacy determination Efficacy was assessed using the full analysis set (FAS) with subjects included in the randomized treatment sequence, regardless of the treatment sequence actually received. For analyses of the primary efficacy endpoint, observed case data were used for the primary analysis (no imputation was performed for missing data). Confirmatory analyses could be performed using the complete randomized population (ARP) with imputation for missing data. For analyses of secondary efficacy endpoints, only observed case data were used. Confirmatory analyses using the ARP with imputation of missing data, where justified, were also performed for secondary efficacy endpoints.

[0290] For all efficacy endpoints, the baseline for a particular day (Visit 1, Visit 2) was defined as -1 hour prior to treatment. The maximum time point was defined as time 0 minutes, the predicted maximum pupil diameter.

[0291] All efficacy data were summarized by treatment group, study date, and time point (-1 hour, 0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours at Visit 1 and Visit 2) as appropriate.

[0292] The primary efficacy endpoint was the change in pharmacologically induced mydriatic (maximal) pupil diameter (0 min) at 2 hours post-treatment in the study eye. The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with mean pupil diameter (mm) as the dependent variable, treatment sequence, subjects within treatment sequence, period, treatment, and mydriatic agent as factors, and change from maximum pupil diameter (0 min) to 2 hours in maximum pupil diameter (0 min) as covariates. ANCOVA was performed using FAS on subjects included in the randomized treatment sequence regardless of the treatment actually received. Only observed case data were used, i.e., missing values ​​were not entered. Least squares means (LSM) and standard errors (SE) were provided for both treatment groups, along with placebo-corrected LSM, its 95% confidence interval (CI), and associated p-values. Confirmatory analysis of the primary efficacy endpoint could be performed using the ARP with missing values ​​imputed. In addition, the primary efficacy endpoint was analyzed by mydriatic agent using the same model as above, but without mydriatic agent as a factor.

[0293] For each of the continuous secondary efficacy endpoints, the same ANCOVA was used as for the primary efficacy endpoint, including the respective baseline (-1 hour) values ​​as covariates [note that all of the secondary efficacy endpoints were related to baseline (-1 hour), whereas the primary efficacy endpoint was related to maximum (0 minutes)]. Each ANCOVA was performed using the FAS on subjects included in the randomized treatment sequence, regardless of the treatment sequence they actually received. Only observed case data were used, i.e., missing values ​​for post-randomization assessments were not entered. The output from each ANCOVA included the LSM and SE for both treatment groups, along with the placebo-corrected LSM, its 95% CI, and associated p-values.

[0294] For each of the secondary endpoints related to the percentage of subjects achieving a particular criterion, analyses were performed using PROC GENMOD with a logit link (generalized linear model) to account for the crossover design. Analyses included treatment sequence, subjects within treatment sequence, time period, treatment, mydriatic agent, and respective baseline, as well as ANCOVA for continuous endpoints. For each analysis, the percentage of subjects in each treatment group meeting the criterion, odds ratios (ORs) with 95% CI, and p-values ​​were provided. For these endpoints, the FAS was used for subjects included in the randomized treatment sequence, regardless of the treatment sequence they actually received.

[0295] In addition, each secondary efficacy endpoint was analyzed by mydriatic agent using the same models shown above, but without mydriatic agent as a factor.

[0296] Safety Analysis Safety was assessed by: Conjunctival hyperemia measured on the CCLRU card 4-point scale. o None (0) = appeared normally white with a few easily observed conjunctival blood vessels. Mild (+1) = Noticeable pinkish-red color of both the globe and palpebral conjunctiva. Moderate (+2) = Bright, vibrant orange-red color of the eye and palpebral conjunctiva. Severe (+3) = Petechia with evidence of subconjunctival hemorrhage, a dark red globe and beefy red color of the palpebral conjunctiva. Subjective ocular tolerability measured on a 4-point scale. ○0 - No discomfort ○1-Mild discomfort 2- Moderate discomfort 3- Severe discomfort · Intraocular pressure (IOP). ·Heart rate (HR) and blood pressure (BP). Adverse events.

[0297] An adverse event (AE) was any untoward medical occurrence in a patient or clinical trial subject administered a study medicinal product (pharmacological / biological product) that does not necessarily have a causal relationship to this medicinal product. Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease temporarily associated with the use of a study medicinal product, whether or not related to the study medicinal product. Study medicinal products included the investigational drug being evaluated and any comparator product or vehicle placebo given or administered during any phase of the study.

[0298] Medical conditions / diseases that were present before starting study treatment were considered AEs only if they worsened after study treatment was started. Abnormal laboratory results constituted AEs only if they induced clinical signs or symptoms, were considered clinically significant, or required therapy.

[0299] The severity of an AE was defined as a qualitative assessment of the level of discomfort of the AE as determined by the investigator or reported by the subject. Severity assessments were to be made regardless of study drug-related or seriousness of the event and were to be rated according to the following scale: · 1 = Mild: Present but not distressing and does not interfere with normal daily activities. · 2 = Moderate: Discomfort sufficient to reduce or affect normal daily activities. · 3 = Severe: Disabled and unable to work or carry out normal daily activities.

[0300] Changes in severity for reported AEs required an end date for the previous severity and a new start and end date for the new severity. For example, a change in severity could be from mild to severe, or from severe to moderate. In either case, the start or end date was to be recorded.

[0301] Part II - Results Data regarding the observed reduction in pupil diameter are provided in Tables 1A-1F, 2A-2L, and 3A-3C below. Data characterizing subjects according to changes in accommodation are provided in Tables 4A and 4B. Analyses were performed for all subjects and for subjects receiving tropicamide (where loss of accommodation was deemed likely), but not for phenylephrine (where loss of accommodation was deemed unlikely). Data characterizing the observed ocular redness (conjunctival injection) are provided in Tables 5A-5E. Subjects in this study did not require administration of LUMIFY®, an ophthalmic solution containing brimonidine tartrate (0.025% weight / weight) sold by Bausch & Lomb, Inc. [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40]

[0302] The observed experimental results from the IOP measurements are provided in Tables 6 and 7 below. [Table 41] [Table 42]

[0303] Example 4 - Improvement of Near Vision using Phentolamine Mesylate in Human Subjects with Open Angle Glaucoma or Ocular Hypertension The ability of phentolamine mesylate to improve near vision in human subjects with bilateral open-angle glaucoma (OAG) or ocular hypertension (OHT) was evaluated according to a clinical trial in which an aqueous ophthalmic solution containing phentolamine mesylate was administered to the patient's eyes, and the patient was then evaluated for improvement in near vision in the eye that received the aqueous ophthalmic solution containing phentolamine mesylate. Approximately 40 subjects with either OAG or OHT were randomized with a target of 36 completed subjects. Subjects were randomized in a 1:1 ratio to receive 1% w / w phentolamine mesylate ophthalmic solution or placebo once daily for 14 days, starting at 8 pm and ending at 10 pm, from day 1 onwards and continuing through day 14. Evaluations of near vision were performed at 8 am, 10 am, and 4 pm at baseline and on treatment-study visit days (day 8 ± 1 and day 15 ± 1). A follow-up visit occurred at 8:00 ± 15 am on day 16 and a phone call on day 22 (7 days after the last treatment-study visit). Further experimental procedures and results are described below.

[0304] Part I - Experimental Procedure The total duration of subject participation was approximately 7–8 weeks with six clinic visits and one telephone follow-up, as summarized below. Screening visit (1 day). Washout visit / period (if necessary) (4-5 weeks with a safety visit at 2 weeks). · Qualification / Baseline Visit (1 day). Treatment-Study Visit Day 8 (1 week). Treatment-Study Visit Day 15 (1 week). · Follow-up clinic visit on day 16 (1st). · Follow-up call on day 22 (1 week).

[0305] Human subjects were screened for potential enrollment and, if eligible, enrolled in the study. The inclusion and exclusion criteria for the study are listed below. Human subjects may be eligible in either eye. Inclusion criteria ·Age 18 or older. A diagnosis of OAG or OHT. The diagnosis of OHT had to be in both eyes. For OAG, the diagnosis could be in either eye with OHT in the fellow eye. A reported history of untreated OHT with IOP ≥ 22mmHg and ≤ 30mmHg was preferred. ·OAG / OHT untreated or treated with ≤2 low intraocular pressure medications. Untreated (post-washout) mean IOP ≥ 22mmHg and ≤ 30mmHg in the study eye at the eligibility visit (8am). · Early Treatment Diabetic Retinopathy Study (ETDRS) corrected visual acuity in each eye of +1.0 logMAR or better in each eye (equivalent to 20 / 200 or better) at the Screening Visit and Eligibility Visit. · Subjects who are otherwise healthy and well-maintained. ·Able and willing to sign informed consent and comply with the study instructions. Ability to self-administer study medication or have study medication administered by a caregiver throughout the study period. Exclusion criteria Closed or very narrow angle (Grade 0-1, Shaffer), or angles deemed obstructive by the investigator and / or with evidence of peripheral anterior synechiae (PAS) ≥ 180 degrees by gonioscopy within 6 months prior to the screening visit in either eye. Glaucoma: pseudoexfoliation or pigment dispersion components, history of angle closure or narrow angle. Note: Previous laser peripheral iridotomy was not allowed. Known hypersensitivity to any alpha-adrenergic receptor antagonist. Previous laser and / or non-laser glaucoma surgery or procedures in either eye. Refractive surgery in either eye (e.g. radial keratotomy, photorefractive keratotomy (PRK), laser-assisted in situ keratotomy (LASIK), or corneal cross-linking). Ocular trauma to either eye within 6 months prior to screening, or ocular surgery or non-refractive laser treatment within 3 months prior to screening. Recent or current evidence of ocular infection or inflammation in either eye. Current evidence of clinically significant blepharitis, conjunctivitis, or a history of herpes simplex or herpes zoster keratitis at screening in either eye. Ophthalmic medications of any kind in either eye within 30 days of screening, except a) low intraocular pressure medications (which had to be washed out), b) lid scrubs (which could be used before screening but could not be used after screening), or c) lubricating drops for dry eyes (preservative-free artificial tears), which could be used throughout the study. Clinically significant ocular disease in either eye judged by the investigator to be likely to interfere with the study (e.g., corneal edema, uveitis, or severe keratoconjunctivitis sicca), including glaucomatous damage so severe that a 1-month washout of the low intraocular pressure medication was not judged safe (i.e., cup-to-disc ratio >0.8, severe visual field loss). History of diabetic retinopathy. -Wearing contact lenses within 3 days prior to and for the duration of the study. Central corneal thickness >600 μm in either eye at screening. Any abnormality in either eye that prevents reliable applanation tonometry (e.g., central corneal scarring). Known hypersensitivity or contraindication to alpha- and / or beta-adrenergic receptor antagonists (e.g., chronic obstructive pulmonary disease or bronchial asthma, abnormally low blood pressure or heart rate, second- or third-degree heart block or congestive heart failure, or severe diabetes mellitus). Clinically significant systemic disease that may interfere with the study (e.g., poorly controlled diabetes mellitus, myasthenia gravis, cancer, hepatic, renal, endocrine, or cardiovascular disorders). Participation in any research study within 30 days prior to screening. Use of any local or systemic adrenergic or cholinergic medication up to 30 days prior to screening or during the study, unless the drug, dose, and regimen have been consistent over the 30 days prior to screening. ·Changes in systemic medications that may have affected IOP within 30 days prior to screening or are anticipated during the study. Women of childbearing potential who were pregnant, lactating, planning to become pregnant, or not using a medically acceptable form of contraception. Adult women were considered to be of childbearing potential unless they were 1 year postmenopausal or 3 months poststerilization. All women of childbearing potential must have had a negative urine pregnancy test result at screening and eligibility testing and intended not to become pregnant during the study. Resting heart rate (HR) outside the normal range (50-110 beats per minute) at the screening or eligibility visit. HR could be repeated only once if outside the normal range after a resting period of at least 5 minutes in a sitting position. Hypertension with resting diastolic (BP) >105mmHg or systolic BP >160mmHg at screening or eligibility visit. BP could be repeated only once if outside the specified range after a rest period of at least 5 minutes in the sitting position.

[0306] Subjects with an ophthalmic history of elevated IOP (≧22 mmHg and ≦30 mmHg) were selected for study participation and screened for study eligibility.

[0307] After screening, eligible subjects were required to wash out and abstain from any glaucoma medications for at least 28 days, but not more than 35 days, prior to the qualification visit if currently being treated with glaucoma medications. Washout subjects returned approximately 2 weeks after beginning the washout period for an IOP safety check. If, in the investigator's judgment, the subject's eye(s) were at risk for any risk or the mean IOP in either eye during washout was >30 mmHg, appropriate rescue or pre-medication was administered and the subject was considered a screening failure. Adverse events occurring during the washout period were also evaluated at this visit. After washout, a qualification visit was conducted prior to dosing on Day 1, if applicable.

[0308] Subjects not previously treated with any glaucoma medications did not require a washout period and could return the following day, or up to 35 days later, for their eligibility / baseline visit.

[0309] At Eligibility / Baseline Visit: Women of childbearing potential took a urine pregnancy test at 8 am. - A concomitant medication review was performed at 8:00 am. Pupil diameter using a Neuroptics pupillometer, near visual acuity using a standard chart held at 14 inches, and distance visual acuity with the ETDRS were measured at 8:00 am. Eye redness (conjunctival injection) was visually assessed at 8am, 10am, and 4pm using the CCLRU Eye Redness Scale. Adverse events were reviewed at each time point.

[0310] The first dose of study medication was administered between 8:00 PM and 10:00 PM at the Baseline Visit (Day 1). Site personnel demonstrated proper instillation technique to subjects at the Eligibility / Baseline Visit (Day 1), and subjects self-administered their dose of artificial tears at the study site, instilling one drop into each eye from the unit-dose bottle (Note: if one drop was not instilled in the eye, subjects were instructed to wait approximately 10-15 seconds and administer the second drop). Subjects received the following instructions regarding proper instillation technique: The subject should be in a sitting position and tilt their head back for administration of the study medication. The bottle of study medication should be held in a nearly vertical position over the eye while gently pulling down the lower eyelid, and one drop is placed into the conjunctival cul-de-sac. The tip of the bottle should not touch the eye. After one drop has been injected into each eye, the subject should gently keep the eye closed for approximately 30 seconds. After successful injection of the eye drops in each eye, the subject should carefully empty any remaining contents as directed.

[0311] Subjects were given their study medication dropper bottle, when to administer the drops (8:00 pm - 10:00 pm), and instructions on when to return to the clinic.

[0312] Subjects were instructed to administer one drop to each eye from a new single unit dose bottle on each night of dosing, gently close their eye for 30 seconds, then empty the remaining bottle contents (store the opened bottle in the provided baggie, place it back in the medication box, and return it to the study facility at the Day 8 visit). Subjects were instructed to follow the same procedure on each subsequent night of dosing (approximately 24 hours between doses). At the Day 8 visit, the medication box containing the opened bottle and any unopened study medication was to be returned to the study facility, the baggies of opened medication were removed, and the study medication box was redistributed with unopened medication. During the second week of treatment, subjects were instructed to continue administering one drop of study medication to each eye each night, using a new bottle for each dose, then emptying the remaining contents of that bottle (store the opened bottle in the baggie, place them back in the box, and return it to the study facility at the Day 15 visit). The day 15 visit was the last day of study treatment and no further study medication was dispensed at that visit.

[0313] Subjects were instructed to contact the investigator if they experienced any adverse events of concern (eg, shortness of breath, fainting, etc.) or to go to an emergency room if the event was life-threatening.

[0314] Two treatment-study visits were conducted, on days 8±1 and 15±1. On study day 8, the following was performed: - A concomitant medication review was performed at 8:00 am. Near and distance visual acuity was measured. · Ocular redness (conjunctival injection) was visually assessed using the CCLRU Eye Redness Scale.

[0315] On study day 15, the following was performed: Subjects were expected to bring their used dropper bottle and any unused medication for medication management purposes. Subjects were asked if they had had any problems with their eyes since their last visit, or if there had been any changes in their medical condition or concomitant medications since their last visit. Any change in the subject's condition was recorded as an adverse event. Near and far vision, as well as far vision, were measured. Ocular redness (conjunctival injection) was visually assessed at each time point using the CCLRU Eye Redness Scale. Adverse events were reviewed at each time point. · Distance and near visual acuity, pupil size, and a complete eye exam, including biomicroscopy, were also performed at 4pm. Subjects completing their Day 15 visit were instructed not to resume their original glaucoma medication(s) until completion of the Day 22 follow-up phone call.

[0316] The follow-up visit occurred at 8:00 ± 15:00 AM on Day 16. Assessments performed at this visit included IOP measurements at 8:00 ± 15:00 AM, visual acuity, pupil diameter, and safety measures. More specifically, the following were performed: Subjects were asked if they had had any problems with their eyes since their last visit, or if there had been any changes in their medical condition or concomitant medications since their last visit. Any change in the subject's condition was recorded as an adverse event. - A concomitant medication review was performed at 8:00 am. IOP was measured twice in the study eye at 8:00 ± 15:00 AM and the two values ​​were averaged. If the difference between the two IOP measurements was >5 mmHg, a third measurement was obtained and the three values ​​were averaged. Pupil diameter, near and distance visual acuity, distance visual acuity, resting HR and BP were measured at 8 am. Blood pressure, and heart rate were measured after at least 3 min of rest in the seated position, using the same cuff size appropriate for the same arm and arm circumference throughout the study. If HR or BP was outside the normal range (HR < 50 or > 110 beats per minute, resting diastolic blood pressure (BP) > 105 mmHg or systolic BP > 160 mmHg), they could be repeated only once after a period of at least 5 min of rest in the seated position. Ocular redness (conjunctival injection) was visually assessed at each time point using the CCLRU Eye Redness Scale. Adverse events were reviewed at 8:00 am. Subjects completing their Day 16 visit were advised not to resume their original glaucoma medication(s) until completion of the Day 22 follow-up phone call.

[0317] A follow-up visit telephone call occurred 7 days after the last dose on day 22. Any concomitant medications, subject-reported conjunctival redness, and adverse events (AEs) were collected.

[0318] The visits on days 8 and 15 were allowed to occur one day earlier or later. If a visit was late, subjects were advised to use an additional dose from one of two spare dropper bottles provided in the study medication box the night before the visit. Subjects were then instructed to empty any remaining contents and store the opened bottle in a provided baggy, which they would then place in the medication box for return to the study facility at their next visit. If the day 15 visit occurred one day earlier or later, the day 16 visit and day 22 phone call were adjusted accordingly.

[0319] All subjects were permitted to voluntarily withdraw from the study at any time without prejudice. A non-completer was defined as a subject who terminated the study of their own volition or at the discretion of the investigator and / or medical monitor before completing all of the protocol-required study procedures.

[0320] Study subjects received study medication according to the treatment group to which they were assigned, as described in Table 1. Study medications are listed in Table 2. [Table 43] [Table 44]

[0321] Part II - Results Baseline visual acuity data collected for subjects prior to administration of phentolamine mesylate at the start of the study are provided in Tables 1-4. Observed improvements in near visual acuity data are provided in Tables 5 and 6. Results of conjunctival hyperemia observations are reported in Tables 7 and 8. The data in Tables 7 and 8 indicate that there was no statistically significant difference in conjunctival hyperemia observed between patients receiving placebo and patients receiving 1% wt / wt phentolamine mesylate ophthalmic solution. Observed changes in pupil diameter are provided in Tables 9A, 9B, 10A, 10B, 11A, and 11B. [Table 45] [Table 46] [Table 47] [Table 48] [Table 49] [Table 50] [Table 51] [Table 52] [Table 53] [Table 54] [Table 55] [Table 56] [Table 57] [Table 58]

[0322] Example 5 - Evaluation of the effect of tetrahydrozoline on pupil constriction induced by phentolamine mesylate in human subjects A double-blind, randomized, three-arm, parallel-design, single-dose study was conducted to compare the tolerability and effect of tetrahydrozoline, phentolamine mesylate, or tetrahydrozoline and phentolamine mesylate on pupil size following topical administration of the agent(s) to the eye. A total of 45 human subjects were randomized into three groups (15 subjects each) and all subjects were treated sequentially with one drop per eye of two separate solutions.

[0323] Group 1 received one drop of ophthalmic tetrahydrozoline (VISINE®) in each eye followed by one drop of 0.2% (weight / volume) ophthalmic phentolamine mesylate in GENTEAL™ ophthalmic solution (i.e., the tetrahydrozoline + phentolamine mesylate group). GENTEAL™ ophthalmic solution is a sterile aqueous ophthalmic solution marketed by Alcon.

[0324] Group 2 received one drop of placebo (GENTEAL® eye drop solution) in each eye followed by one drop of 0.2% (weight / volume) ophthalmic phentolamine mesylate in GENTEAL® eye drop solution (i.e., the phentolamine mesylate group). Group 3 received one drop of ophthalmic tetrahydrozoline (VISINE®) in each eye followed by one drop of placebo (GENTEAL® eye drop solution) (i.e., the tetrahydrozoline group). Pupil size was measured. Additionally, ocular redness was measured.

[0325] The results observed from the study showed that administration of VISINE® (tetrahydrozoline ophthalmic solution) did not reduce the ability of 0.2% (weight / volume) ophthalmic phentolamine mesylate to reduce pupil diameter. The experimental results for pupil diameter are shown in Figure 2. The results observed from the study also showed that (tetrahydrozoline ophthalmic solution) reduced eye redness caused by phentolamine mesylate. The experimental results for eye redness are shown in Figure 3.

[0326] Example 6 - Evaluation of phentolamine mesylate to cause burning or redness following ocular administration to human subjects One drop of 1% w / w phentolamine mesylate ophthalmic solution was administered to the eye of a human subject. The subject was asked to report any burning sensation or redness. The observed results are presented in Table 1 below for a study involving 32 patients who received 1% w / w phentolamine mesylate ophthalmic solution. One drop of 1% wt / w phentolamine mesylate ophthalmic solution produced less burning and redness than that reported for REV-EYES® (0.5% wt / w dapiprazole hydrochloride ophthalmic solution containing mannitol (2% wt / w), sodium chloride, hydroxypropyl methylcellulose (0.4% wt / w), sodium edetate (0.01% wt / w), sodium phosphate dibasic, sodium phosphate monobasic, water for injection, and benzalkonium chloride (0.01% wt / w) having a pH of about 6.6 and an osmolality of about 415 mOsm), two drops of REV-EYES® solution were administered to the patient's eye, followed by two more drops of REV-EYES® solution five minutes later. [Table 59]

[0327] The composition of 1% w / w phentolamine mesylate ophthalmic solution is provided in the table below. [Table 60]

[0328] Example 7 - Treatment of Presbyopia with Phentolamine Mesylate in Human Subjects The ability of phentolamine mesylate to treat human subjects suffering from presbyopia was evaluated according to the experimental procedures described below. The results observed are described below.

[0329] Part I - Experimental Procedure Subjects' pupil diameter and visual acuity were measured at baseline (time = The time interval between time points was determined to be −5 minutes, and then the subject was administered a 1% wt / wt phentolamine mesylate ophthalmic solution (one drop in each eye, time = 0 minutes). At time = 40 minutes, one drop of 1% pilocarpine HCl ophthalmic solution was administered to the subject's left eye only.

[0330] Pupil diameter and visual acuity were measured under photopic and mesopic conditions at times = -5, 15, 30, 45, 60, 75, and 90 minutes. Pupil diameter was further measured at time = 14 hours. Pupil diameter was measured under scotopic conditions ("mesopic pupil diameter") and photopic conditions ("photopic pupil diameter") using an infrared pupillometer. Visual acuity was measured under mesopic conditions with mesopic filters ("mesopic visual acuity") and under photopic conditions with mesopic filters ("photopic visual acuity") with an ETDRS chart held at a distance of 14 inches. For reference, the rows of the ETDRS chart are 20 / 125, 20 / 100, 20 / 80, 20 / 63, 20 / 50, 20 / 40, 20 / 32, 20 / 25, and 20 / 20.

[0331] The composition of 1% w / w phentolamine mesylate ophthalmic solution is provided in the table below. [Table 61]

[0332] Part II - Results Pupil diameter and near visual acuity data from the study are shown below in Table 1. Each eye experienced a reduction in pupil diameter and a reduction in near visual acuity of 1, 2, 3, or 4 lines relative to baseline. [Table 62]

[0333] Example 8 - Treatment of Presbyopia with Phentolamine Mesylate in Human Subjects The ability of phentolamine mesylate to treat human subjects suffering from presbyopia can be evaluated according to a clinical trial in which an aqueous ophthalmic solution containing phentolamine mesylate is administered to the patient's eye, and the patient is then evaluated for improvement in visual performance, including near visual performance. The experimental procedure and results are described below.

[0334] Part I - Experimental Procedure Human subjects are screened for potential enrollment and, if eligible, enrolled in the study. Exemplary inclusion and exclusion criteria for the study are provided below. If a subject does not meet the inclusion / exclusion criteria but the study investigator believes the subject should participate in the study, deviations may be allowed after discussion between the study director and the study sponsor. Inclusion criteria Age: ≥ 40~≤ 65 · Have a corrected distance and near visual acuity (DCNVA) of 20 / 50 or better in both eyes. · Best corrected distance visual acuity (BCDVA) of 20 / 20 or better in both eyes and currently dependent on reading or bifocal glasses with near add power >+1.00 diopters - Otherwise healthy and well-maintained subjects. ·Able and willing to sign informed consent and comply with the study instructions. Ability to self-administer study medication or have study medication administered by a caregiver throughout the study period. Exclusion criteria Ophthalmology: Clinically significant ocular disease that is judged by the investigator to be likely to interfere with the study (e.g., untreated cataract, treated glaucoma, corneal edema, uveitis, severe keratoconjunctivitis sicca). Known hypersensitivity to any alpha-adrenergic receptor antagonist or cholinergic parasympathomimetic agent. -Unwilling or unable to discontinue contact lens wear during treatment. Ocular trauma, ocular surgery (e.g., IOL), or laser procedure (e.g., LASIK, PRK) within 5 weeks prior to screening. Recent or current evidence of ocular infection or inflammation in either eye. Current evidence of clinically significant blepharitis, conjunctivitis, or a history of herpes simplex or herpes zoster keratitis at screening in either eye. Ophthalmic medications of any kind in either eye within 30 days of screening, except for a) low intraocular pressure medications (which must be washed out according to the schedule provided), b) lid scrubs (which may be used pre-screening but not post-screening), or c) lubricating drops for dry eyes (artificial tears), which may be used throughout the study. Whole body: Known hypersensitivity or contraindication to α- and / or β-adrenergic receptor antagonists (e.g., chronic obstructive pulmonary disease or bronchial asthma, abnormally low blood pressure (BP) or heart rate (HR), second or third degree heart block or congestive heart failure (CHF), severe diabetes mellitus). ·Known hypersensitivity or contraindication to cholinergic parasympathomimetics. Clinically significant systemic disease that may interfere with the study (e.g., poorly controlled diabetes mellitus, myasthenia gravis, cancer, hepatic, renal, endocrine, or cardiovascular disorders). Initiation of treatment with any local or systemic adrenergic or cholinergic medication, or any change to its current dose, medication, or regimen, up to 7 days prior to screening or during the study. Participation in any research study within 30 days prior to screening. Women of childbearing potential who are pregnant, nursing, planning to become pregnant, or not using a medically acceptable form of contraception. Acceptable methods include use of at least one of the following: intrauterine device (IUD), hormonal (oral, injection, patch, implant, ring), barrier with spermicide (condom, diaphragm), or abstinence. Adult women are considered of childbearing potential unless they are 1 year postmenopausal or 3 months poststerilization. All women of childbearing potential must have a negative urine pregnancy test result at Visit 1 / Screening and Visit 2 testing and intend not to become pregnant during the study. Resting HR outside the normal range (50-110 beats per minute) at the screening visit. HR may be repeated only once if outside the normal range after a resting period of at least 5 minutes in a seated position. Hypertension with resting diastolic BP >105mmHg or systolic BP >160mmHg at the screening visit. BP may be repeated only once if outside the specified range after a rest period of at least 5 minutes in the sitting position.

[0335] Human subjects enrolled in the study will be randomized in a 1:1 randomization into two (or more) treatment arms. The treatment arms will receive one of the following doses: Placebo ophthalmic solution, 1% w / w phentolamine mesylate ophthalmic solution, 1.5% w / w phentolamine mesylate ophthalmic solution, 2% w / w phentolamine mesylate ophthalmic solution, 1% w / w phentolamine mesylate ophthalmic solution and 1% pilocarpine HCl ophthalmic solution, 1% weight / weight phentolamine mesylate ophthalmic solution and 0.2% to 0.25% pilocarpine HCl ophthalmic solution, or ·1% w / w phentolamine mesylate ophthalmic solution and 0.4% to 0.5% pilocarpine HCl ophthalmic solution.

[0336] Preferably, the dose is a single drop of ophthalmic solution administered to the subject's eye. Treatment groups receiving pilocarpine-containing treatments may receive them as an aqueous solution with or without the addition of vegetable or mineral oil (e.g., castor oil). A description of the specific test medications is provided in the table below. [Table 63]

[0337] Doses of study medication will be given once daily during week 1 and twice daily during week 2. Visual performance will be assessed, which may include near visual acuity, distance-corrected near visual acuity (DCNVA), uncorrected near visual acuity (UNVA), uncorrected intermediate visual acuity (UIDVA), best corrected distance visual acuity (BCDVA), other types of visual acuity measurements, and / or analysis of visual acuity questionnaires.

[0338] Performance measures include change in baseline visual acuity in the study eye, non-study eye, both eyes, and / or binocular.Examples of efficacy endpoints include the proportion of subjects gaining ≥3 lines in mesopic, high contrast, and binocular DCNVA, the proportion of subjects with ≥2 line improvement from baseline in UNVA, visual function questionnaire responses at baseline pretreatment timepoints and across treatment groups at various study days, and other visual performance and safety measures.

[0339] Incorporation by Reference The entire disclosure of each of the patent documents and scientific articles referenced herein is incorporated by reference for all purposes.

[0340] Equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects as illustrative rather than limiting of the invention described herein. The scope of the invention is therefore indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. 1. A pharmaceutical composition for treating presbyopia comprising phentolamine mesylate, wherein the pharmaceutical composition is for administering a dosage of phentolamine mesylate in an amount of 0.2-0.7 mg to an eye of a patient in need thereof, wherein the dosage is in the form of eye drops, wherein the dosage is administered to the eye no more than once per day, and wherein the pharmaceutical composition is used in combination with an additional agent selected from pilocarpine and a pharma- ceutical acceptable salt thereof, wherein the additional agent is administered to the eye of the patient in an amount of 0.1 mg-1.0 mg.

2. 2. The pharmaceutical composition of claim 1, wherein the dosage of phentolamine mesylate is administered at or near bedtime for the patient.

3. 1. A pharmaceutical composition for treating presbyopia while minimizing redness of the patient's eye during waking hours, comprising phentolamine mesylate, wherein the pharmaceutical composition is for administering a dosage of phentolamine mesylate in an amount of 0.2-0.7 mg to the eye of a patient in need thereof, wherein the dosage is administered to the eye of the patient only at or near the patient's bedtime, wherein the dosage is in the form of eye drops, and wherein the pharmaceutical composition is used in combination with an additional agent selected from pilocarpine and a pharma- ceutical acceptable salt thereof, wherein the additional agent is administered to the eye of the patient in an amount of 0.1 mg to 1.0 mg.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the additional agent is pilocarpine hydrochloride.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the additional agent is administered to the patient's eye in an amount ranging from 0.1 mg to 0.5 mg.

6. The pharmaceutical composition of any one of claims 1 to 4, wherein the additional agent is administered to the patient's eye in an amount ranging from 0.125 mg to 0.25 mg.

7. The pharmaceutical composition of any one of claims 1 to 4, wherein the additional agent is administered to the patient's eye in an amount ranging from 0.25 mg to 0.50 mg.

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the dosage comprises 0.25 mg of phentolamine mesylate.

9. A pharmaceutical composition according to any one of claims 1 to 7, wherein the dosage comprises from 0.4 mg to 0.6 mg of phentolamine mesylate.

10. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the pharmaceutical composition is a 1% (w / w) solution of phentolamine mesylate and the dosage is a single eye drop comprising 0.03 mL to 0.05 mL of the pharmaceutical composition.

11. 1. A pharmaceutical composition for treating presbyopia according to a monotherapy treatment regimen comprising phentolamine mesylate, said pharmaceutical composition for administering a single therapeutic dose in an amount of 0.2-0.7 mg or 0.8-1.2 mg of phentolamine mesylate to an eye of a patient in need thereof, and said dose is in the form of eye drops.

12. 12. The pharmaceutical composition of claim 11, wherein the dosage is administered at or near bedtime for the patient.

13. 13. The pharmaceutical composition of claim 11 or 12, wherein the dosage comprises 0.25 mg of phentolamine mesylate.

14. The pharmaceutical composition of claim 11 or 12, wherein the dosage comprises 0.4 mg to 0.6 mg of phentolamine mesylate.

15. 13. The pharmaceutical composition of claim 11 or 12, wherein the pharmaceutical composition is a 1% (w / w) solution of phentolamine mesylate and the dosage is a single eye drop comprising 0.03 mL to 0.05 mL of the pharmaceutical composition.

16. 13. The pharmaceutical composition of claim 11 or 12, wherein the pharmaceutical composition is a 1% (w / w) solution of phentolamine mesylate and the dosage is two eye drops containing 0.03 mL to 0.05 mL of the pharmaceutical composition.

17. 17. The pharmaceutical composition of any one of claims 1-16, wherein the patient experiences an increase in ocular redness of no more than 2 grades as measured using the CCLRU Redness Rating Scale during the patient's waking hours compared to the patient's level of ocular redness not receiving the dosage of phentolamine mesylate.

18. 17. The pharmaceutical composition of any one of claims 1-16, wherein the patient experiences an increase in ocular redness of no more than 1 grade as measured using the CCLRU Redness Rating Scale during the patient's waking hours compared to the patient's level of ocular redness not receiving the dosage of phentolamine mesylate.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein said pharmaceutical composition provides a therapeutic effect against presbyopia for a sustained period of at least 6 hours.

20. The pharmaceutical composition of any one of claims 1 to 18, wherein said pharmaceutical composition provides a therapeutic effect against presbyopia for a sustained period of at least 12 hours.

21. 21. The pharmaceutical composition of any one of claims 1 to 20, wherein the pharmaceutical composition provides an improvement in visual acuity characterized by at least one line improvement in the patient's visual acuity as measured using an eye chart.

22. 21. The pharmaceutical composition of any one of claims 1 to 20, wherein the pharmaceutical composition results in an improvement in visual acuity characterized by an improvement of at least two lines in the patient's visual acuity as measured using an eye chart.

23. 21. The pharmaceutical composition of any one of claims 1 to 20, wherein the pharmaceutical composition results in an improvement in visual acuity characterized by an improvement of at least three lines in the patient's visual acuity as measured using an eye chart.

24. The pharmaceutical composition of any one of claims 21 to 23, wherein the pharmaceutical composition provides improved near vision.

25. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein as a result of said administration, said patient experiences the effect of having a pupil diameter of less than 3.0 mm in the eye that received said dose, when measured under photopic conditions.

26. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein as a result of said administration, said patient experiences the effect of having a pupil diameter of less than 2.4 mm in the eye that received said dose, when measured under photopic conditions.

27. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein as a result of said administration, said patient experiences the effect of having a pupil diameter of less than 2 mm in the eye that received said dose, when measured under photopic conditions.

28. 28. The pharmaceutical composition of any one of claims 25 to 27, wherein the patient experiences the effect for a duration of at least 6 hours.

29. 28. The pharmaceutical composition of any one of claims 25 to 27, wherein the patient experiences the effect for a duration of at least 12 hours.

30. 1. A pharmaceutical composition for treating mydriasis comprising phentolamine mesylate, wherein said mydriasis is due to said patient receiving one or more of tropicamide, phenylephrine, or pharma- ceutically acceptable salts thereof, said pharmaceutical composition for administering a dosage of phentolamine mesylate in an amount of 0.2-0.7 mg to an eye of a patient in need thereof, and wherein said dosage is in the form of eye drops.

31. 31. The pharmaceutical composition of claim 30, wherein the mydriasis is due to the patient receiving tropicamide or a pharma- ceutically acceptable salt thereof.

32. 31. The pharmaceutical composition of claim 30, wherein the mydriasis is due to the patient receiving phenylephrine or a pharma- ceutically acceptable salt thereof.

33. A pharmaceutical composition according to any one of claims 30 to 32, wherein the dosage comprises 0.25 mg of phentolamine mesylate.

34. A pharmaceutical composition according to any one of claims 30 to 32, wherein the dosage comprises from 0.4 mg to 0.6 mg of phentolamine mesylate.

35. 33. The pharmaceutical composition of any one of claims 30 to 32, wherein the pharmaceutical composition is a 1% (w / w) solution of phentolamine mesylate and the dosage is a single eye drop comprising 0.03 mL to 0.05 mL of the pharmaceutical composition.

36. The pharmaceutical composition of any one of claims 30 to 35, wherein the dosage is administered to the eye no more than once per day.

37. 37. The pharmaceutical composition of any one of claims 30-36, wherein the patient experiences a reduction in pupil diameter of at least 2 mm when measured under photopic conditions relative to the pupil diameter of the patient not receiving the dose, but under the same photopic conditions.

38. 37. The pharmaceutical composition of any one of claims 30-36, wherein the patient experiences a reduction in pupil diameter of at least 3 mm when measured under photopic conditions relative to the pupil diameter of the patient not receiving the dose but under the same photopic conditions.

39. 39. The pharmaceutical composition of any one of claims 30-38, wherein the patient experiences a reduction in pupil diameter, when measured under photopic conditions, in the range of 0.5 mm to 5 mm relative to the pupil diameter of the patient not receiving the dose, but under the same photopic conditions.

40. 40. The pharmaceutical composition of any one of claims 30 to 39, wherein the therapeutic effect can be observed within 30 minutes after administering the dose of phentolamine mesylate to the eye of the patient.

41. 40. The pharmaceutical composition of any one of claims 30 to 39, wherein the therapeutic effect can be observed within 1 hour after administering said dose of phentolamine mesylate to the eye of said patient.

42. 42. The pharmaceutical composition of any one of claims 1 to 41, wherein the dosage is an ophthalmic solution comprising a pharma- ceutically acceptable aqueous carrier and phentolamine mesylate.

43. 42. The pharmaceutical composition of any one of claims 1 to 41, wherein the dosage is an ophthalmic solution comprising water, mannitol, and phentolamine mesylate.

44. The pharmaceutical composition according to any one of claims 1 to 43, wherein the patient is an adult human.

45. The pharmaceutical composition of any one of claims 1 to 44, wherein the patient's distance vision is not reduced.

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