Methods and compositions for treating mydriasis, glaucoma, and other ocular conditions - Patents.com

Abstract

The present invention provides methods, compositions, and kits containing an alpha adrenergic antagonist (such as phentolamine), either alone or in combination with a muscarinic acetylcholine receptor agonist (such as pilocarpine), for the treatment of ophthalmic conditions. Specifically, the present invention provides methods for dilating the pupil, treating patients with glaucoma (such as closed-angle glaucoma or narrow-angle attacks), and improving aspects of vision in dim light (such as improving visual performance, reducing pupil diameter, and reducing abnormal focusing of scattered light).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application Serial No. 63 / 178,578, filed April 23, 2021, 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 treating patients suffering from mydriasis, glaucoma, and other ocular conditions. [Background technology]

[0003] Mydriasis is an eye disorder characterized by abnormally enlarged pupils, often caused by one or more of disease, trauma, or pharmacological agents. The pharmacological agent may be a drug administered to the eye to cause pupil dilation, for example, 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 drug administered to the patient on a single occasion or on multiple occasions. Negative effects of mydriasis may include sensitivity to light and 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 characteristics. Better treatments are needed for mydriasis.

[0004] Glaucoma is an eye disease that often affects the retina and / or optic nerve and can lead to blindness if left untreated. Long-term elevated intraocular pressure is a common feature of many forms of glaucoma. Such long-term elevated intraocular pressure can lead to irreversible damage to the retina and optic nerve, resulting in progressive and permanent vision loss. Treatments that reduce intraocular pressure provide benefits to patients suffering from glaucoma. However, existing drug treatments that reduce intraocular pressure are not effective for all patients and / or have undesirable side effects. Better treatments are needed for glaucoma.

[0005] Deficits in visual performance under dim light conditions can have a significant negative impact on a patient's quality of life, for example affecting the ability to drive a car at night. Patients who are likely to experience night vision problems include those with night myopia, those with equatorial cortical cataracts, those who have undergone surgery to insert intraocular lenses, and / or those who have undergone LASIK surgery. Exemplary symptoms of poor night vision include glare, halos, starbursts, ghost patterns, and / or poor depth perception. Treatment is required to improve a patient's visual performance under dim light conditions.

[0006] The present invention addresses the aforementioned need for methods and compositions for treating patients suffering from mydriasis, glaucoma and other ocular conditions, 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 treating patients suffering from mydriasis, glaucoma, and other ocular conditions. The α-adrenergic antagonist (such as phentolamine) is administered topically to the patient's eye, preferably in the form of an aqueous liquid ophthalmic formulation. In certain embodiments, a muscarinic acetylcholine receptor agonist (such as pilocarpine or a pharma- ceutically acceptable salt thereof) is administered topically 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 mydriasis in a patient. The method comprises administering to an eye of a patient in need thereof an amount of an α-adrenergic antagonist and an amount of a muscarinic acetylcholine receptor agonist in amounts effective to treat mydriasis therewith. In certain embodiments, the α-adrenergic antagonist is phentolamine mesylate. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

[0009] Another aspect of the present invention provides a method for treating mydriasis in a patient suffering from glaucoma while reducing the risk of angle-closure glaucoma attacks. The method comprises administering a dosage of an α-adrenergic antagonist to an eye of a patient in need thereof in an amount effective to treat mydriasis and reduce the risk of angle-closure glaucoma attacks. In certain embodiments, the α-adrenergic antagonist is phentolamine mesylate. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

[0010] Another aspect of the present invention provides a method for improving visual performance under dim light conditions in a patient. The method comprises administering to the eye of a patient in need thereof an amount of an α-adrenergic antagonist and an amount of a muscarinic acetylcholine receptor agonist in an amount effective to thereby improve visual performance under dim light conditions. In certain embodiments, the α-adrenergic antagonist is phentolamine mesylate. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

[0011] Another aspect of the present invention provides a method for reducing pupil diameter under dim light conditions in a patient. The method comprises administering to an eye of a patient in need thereof an amount of an α-adrenergic antagonist and an amount of a muscarinic acetylcholine receptor agonist in an amount effective to thereby reduce pupil diameter under dim light conditions. In certain embodiments, the α-adrenergic antagonist is phentolamine mesylate. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

[0012] Another aspect of the present invention provides a method for reducing abnormal focusing of scattered light in a patient's eye under dim light conditions. The method comprises administering to the eye of a patient in need thereof an amount of an α-adrenergic antagonist and an amount of a muscarinic acetylcholine receptor agonist in an amount effective to thereby reduce abnormal focusing of scattered light in the patient's eye under dim light conditions. In certain embodiments, the α-adrenergic antagonist is phentolamine mesylate. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

[0013] Another aspect of the present invention provides a method for treating acute angle-closure glaucoma in a patient. The method comprises administering a dosage of an α-adrenergic antagonist selected from phentolamine or a pharma- ceutically acceptable salt thereof to an eye of a patient in need thereof in an amount effective to treat acute angle-closure glaucoma. In certain embodiments, the α-adrenergic antagonist is phentolamine mesylate. In certain embodiments, the method further comprises administering a muscarinic acetylcholine receptor agonist to the eye of the patient. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

[0014] Another aspect of the present invention provides a method for preventing angle-closure glaucoma in a patient. The method comprises administering a dosage of an α-adrenergic antagonist selected from phentolamine or a pharma- ceutically acceptable salt thereof to an eye of a patient in need thereof in an amount effective for preventing angle-closure glaucoma. In certain embodiments, the α-adrenergic antagonist is phentolamine mesylate. In certain embodiments, the method further comprises administering a muscarinic acetylcholine receptor agonist to the eye of the patient. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

[0015] Another aspect of the present invention provides a method for treating or preventing narrow angle attacks in a patient. The method comprises administering a dosage of an α-adrenergic antagonist selected from phentolamine or a pharma- ceutically acceptable salt thereof to an eye of a patient in need thereof in an amount effective to treat or prevent narrow angle attacks. In certain embodiments, the eye of the patient has a narrow angle. In certain embodiments, the α-adrenergic antagonist is phentolamine mesylate. In certain embodiments, the method further comprises administering a muscarinic acetylcholine receptor agonist to the eye of the patient. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride. [Brief description of the drawings]

[0016] [Figure 1] 1 depicts exemplary ocular hyperemia measured according to (1) the CCLRU Hyperemia Grading Scale, and (2) the NYX-001 Hyperemia Grading Scale. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention provides methods, compositions, and kits containing an α-adrenergic antagonist (such as phentolamine) for treating patients suffering from mydriasis, glaucoma, and other ocular conditions. The α-adrenergic antagonist (such as phentolamine) is administered topically to the patient's eye, preferably in the form of an aqueous liquid ophthalmic formulation. In certain embodiments, a muscarinic acetylcholine receptor agonist (such as pilocarpine or a pharma- ceutically acceptable salt thereof) is administered topically to the patient's eye. Various aspects of the invention are described below in sections, although aspects of the invention described in one particular section are not limited to any particular section.

[0018] definition To facilitate the understanding of this invention, a number of terms and phrases are defined below.

[0019] The terms "a," "an," and "the" as used herein mean "one or more" and include plurals, unless the context is inappropriate.

[0020] As used herein, the term "patient" refers to an organism treated by the methods of the present invention, preferably including, but not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, and the like), and most preferably, humans.

[0021] As used herein, the term "effective amount" refers to an amount of a compound sufficient to achieve a beneficial or desired result. Unless otherwise specified, an effective amount may be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a specific formulation or route of administration. As used herein, the term "treating" includes any effect (e.g., alleviation, reduction, regulation, amelioration, or elimination) that results in the improvement of, or relief from, symptoms of, conditions, diseases, disorders, and the like.

[0022] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier, which combination makes the composition particularly suitable for in vivo or ex vivo therapeutic uses.

[0023] 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 stabilizing and preservative substances. For examples of carriers, stabilizers, and adjuvants, see Martin in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0024] 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 provide the compound of the present invention upon administration to a subject. 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 inorganic or organic 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) are not themselves pharmaceutically acceptable, but may be used in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0025] Examples of bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of the formula NW3, where W is C 1-4 alkyl), and the like.

[0026] Examples of salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, and the like. Examples of salts include, but are not limited to, sodium phosphate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and the like. + , NH4 + , and NW4 + (Wherein, W is C 1-4 Suitable cations include those which are alkyl groups, as well as the anions of the compounds of the present invention combined with the same.

[0027] For therapeutic use, the salts of the compounds of the invention are contemplated as pharma-ceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharma-ceutically acceptable compound.

[0028] The term "alkanoate" is art-recognized and refers to alkyl-C(O)O - Refers to...

[0029] The term "alkyl" is art-recognized and encompasses 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 carbon atoms in its backbone (e.g., C1-C4 for a straight chain). 30, for branched chains C3-C 30 ), and alternatively having 20 or fewer carbon atoms. Similarly, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.

[0030] The term "about" refers to within ±10% of the stated value. The invention encompasses embodiments where a value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0031] Throughout this specification, when compositions and kits are described as having, including, or comprising specified components, or when processes and methods are described as having, including, or comprising specified steps, it is contemplated that there are additionally compositions and kits of the invention that consist essentially of or consist of the recited components, and processes and methods according to the invention that consist essentially of or consist of the recited processing steps.

[0032] As a general matter, compositions specifying percentages are by weight unless otherwise specified. Further, if no definition is accompanied by a variable, then the previous definition of the variable takes precedence.

[0033] I. Treatment method The present invention provides a method of treating a patient suffering from mydriasis, glaucoma, and other ocular conditions by administering an alpha-adrenergic antagonist (such as phentolamine) to the patient's eye. The alpha-adrenergic antagonist is administered topically to the patient's eye, preferably in the form of an aqueous liquid ophthalmic formulation. In certain embodiments, a muscarinic acetylcholine receptor agonist (such as pilocarpine or a pharma- ceutically acceptable salt thereof) is administered topically to the patient's eye. Various aspects and embodiments of the treatment methods are described in the following sections. These sections are arranged for convenience, and information in one section is not limited to that section, but may be applicable to the methods in other sections.

[0034] A. First Method One aspect of the invention provides a method of treating mydriasis in a patient, the method comprising administering to an eye of a patient in need thereof a dosage of an α-adrenergic antagonist and a dosage of a muscarinic acetylcholine receptor agonist in amounts effective to treat mydriasis therewith.

[0035] In certain embodiments, the patient suffers from glaucoma. In certain embodiments, the patient suffers from glaucoma and has a narrow angle. In the context of glaucoma, the term angle refers to the drainage area (called the angle) formed by the cornea and iris through which ocular fluid flows. A narrow angle refers to a situation in which the flow of ocular fluid through the angle is partially obstructed.

[0036] In certain embodiments, the method reduces the risk of narrow angle stroke in a patient.

[0037] In certain embodiments, the method reduces the risk of angle-closure attacks.

[0038] The methods may be further characterized by additional features such as the dosing regimen and the identity of the alpha-adrenergic antagonist, the identity of the muscarinic acetylcholine receptor agonist, and the dosages of the above. The invention encompasses all permutations and combinations of these features.

[0039] B. Second Method One aspect of the invention provides a method of treating mydriasis in a patient suffering from glaucoma while reducing the risk of angle-closure glaucoma attacks, comprising 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 and reduce the risk of angle-closure glaucoma attacks.

[0040] In certain embodiments, the patient suffers from glaucoma and has narrow angles.

[0041] In certain embodiments, the method further comprises administering a muscarinic acetylcholine receptor agonist to the eye of a patient in need thereof.

[0042] The methods may be further characterized by additional features such as the dosing regimen and the identity of the alpha-adrenergic antagonist, the identity of the optional muscarinic acetylcholine receptor agonist, and the dosages of the above. The invention encompasses all permutations and combinations of these features.

[0043] C. The third method One aspect of the present invention provides a method for improving visual performance under dim light conditions in a patient, comprising administering to the eye of a patient in need thereof an amount of an α-adrenergic antagonist and an amount of a muscarinic acetylcholine receptor agonist, in amounts effective to thereby improve visual performance under dim light conditions.

[0044] In certain embodiments, the improvement in visual ability provided by the method is an improvement in visual acuity. In certain embodiments, the method provides an improvement in visual acuity characterized by an improvement of at least one line in the patient's visual acuity measured using a Snellen eye chart. In certain embodiments, the method provides an improvement in visual acuity characterized by an improvement of at least two lines in the patient's visual acuity measured using a Snellen eye chart.

[0045] In certain embodiments, the improvement of visual ability provided by the method is an improvement in contrast sensitivity. The benefit provided by the treatment method can be characterized according to the improvement of the contrast sensitivity of the patient. For example, in certain embodiments, the improvement of contrast sensitivity is at least 10% (or 20%, 30%, 50%, 60%, or 70%) improvement when measured under mesopic conditions using a Holladay automated contrast sensitivity system. In certain embodiments, the improvement of contrast sensitivity is at least 10% (or 20%, 30%, 50%, 60%, or 70%) improvement when measured under photopic conditions using a Holladay automated contrast sensitivity system. In certain other embodiments, the improvement of contrast sensitivity is at least 10% (or 20%, 30%, 50%, 60%, or 70%) improvement when measured under mesopic conditions or scotopic conditions using a Holladay automated contrast sensitivity system.

[0046] In certain other embodiments, the improvement in visual performance provided by the method is both (i) improved visual acuity and (ii) improved contrast sensitivity.

[0047] The methods may be further characterized by additional features such as the dosing regimen and the identity of the alpha-adrenergic antagonist, the identity of the muscarinic acetylcholine receptor agonist, and the dosages of the above. The invention encompasses all permutations and combinations of these features.

[0048] D. The fourth method One aspect of the invention provides a method of reducing pupil diameter under dim light conditions in a patient, the method comprising administering to an eye of a patient in need thereof an amount of an α-adrenergic antagonist and an amount of a muscarinic acetylcholine receptor agonist, in amounts effective to thereby reduce pupil diameter under dim light conditions.

[0049] In certain embodiments, the method results in at least a 20% reduction in pupil diameter under dim light conditions. In certain embodiments, the method results in at least a 30% reduction in pupil diameter under dim light conditions. In certain embodiments, the method results in at least a 35% reduction in pupil diameter under dim light conditions.

[0050] The methods may be further characterized by additional features such as the dosing regimen and the identity of the alpha-adrenergic antagonist, the identity of the muscarinic acetylcholine receptor agonist, and the dosages of the above. The invention encompasses all permutations and combinations of these features.

[0051] E. The fifth method One aspect of the invention provides a method for reducing aberrant focusing of scattered light in the eye of a patient under dim light conditions, the method comprising administering to the eye of a patient in need thereof a dosage of an α-adrenergic antagonist and a dosage of a muscarinic acetylcholine receptor agonist in amounts effective to thereby reduce aberrant focusing of scattered light in the eye of the patient under dim light conditions.

[0052] In certain embodiments, the method reduces abnormal focusing of scattered light in the patient's eye under dim light conditions for at least 3 hours. In certain embodiments, the method reduces abnormal focusing of scattered light in the patient's eye under dim light conditions for at least 6 hours. In certain embodiments, the method reduces abnormal focusing of scattered light in the patient's eye under dim light conditions for at least 12 hours. In certain embodiments, the method reduces abnormal focusing of scattered light in the patient's eye under dim light conditions for at least 24 hours.

[0053] The methods may be further characterized by additional features such as the dosing regimen and the identity of the alpha-adrenergic antagonist, the identity of the muscarinic acetylcholine receptor agonist, and the dosages of the above. The invention encompasses all permutations and combinations of these features.

[0054] F. Method 6 One aspect of the present invention provides a method of treating acute angle-closure glaucoma in a patient, comprising administering to an eye of a patient in need thereof a dosage of an α-adrenergic antagonist selected from phentolamine or a pharma- ceutically acceptable salt thereof, in an amount effective to treat acute angle-closure glaucoma.

[0055] In certain embodiments, the patient presents with at least two symptoms selected from the group consisting of severe eye pain, bloodshot eyes, reduced vision, and blurred vision.

[0056] In certain embodiments, the method further comprises administering a muscarinic acetylcholine receptor agonist to the eye of the patient.

[0057] The methods may be further characterized by additional features such as the dosing regimen and the identity of the alpha-adrenergic antagonist, the identity of the optional muscarinic acetylcholine receptor agonist, and the dosages of the above. The invention encompasses all permutations and combinations of these features.

[0058] G. Seventh Method One aspect of the present invention provides a method for preventing angle-closure glaucoma in a patient, the method comprising administering to an eye of a patient in need thereof a dosage of an α-adrenergic antagonist selected from phentolamine or a pharma- ceutically acceptable salt thereof, in an amount effective to prevent angle-closure glaucoma.

[0059] In certain embodiments, the angle-closure glaucoma is acute angle-closure glaucoma.

[0060] In certain embodiments, the method further comprises administering a muscarinic acetylcholine receptor agonist to the eye of the patient.

[0061] The method can be further characterized according to the dosing regimen. For example, in certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 3 consecutive days. In certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 7 consecutive days. In certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 14 consecutive days. In certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 3 days in a 5-day period. In certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 3 days in a 7-day period. In certain embodiments, the dose of the α-adrenergic antagonist is administered for one day in a 3-day period. In certain embodiments, the dose of the α-adrenergic antagonist is administered for one day in a 5-day period.

[0062] The methods may be further characterized by additional features such as the dosing regimen and the identity of the alpha-adrenergic antagonist, the identity of the optional muscarinic acetylcholine receptor agonist, and the dosages of the above. The invention encompasses all permutations and combinations of these features.

[0063] H. Method 8 One aspect of the present invention provides a method of treating or preventing a narrow angle attack in a patient, the method comprising administering to an eye of a patient in need thereof a dosage of an alpha-adrenergic antagonist selected from phentolamine or a pharma- ceutically acceptable salt thereof, in an amount effective to treat or prevent the narrow angle attack.

[0064] In certain embodiments, the method further comprises administering a muscarinic acetylcholine receptor agonist to the eye of the patient.

[0065] The method can be further characterized according to the dosing regimen. For example, in certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 3 consecutive days. In certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 7 consecutive days. In certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 14 consecutive days. In certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 3 days in a 5-day period. In certain embodiments, the dose of the α-adrenergic antagonist is administered for at least 3 days in a 7-day period. In certain embodiments, the dose of the α-adrenergic antagonist is administered for one day in a 3-day period. In certain embodiments, the dose of the α-adrenergic antagonist is administered for one day in a 5-day period.

[0066] The methods may be further characterized by additional features such as the dosing regimen and the identity of the alpha-adrenergic antagonist, the identity of the optional muscarinic acetylcholine receptor agonist, and the dosages of the above. The invention encompasses all permutations and combinations of these features. I. Additional Features of the First and Second Treatment Methods

[0067] The first and second treatment methods may be further characterized, for example, according to the type of mydriasis. In certain embodiments, the mydriasis is pharmacologically induced mydriasis. In certain embodiments, the mydriasis is due to the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, flubiprofen, suprofen, hydroxyamphetamine, phenylephrine, ketorolac, or pharmaceutically acceptable salts thereof. In certain embodiments, the mydriasis is due to the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, or pharmaceutically acceptable salts thereof. In certain embodiments, the mydriasis is due to the patient receiving one or more of tropicamide, phenylephrine, or pharmaceutically acceptable salts thereof.

[0068] J. Additional Features of Methods 1, 2, 6, 7, and 8 The first, second, sixth, seventh, and eighth treatment methods may be further characterized according to, for example, improving the patient's visual ability, reducing pupil diameter, and / or reducing abnormal focusing of scattered light rays in the patient's eye.

[0069] Improved visual ability One benefit of the treatment methods is that the patient may also experience an improvement in visual ability, which refers to the overall quality of the patient's vision and includes the patient's ability to see clearly and to distinguish between objects and their background.

[0070] One aspect of visual ability is visual acuity. Visual acuity is a measurement 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.

[0071] 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 under various lighting conditions, including, for example, photopic, mesopic and scotopic conditions, each without or with glare. In certain embodiments, contrast sensitivity is measured under mesopic conditions, either with or without glare.

[0072] In certain embodiments, the improved visual performance provided by the method is an improved visual acuity. In certain embodiments, the improved visual performance provided by the method is an improved visual acuity under scotopic conditions. In certain embodiments, the improved visual performance provided by the method is an improved visual acuity under mesopic conditions. In certain embodiments, the improved visual performance provided by the method is an improved visual acuity under photopic conditions. In certain embodiments, the improved visual acuity is an improvement of 2 lines in the patient's visual acuity measured using a Snellen chart. In certain other embodiments, the improved visual acuity is an improvement of 1 line in the patient's visual acuity measured using a Snellen chart.

[0073] In certain embodiments, the improved visual performance provided by the method is an 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 improved visual performance provided by the method is an improved contrast sensitivity under photopic conditions. In certain embodiments, the improved visual performance provided by the method is an improved contrast sensitivity under mesopic conditions. In certain embodiments, the improved visual performance provided by the method is an 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.

[0074] The benefit provided by the treatment method can be characterized according to the improvement of the contrast sensitivity of the patient.For example, in certain embodiments, the improvement of contrast sensitivity is at least 10% (or 20%, 30%, 50%, 60%, or 70%) improvement when measured under mesopic conditions using a Holladay automated contrast sensitivity system.In certain embodiments, the improvement of contrast sensitivity is at least 10% (or 20%, 30%, 50%, 60%, or 70%) improvement when measured under photopic conditions using a Holladay automated contrast sensitivity system.In certain other embodiments, the improvement of contrast sensitivity is at least 10% (or 20%, 30%, 50%, 60%, or 70%) improvement when measured under mesopic conditions or scotopic conditions using a Holladay automated contrast sensitivity system.

[0075] In certain other embodiments, the improved visual performance provided by the method is both (i) improved visual acuity (such as under scotopic, mesopic, and / or photopic conditions) and (ii) improved contrast sensitivity (such as under scotopic, mesopic, and / or photopic conditions).

[0076] In certain embodiments, the improved visual performance is improved near visual performance. In certain embodiments, the improved visual performance is improved far-away visual performance. In certain embodiments, the improved visual performance is improved visual performance under low light conditions. In certain embodiments, the improved visual performance is improved visual acuity. In certain embodiments, the improved visual performance is improved contrast sensitivity. In certain embodiments, the method provides at least a 10% reduction in pupil diameter in the patient's eye. In certain embodiments, the method provides at least a 15% reduction in pupil diameter in the patient's eye. In certain embodiments, the method provides at least a 20% reduction in pupil diameter in the patient's eye. In certain embodiments, the method provides at least a 25% reduction in pupil diameter in the patient's eye. In certain embodiments, the method provides at least a 30% reduction in pupil diameter in the patient's eye.

[0077] Reduction of pupil diameter One benefit of the treatment method is that the patient may also experience a reduction in pupil diameter, which may result in an improvement in visual ability.

[0078] The reduction in pupil diameter may be characterized, for example, according to the percent reduction in pupil diameter and size of the pupil measured under certain light conditions. Thus, in certain embodiments, the reduction in pupil diameter under mesopic conditions is at least 5% compared to the pupil diameter of the patient under the same mesopic conditions but not receiving the treatment 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 the patient under the same mesopic conditions but not receiving the treatment 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 compared to the pupil diameter of the patient under the same mesopic conditions but not receiving the treatment defined by the method. In certain other embodiments, the patient experiences a reduction in pupil diameter, when measured under mesopic 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, as compared to the diameter of the patient's pupil under the same mesopic conditions but not receiving a treatment defined by the method. In certain other embodiments, the patient experiences a reduction in pupil diameter, when measured under mesopic conditions, in the range of about 0.6 mm to about 1.2 mm, as compared to the diameter of the patient's pupil under the same mesopic conditions but not receiving a treatment 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 mesopic conditions due to the treatment 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 mesopic conditions due to the treatment defined by the method.

[0079] In certain embodiments, the method provides for at least a 10% reduction in pupil diameter in the patient's eye. In certain embodiments, the method provides for at least a 15% reduction in pupil diameter in the patient's eye. In certain embodiments, the method provides for at least a 20% reduction in pupil diameter in the patient's eye. In certain embodiments, the method provides for at least a 25% reduction in pupil diameter in the patient's eye. In certain embodiments, the method provides for at least a 30% reduction in pupil diameter in the patient's eye.

[0080] In certain embodiments, the method achieves a pupil diameter in the range of about 2.5 mm to about 5.5 mm under dim light conditions. In certain embodiments, the method achieves a pupil diameter in the range of about 3 mm to about 5 mm under dim light conditions. In certain embodiments, the method achieves a pupil diameter in the range of about 3 mm to about 4.5 mm under dim light conditions.

[0081] Reducing abnormal focusing of scattered light rays in a patient's eye One benefit of the treatment method is that the patient can also experience a reduction in the abnormal focus of scattered light in the patient's eye. This can provide an improvement in the patient's visual ability. In certain embodiments, the treatment method provides a reduction in the abnormal focus 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 focus 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 focus of scattered light in the patient's eye for at least 36 hours, 48 ​​hours, 60 hours, or 72 hours.

[0082] K. 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-J above) are provided below, including, for example, the identity of the α-adrenergic antagonist, the frequency of administration of the α-adrenergic antagonist, the dosage of the α-adrenergic antagonist, the identity of the muscarinic acetylcholine receptor agonist, the degree of ocular hyperemia, the reduction in intraocular pressure in the eye resulting from the method, the duration of the reduction in intraocular pressure, and the patient population that may derive particular benefit from the method of treatment. A more detailed description of such features is provided below. The present invention encompasses all permutations and combinations of these features.

[0083] 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, tradozone, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin, silodosin, atipamezole, idazoxan, mirtazapine, yohimbine, fenoldopam, thymoxamine, or any of the above-mentioned pharmaceutically acceptable salts.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 embodiments, the alpha-adrenergic antagonist is fenoldopam mesylate.

[0084] 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.

[0085] In certain embodiments, an α-adrenergic antagonist is characterized according to its activity toward a certain α-adrenergic receptor. Thus, in certain embodiments, an α-adrenergic antagonist has antagonist activity toward the α-1 adrenergic receptor. The activity toward the α-1 adrenergic receptor may be further characterized according to whether the activity is toward one or more of the α-1 adrenergic receptor subtypes (e.g., α-1A, α-1B, and α-1D). Thus, in certain embodiments, an α-adrenergic antagonist has antagonist activity toward the α-1A adrenergic receptor. In certain embodiments, an α-adrenergic antagonist has antagonist activity toward the α-1B adrenergic receptor. In certain embodiments, the alpha-adrenergic antagonist has antagonist activity towards the alpha-1D adrenergic receptor. In certain embodiments, the alpha-adrenergic antagonist has antagonist activity towards each of the alpha-1 adrenergic receptor subtypes.

[0086] In certain embodiments, the α-adrenergic antagonist has antagonist activity toward the α-2 adrenergic receptor. Activity toward the α-2 adrenergic receptor may be further characterized according to whether the activity is toward 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 toward the α-2A adrenergic receptor. In certain embodiments, the α-adrenergic antagonist has antagonist activity toward the α-2B adrenergic receptor. In certain embodiments, the α-adrenergic antagonist has antagonist activity toward the α-2C adrenergic receptor. In certain embodiments, the alpha-adrenergic antagonist has antagonist activity toward each of the alpha-2 adrenergic receptor subtypes.

[0087] Alpha-adrenergic antagonists may be characterized according to their activity towards (i) the alpha-1 adrenergic receptor vs. (ii) the alpha-2 adrenergic receptor. In certain embodiments, an alpha-adrenergic antagonist has antagonist activity towards both (i) the alpha-1 adrenergic receptor and (ii) the alpha-2 adrenergic receptor. In certain embodiments, an alpha-adrenergic antagonist has antagonist activity towards (i) the alpha-1 adrenergic receptor but not (ii) the alpha-2 adrenergic receptor. In certain embodiments, an alpha-adrenergic antagonist has antagonist activity towards (i) the alpha-2 adrenergic receptor but not (ii) the alpha-1 adrenergic receptor. In certain embodiments, (i) the inhibitory activity of an α-adrenergic antagonist toward an α-1 adrenergic receptor (e.g., IC 50In certain embodiments, (i) the inhibitory activity of the alpha-adrenergic antagonist towards the alpha-2 adrenergic receptor (e.g., as measured by IC 50 value) is at least 10-fold higher compared to alpha-1 adrenergic receptors.

[0088] Frequency of administration of α-adrenergic antagonists The methods may be further characterized according to the frequency of administration of the alpha adrenergic antagonist. For example, in certain embodiments, a dosage of the alpha adrenergic antagonist is administered to the eye no more than once per day.

[0089] Alpha-adrenergic antagonist dosing The method may be further characterized according to the dosage of the α-adrenergic antagonist (e.g., phentolamine or a pharma- ceutically acceptable salt thereof). For example, in certain embodiments, the dosage of the α-adrenergic antagonist contains about 0.1 mg to about 2.0 mg of phentolamine or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the dosage of the α-adrenergic antagonist contains about 0.1 mg to about 2.0 mg of phentolamine or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the dosage of the α-adrenergic antagonist contains about 0.1 mg to about 2.0 mg of phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist contains about 0.3 mg to about 0.7 mg of phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist contains about 0.5 mg of phentolamine mesylate. In certain other embodiments, the dosage of the α-adrenergic antagonist contains about 0.8 mg to about 1.2 mg of phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist contains about 1 mg of phentolamine mesylate.

[0090] In certain embodiments, the dosage of the α-adrenergic antagonist contains about 0.3 mg to about 0.6 mg of phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist contains about 0.3 mg to about 0.4 mg of phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist contains about 0.3 mg of phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist contains about 0.5 mg to about 0.7 mg of phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist contains about 0.6 mg to about 0.7 mg of phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist contains about 0.6 mg of phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist is in the form of an ophthalmic solution containing an aqueous pharma- ceutically acceptable carrier and phentolamine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the dosage of the α-adrenergic antagonist is in the form of an ophthalmic solution containing an aqueous pharma- ceutically acceptable carrier and phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist is in the form of an ophthalmic solution containing an aqueous pharma- ceutically acceptable carrier and about 0.1% (w / v) to about 2% (w / v) phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist is in the form of an ophthalmic solution containing water, mannitol, and phentolamine mesylate. In certain embodiments, the dosage of the α-adrenergic antagonist is in the form of an ophthalmic solution containing water, mannitol, sodium acetate, and phentolamine mesylate.

[0091] In certain embodiments, the dosage of the alpha-adrenergic antagonist is one drop of a solution containing 1% w / w phentolamine mesylate. In certain embodiments, the dosage of the alpha-adrenergic antagonist is two drops of a solution containing 1% w / w phentolamine mesylate.

[0092] The dosage of an α-adrenergic antagonist (e.g., 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. A standard eye drop typically contains about 0.03 mL to about 0.05 mL of solution.

[0093] In certain embodiments, the dosage of the alpha-adrenergic antagonist may be in the form of an aqueous ophthalmic solution. For example, in certain embodiments, the dosage of the alpha-adrenergic antagonist may be in the form of an aqueous ophthalmic solution. (a) about 0.1% (w / v) to about 2% (w / v) 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 1. 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.

[0094] In certain embodiments, the dosing of the α-adrenergic antagonist is (a) about 0.5% (w / v) to about 2% (w / v) 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 1. 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.

[0095] In certain embodiments, the at least one polyol is mannitol. In certain embodiments, the solution contains 4% (w / v) mannitol. In certain embodiments, the alkali metal acetate salt is sodium acetate. In certain embodiments, the solution contains 3 mM sodium acetate.

[0096] In certain embodiments, the dosing of the α-adrenergic antagonist is (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 1. 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.

[0097] In certain embodiments, the dosing of the α-adrenergic antagonist is (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 1. 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.

[0098] In certain embodiments, the dosing of the α-adrenergic antagonist is (a) about 0.5% (w / v) to about 1% (w / v) phentolamine mesylate; (b) about 4% mannitol; (c) approximately 3 mM sodium acetate; and (d) water 1. 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.

[0099] In certain embodiments, the dosing of the α-adrenergic antagonist is (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 1 mM to about 6 mM sodium acetate; and (d) water An aqueous ophthalmic solution comprising: 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.

[0100] In certain embodiments, the dosing of the α-adrenergic antagonist is (a) about 1% (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; and (d) water An aqueous ophthalmic solution comprising: 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.

[0101] In certain embodiments, the dosing of the α-adrenergic antagonist is (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 An aqueous ophthalmic solution comprising: 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.

[0102] In certain embodiments, the dosing of the α-adrenergic antagonist is (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; and (d) water An aqueous ophthalmic solution comprising: 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.

[0103] In certain embodiments, the dosing of the α-adrenergic antagonist is (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; and (d) water An aqueous ophthalmic solution comprising: 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.

[0104] In certain embodiments, the dosage of the alpha-adrenergic antagonist is an aqueous ophthalmic solution comprising: (a) about 1% (w / v) phentolamine mesylate; (b) about 4% (w / v) mannitol; (c) a buffer comprising about 3 mM sodium acetate; and (d) water; 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.

[0105] In certain embodiments, the dosage of the alpha adrenergic antagonist is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 1% (w / v) phentolamine mesylate; (b) about 4% (w / v) mannitol; (c) a buffer comprising about 3 mM sodium acetate; and (d) water; the solution has a pH in the range of 4.0 to 7.5 and does not contain a chelating agent.

[0106] Identity and dosage of muscarinic acetylcholine receptor agonist The method can be further characterized according to the identity and dosage of muscarinic acetylcholine receptor agonist.For example, in certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine or a pharmaceutically acceptable salt thereof.In certain embodiments, the muscarinic acetylcholine receptor agonist is a pharmaceutically acceptable salt of pilocarpine.In certain embodiments, the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

[0107] In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is less than about 2 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is less than about 1 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is less than about 0.5 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is less than about 0.25 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.1 mg to about 1.5 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.1 mg to about 1.0 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.1 mg to about 0.5 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.1 mg to about 0.3 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.2 mg to about 0.4 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, or about 0.4 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, or about 0.4 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.1 mg to about 0.2 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.1 mg to about 0.2 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.1 mg to about 0.15 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.05 mg to about 0.15 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.05 mg to about 0.3 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.3 mg to about 0.7 mg.In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.3 mg to about 0.8 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.2 mg to about 0.9 mg. In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, or about 0.9 mg.

[0108] In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is 1 drop of a solution containing 0.4% w / w pilocarpine hydrochloride.In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is 2 drops of a solution containing 0.4% w / w pilocarpine hydrochloride.In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is 1 drop of a solution containing 1.25% w / w pilocarpine hydrochloride.

[0109] In certain embodiments, the dosage of the muscarinic acetylcholine receptor agonist is administered in the form of an ophthalmic solution containing the muscarinic acetylcholine receptor agonist, a lipid, and a pharma- ceutically acceptable carrier. In certain embodiments, the muscarinic acetylcholine receptor agonist is present in the ophthalmic solution at a concentration ranging from about 0.1% (w / v) to about 4% (w / v). In certain embodiments, the muscarinic acetylcholine receptor agonist is present in the ophthalmic solution at a concentration ranging from about 0.1% (w / v) to about 2% (w / v). In certain embodiments, the muscarinic acetylcholine receptor agonist is present in the ophthalmic solution at a concentration ranging from about 0.1% (w / v) to about 1% (w / v). In certain embodiments, the muscarinic acetylcholine receptor agonist is present in the ophthalmic solution at a concentration ranging from about 0.2% (w / v) to about 1% (w / v). In certain embodiments, the muscarinic acetylcholine receptor agonist is present in the ophthalmic solution at a concentration ranging from about 0.1% (w / v) to about 0.5% (w / v). In certain embodiments, the muscarinic acetylcholine receptor agonist is present in the ophthalmic solution at a concentration ranging from about 0.4% (w / v). In certain embodiments, the muscarinic acetylcholine receptor agonist is present in the ophthalmic solution at a concentration ranging from about 1% (w / v) to about 1.5% (w / v). In certain embodiments, the muscarinic acetylcholine receptor agonist is present in the ophthalmic solution at a concentration ranging from about 1.25% (w / v).

[0110] In certain embodiments, the muscarinic acetylcholine receptor agonist dosage is administered locally to the eye in the form of eye drops.

[0111] In certain embodiments, a dosage of the muscarinic acetylcholine receptor agonist is administered to the eye no more than once per day.

[0112] Administration of a second dose of a muscarinic acetylcholine receptor agonist The method may be further characterized according to optionally administering a second dosage of a muscarinic acetylcholine receptor agonist to the patient. For example, in certain embodiments, the method further comprises topically administering a second dosage of a muscarinic acetylcholine receptor agonist to the patient's eye in an amount effective to further reduce the diameter of the patient's pupil. In certain embodiments, the second dosage of the muscarinic acetylcholine receptor agonist is an ophthalmic solution comprising a muscarinic acetylcholine receptor agonist at a concentration of about 0.1% (w / v) to about 1% (w / v). In certain embodiments, the second dosage of the muscarinic acetylcholine receptor agonist is an ophthalmic solution comprising a muscarinic acetylcholine receptor agonist at a concentration of about 0.1% (w / v) to about 2% (w / v).

[0113] Reduction of pupil diameter The method may be further characterized according to the degree of reduction in pupil diameter. For example, in certain embodiments, the patient experiences at least a 1 mm reduction in pupil diameter when measured under photopic conditions by the method. In certain embodiments, the patient experiences at least a 2 mm reduction in pupil diameter when measured under photopic conditions by the method. In certain embodiments, the patient experiences at least a 3 mm reduction in pupil diameter when measured under photopic conditions by the method. In certain embodiments, the patient experiences a reduction in pupil diameter ranging from about 0.5 mm to about 5 mm when measured under photopic conditions by the method. In certain embodiments, the patient experiences at least a 1 mm reduction in pupil diameter when measured under mesopic conditions by the method. In certain embodiments, the patient experiences at least a 2 mm reduction in pupil diameter when measured under mesopic conditions by the method. In certain embodiments, the patient experiences at least a 3 mm reduction in pupil diameter when measured under mesopic conditions by the method. In certain embodiments, the patient experiences a reduction in pupil diameter in the range of about 0.5 mm to about 5 mm when measured under mesopic conditions by the method.

[0114] 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 dim light conditions due to a treatment 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 dim light conditions due to a treatment defined by the method.

[0115] Degree of eye congestion The method may be further characterized according to the degree of ocular redness experienced by the patient. The degree of ocular redness may be assessed and characterized using procedures described in the literature, such as the Cornea and Contact Lens Research Unit (CCLRU) redness grading scale developed by the School of Optometry at the 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 grading scale assesses ocular redness on a four-point scale: (0) no ocular redness, (1) very slight ocular redness, (2) slight ocular redness, (3) moderate ocular redness, and (4) severe ocular redness. See FIG. 1 for an example of the ocular redness scale.

[0116] In certain embodiments, the patient experiences an increase in ocular redness of no more than 2 grades as measured using the CCLRU Hyperemia Grading Scale according to the method. In certain embodiments, the patient experiences an increase in ocular redness of no more than 1 grade as measured using the CCLRU Hyperemia Grading Scale according to the method.

[0117] Route of administration The method may be further characterized according to the route of administration of the α-adrenergic antagonist and / or the optional muscarinic acetylcholine receptor agonist. For example, in certain embodiments, the α-adrenergic antagonist is administered topically to the patient's eye. In certain embodiments, the α-adrenergic antagonist is administered topically to the patient's eye in the form of eye drops.

[0118] In certain embodiments, the muscarinic acetylcholine receptor agonist is administered topically to the patient's eye. In certain embodiments, the muscarinic acetylcholine receptor agonist is administered topically to the patient's eye in the form of eye drops.

[0119] Time of administration The method can be further characterized according to the time of day that the α-adrenergic antagonist is administered to the patient.In certain embodiments, the α-adrenergic antagonist is administered to the patient's eye at or near the time the patient goes to bed.In certain embodiments, the dosage of the α-adrenergic antagonist is administered within 2 hours, 1.5 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes of the time the patient goes to bed.In certain embodiments, the dosage of the α-adrenergic antagonist is administered within 1 hour of the time the patient goes to bed.

[0120] In certain embodiments, the α-adrenergic antagonist and the optional muscarinic acetylcholine receptor agonist are administered simultaneously to the patient's eye, hi certain embodiments, the α-adrenergic antagonist and the optional muscarinic acetylcholine receptor agonist are administered separately to the patient's eye.

[0121] Reducing intraocular pressure in the eye The method may be further characterized according to the reduction in intraocular pressure in the eye resulting from the method. For example, in certain embodiments, the patient experiences at least a 5% reduction in intraocular pressure in the eye resulting from the method. In certain embodiments, the patient experiences at least a 10% reduction in intraocular pressure in the eye resulting from the method. In certain embodiments, the patient experiences at least a 15% reduction in intraocular pressure in the eye resulting from the method. In certain embodiments, the patient experiences at least a 20% reduction in intraocular pressure in the eye resulting from the method. In certain embodiments, the patient experiences at least a 25% reduction in intraocular pressure in the eye resulting from the method. In certain embodiments, the patient experiences at least a 30% reduction in intraocular pressure in the eye resulting from the method. In certain embodiments, the patient experiences at least a 40% reduction in intraocular pressure in the eye resulting from the method. In certain embodiments, the patient experiences at least a 50% reduction in intraocular pressure in the eye resulting from the method.

[0122] In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 1 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 2 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 3 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 4 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 5 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 6 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 7 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 8 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 10 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 15 mmHg due to the method, hi certain embodiments, the patient experiences a reduction in intraocular pressure in the eye of at least 20 mmHg due to the method.

[0123] In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye ranging from about 1 mmHg to about 5 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye ranging from about 5 mmHg to about 10 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye ranging from about 10 mmHg to about 15 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye ranging from about 4 mmHg to about 8 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye ranging from about 8 mmHg to about 12 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye ranging from about 10 mmHg to about 25 mmHg due to the method. In certain embodiments, the patient experiences a reduction in intraocular pressure in the eye resulting from the method in the range of about 15 mmHg to about 25 mmHg.

[0124] Duration of reduction in intraocular pressure The method can be further characterized according to the duration of the reduction of intraocular pressure.For example, in certain embodiments, the reduction of intraocular pressure lasts for at least 6 hours.In certain embodiments, the reduction of intraocular pressure lasts for at least 12 hours.In certain embodiments, the reduction of intraocular pressure lasts for at least 24 hours.In certain embodiments, the reduction of intraocular pressure lasts for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21 or 24 hours.

[0125] In certain embodiments, the reduction in intraocular pressure lasts for at least 2 days. In certain embodiments, the reduction in intraocular pressure lasts for at least 5 days. In certain embodiments, the reduction in intraocular pressure lasts for at least 7 days. In certain embodiments, the reduction in intraocular pressure lasts for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21, or 28 days.

[0126] In certain embodiments, the reduction in intraocular pressure lasts for a duration of about 5 to about 24 hours. In certain embodiments, the reduction in intraocular pressure lasts for a duration of about 12 to about 24 hours. In certain embodiments, the reduction in intraocular pressure lasts for a duration of about 1 day to about 3 days. In certain embodiments, the reduction in intraocular pressure lasts for a duration of about 3 days to about 5 days. In certain embodiments, the reduction in intraocular pressure lasts for a duration of about 5 days to about 7 days. In certain embodiments, the reduction in intraocular pressure lasts for a duration of about 7 days to about 14 days.

[0127] Patient populations that may derive particular benefit from the treatment approach Method can be further characterized according to the patient population that can derive particular benefit from the treatment method.For example, in certain embodiments, patient's eye has intraocular pressure of more than about 22mmHg before the method is performed.In certain embodiments, patient's eye has intraocular pressure of more than about 25mmHg before the method is performed.In certain embodiments, patient's eye has intraocular pressure of more than about 30mmHg before the method is performed.In certain embodiments, patient's eye has intraocular pressure of more than about 40mmHg before the method is performed.

[0128] In certain other embodiments, the patient at which treatment is initiated is characterized as having an intraocular pressure in the range of about 20 mmHg to about 50 mmHg. In certain other embodiments, the patient at which treatment is initiated is characterized as having an intraocular pressure in the range of about 30 mmHg to about 50 mmHg. In certain other embodiments, the patient at which treatment is initiated is characterized as having an intraocular pressure in the range of about 25 mmHg to about 30 mmHg.

[0129] In certain other embodiments, the patient initiating treatment is characterized as having an intraocular pressure in the range of about 20 mmHg to about 30 mmHg before the method is performed. In certain embodiments, the patient initiating treatment is characterized as having an intraocular pressure in the range of about 20 mmHg to about 25 mmHg before the method is performed.

[0130] In certain other embodiments, the patient's eye has an intraocular pressure of about 22 mmHg or less before the method is performed. In certain other embodiments, the patient at which treatment is initiated is characterized as having an intraocular pressure in the range of about 12 mmHg to about 22 mmHg. In certain other embodiments, the patient at which treatment is initiated is characterized as having an intraocular pressure in the range of about 15 mmHg to about 22 mmHg. In certain other embodiments, the patient at which treatment is initiated is characterized as having an intraocular pressure in the range of about 18 mmHg to about 22 mmHg.

[0131] In certain other embodiments, the patient initiating treatment is characterized as having an intraocular pressure in the range of about 17 mmHg to about 36 mmHg, about 17 mmHg to about 32 mmHg, about 17 mmHg to about 28 mmHg, about 17 mmHg to about 26 mmHg, about 17 mmHg to about 24 mmHg, or about 17 mmHg to about 22 mmHg. In certain other embodiments, the patient initiating treatment is characterized as having an intraocular pressure in the range of about 20 mmHg to about 36 mmHg, about 20 mmHg to about 32 mmHg, about 20 mmHg to about 28 mmHg, about 20 mmHg to about 26 mmHg, about 20 mmHg to about 24 mmHg, or about 20 mmHg to about 22 mmHg. In certain other embodiments, the patient initiating treatment is characterized as having an intraocular pressure in the range of about 20 mmHg to about 26 mmHg, about 20 mmHg to about 25 mmHg, about 20 mmHg to about 24 mmHg, about 20 mmHg to about 23 mmHg, or about 20 mmHg to about 22 mmHg. In certain other embodiments, the patient initiating treatment is characterized as having an intraocular pressure of less than about 23, 24, 25, or 26 mmHg.

[0132] In certain embodiments, the patient is a human. In certain embodiments, the patient is an adult human. In certain embodiments, the patient is a pediatric human.

[0133] In certain embodiments, the patient's eye has a narrow angle.

[0134] Medication to reduce eye redness The method may be further characterized according to the optional administration of an agent to the patient's eye that reduces ocular redness (e.g., ocular redness caused by an α-adrenergic antagonist). For example, in certain embodiments, the method further comprises topically administering an agent to the patient's eye that reduces ocular redness. Exemplary agents that reduce ocular redness include brimonidine, tetrahydrozoline, oxymetazoline, naphthazoline, or pharma- ceutically acceptable salts thereof, such as LUMIFY® (a commercially available ophthalmic solution containing brimonidine tartrate (0.025% w / w)).

[0135] In certain embodiments, the method further comprises topically administering brimonidine or a pharma- ceutically acceptable salt thereof to the patient's eye. In certain embodiments, the method further comprises topically administering brimonidine tartrate to the patient's eye. In certain embodiments, the method further comprises topically administering an ophthalmic solution comprising about 0.025% (w / w) brimonidine tartrate to the patient's eye.

[0136] II. Administration of Additional Therapeutic Agents Another aspect of the present invention provides for the administration of an additional therapeutic agent. The methods described above may optionally further comprise administering one or more additional therapeutic agents to the patient. Exemplary additional therapeutic agents include, for example: Prostaglandin analogues (such as latanoprost, bimatoprost, travoprost, tafluprost, latanoprost bunod, or pharma- ceutically acceptable salts thereof); · beta-blockers (such as timolol or its pharma- ceutically acceptable salts); · alpha agonists (such as brimonidine or its pharma- ceutically acceptable salts); Carbonic anhydrase inhibitors (such as dorzolamide, brinzolamide, acetazolamide, methazolamide, or their pharma- ceutically acceptable salts); and Rho kinase inhibitors (netarsudil or its pharma- ceutically acceptable salts, etc.) Examples include:

[0137] Latanoprost may be administered in the form of a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol / kg, each 1 mL of solution containing 50 micrograms of latanoprost. The solution may optionally contain benzalkonium chloride (0.02% w / w), sodium chloride, sodium dihydrogen phosphate monohydrate, and disodium hydrogen phosphate.

[0138] Latanaoprost may be administered to a patient according to the procedures described in the XALATAN® Prescribing Information (herein incorporated by reference). In certain embodiments, a single daily dose of 1.5 micrograms of latanaoprost is administered to the patient's eye. In certain embodiments, a single daily dose of latanaoprost ranging from about 0.5 to about 1.0 micrograms, about 1.0 to about 1.5 micrograms, or about 1.5 to about 2.0 micrograms is administered to the patient's eye.

[0139] Timolol can be administered as timolol maleate in the form of ophthalmic solution.A solution containing 3.4mg timolol maleate per 1mL basis, 1 drop or 2 drops per day, can be administered to the patient's eye.Alternatively, a solution containing 6.8mg timolol maleate per 1mL basis, 1 drop per day, can be administered to the patient's eye.

[0140] Netarsudil may be administered to a patient in the form of an ophthalmic solution, such as a sterile, isotonic, buffered aqueous solution containing netarsudil dimesylate (0.02% w / w) having a pH of approximately 5 and an osmolality of approximately 295 mOsmol / kg. Each 1 mL of solution contains 0.28 mg of netarsudil dimesylate. The aqueous solution may contain benzalkonium chloride (e.g., 0.015% w / w), boric acid, and mannitol. Netarsudil dimesylate may be administered to a patient once per day as an eye drop of a sterile, isotonic, buffered aqueous solution containing netarsudil dimesylate (0.02% w / w) having a pH of approximately 5 and an osmolality of approximately 295 mOsmol / kg.

[0141] 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 combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or pharmaceutical composition(s) comprising the therapeutic agents, may be administered in any order (e.g., sequentially, in parallel, together, simultaneously, contemporaneously, etc.).

[0142] In certain embodiments, therapeutic agents may act additively or synergistically. A synergistic combination may allow for the use of lower dosages of one or more agents and / or less frequent administration of one or more agents of the combination therapy. Lower dosages or less frequent administration of one or more agents may reduce the toxicity of the therapy without reducing the efficacy of the therapy.

[0143] III. Implantable Ophthalmic Devices The compositions described herein can be administered to the patient's eye via an implantable ophthalmic device that dispenses the composition. The implantable ophthalmic device can be configured to dispense the composition at a desired rate and / or frequency. In certain embodiments, the implantable ophthalmic device is a sustained release insert.

[0144] IV. Ophthalmic solution The therapeutically active agent is desirably administered to a 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 permit distribution of the ophthalmic solution through normal distribution channels for 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 alkylene glycol polymers, dextrans, cellulose agents, buffers, tonicity modifiers, preservatives, antioxidants, viscosity modifiers, corneal permeation enhancers, solubilizers, stabilizers, surfactants, demulcent polymers, wetting agents, and other materials.

[0145] The ophthalmic solution 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.

[0146] The various treatment methods described above include administering a dosage of phentolamine or a pharma- ceutically acceptable salt thereof to a patient. The dosage 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 duration (such as hours, days, or weeks).

[0147] The ophthalmic solution desirably comprises an aqueous pharma- ceutically acceptable carrier and phentolamine or a pharma- ceutically acceptable salt thereof. The ophthalmic solution may contain excipient(s) suitable for administration to the eye. Various pharma- ceutically 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 an aqueous pharma- ceutically acceptable carrier and phentolamine mesylate.

[0148] Thus, in certain embodiments, the medication utilized in the method is an ophthalmic solution comprising an aqueous pharma- ceutically acceptable carrier and phentolamine or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the medication is an ophthalmic solution comprising an aqueous pharma- ceutically acceptable carrier and phentolamine mesylate. In certain other embodiments, the medication is an ophthalmic solution comprising water, a polyol, and phentolamine or a pharma- ceutically acceptable salt thereof. In certain other embodiments, the medication is an ophthalmic solution comprising water, mannitol, and phentolamine mesylate. In certain other embodiments, the medication 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 medication is an ophthalmic solution comprising water, mannitol, sodium acetate, and phentolamine mesylate.

[0149] 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.

[0150] Ophthalmic solutions 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 ranging from 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.

[0151] The ophthalmic solution may be further characterized according to the release rate of any active ingredient. For example, in certain embodiments, the ophthalmic solution is an immediate release ophthalmic solution. In certain embodiments, the ophthalmic solution is an extended release ophthalmic solution.

[0152] Chelating agent-free water-based eye 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; 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 storage stability, minimal irritation to the patient's eye, and enhanced permeation of phentolamine into the patient's eye.

[0153] 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; the solution has a pH in the range of 4.0 to 7.5 and does not contain a chelating agent.

[0154] Exemplary components and features of the aqueous ophthalmic solution are described in more detail below.

[0155] 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.

[0156] The amount of phentolamine or its pharmaceutically acceptable salt in the aqueous ophthalmic solution can be adjusted to achieve the desired performance characteristics.For example, when it is desired to provide a large amount of phentolamine (or its pharmaceutically acceptable salt) to the patient in 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 a longer duration of reduced intraocular pressure, since more phentolamine (or its pharmaceutically acceptable salt) is administered to the patient.

[0157] Thus, in certain embodiments, the aqueous ophthalmic solution comprises about 0.1% (w / v) to about 5% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the aqueous ophthalmic solution comprises about 0.1% (w / v) to about 1% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof, about 1% (w / v) to about 2% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof, about 2% (w / v) to about 3% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof, about 3% (w / v) to about 4% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof, or about 4% (w / v) to about 5% (w / v) phentolamine or a pharma- ceutically acceptable salt thereof. In certain embodiments, the aqueous ophthalmic solution comprises about 0.1% (w / v) to about 2% (w / v) 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 from about 0.1% (w / v) to about 4% (w / v) phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises from 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.In certain other embodiments, the aqueous ophthalmic solution comprises about 0.25% (w / v) or about 0.5% (w / v) phentolamine mesylate.

[0158] 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 modify the isotonicity of the aqueous ophthalmic solution. Exemplary polyol compounds include, for example, mannitol, glycerol, propylene glycol, ethylene glycol, sorbitol, and xylitol.

[0159] 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.

[0160] 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 modify the isotonicity of the solution to make it more suitable for administration to the patient's eye. In certain embodiments, the aqueous ophthalmic solution comprises from about 2% (w / v) to about 5% (w / v) of at least one polyol compound. In certain other embodiments, the aqueous ophthalmic solution comprises from about 3.5% (w / v) to about 4.5% (w / v) of at least one polyol compound. In certain other embodiments, the aqueous ophthalmic solution comprises from about 4% (w / v) of at least one polyol compound. In certain other embodiments, the aqueous ophthalmic solution comprises from about 2% (w / v) to about 3% (w / v) of mannitol and from about 0.5% (w / v) to about 1.5% (w / v) of glycerin. In certain other embodiments, the mannitol described in the above embodiments is D-mannitol.

[0161] In certain embodiments, the amount of polyol can be selected based on the amount of phentolamine (or its pharma- ceutically acceptable salt) so that 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 embodiments where the aqueous ophthalmic solution contains about 2% (w / v) phentolamine, mannitol is present in the solution at a concentration of about 3% (w / v). In embodiments where the aqueous ophthalmic solution contains about 1% (w / v) phentolamine, mannitol is present in the solution at a concentration of about 4% (w / v). To further illustrate this principle, in embodiments where the aqueous ophthalmic solution contains about 0.5% (w / v) phentolamine, mannitol can be present in the solution at a concentration of about 4.5% (w / v). In certain embodiments, the mannitol described in the above embodiment is D-mannitol.

[0162] It is recognized that the aqueous ophthalmic solution may 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, such as polypropylene glycol having a weight average molecular weight in the range of about 5,000 g / mol to about 100,000 g / mol.

[0163] Poly(C 2-4 (alkylene) glycol polymer The aqueous ophthalmic solution is 2-4 An exemplary poly(C) glycol polymer may optionally be included. 2-4 The alkylene) glycol polymer is polypropylene glycol (e.g., polypropylene glycol 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).

[0164] Dextran The aqueous ophthalmic solution may optionally include dextran. Dextran is a branched polysaccharide containing glucose molecules that is commercially available. The amount of dextran in the aqueous ophthalmic solution may be selected to achieve specific performance characteristics. In certain embodiments, the aqueous ophthalmic solution includes from about 0.01% (w / v) to about 2% (w / v) dextran. In certain other embodiments, the aqueous ophthalmic solution includes from about 0.01% (w / v) to about 1% (w / v) dextran.

[0165] 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.

[0166] Cellulose Agent The aqueous ophthalmic solution may optionally include a cellulose agent. Exemplary cellulose agents include, for example, cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxpropylcellulose, and hydroxypropylmethylcellulose. In certain embodiments, the cellulose agent is hydroxypropylmethylcellulose. In certain other embodiments, the cellulose agent is cellulose, carboxymethylcellulose, hydroxyethylcellulose, or hydroxpropylcellulose. The amount of the cellulose agent in the aqueous ophthalmic solution may be selected to achieve the desired performance characteristics. For example, in certain embodiments, the aqueous ophthalmic solution includes about 0.01% (w / v) to about 2% (w / v) of the cellulose agent.

[0167] 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.

[0168] buffer 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 little 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 component, an inorganic component, or a combination of an organic component and an inorganic component. It should be understood that the buffer will at least partially dissociate in the aqueous solution, forming, 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, where the acid and the base are not conjugated. For example, the acid can be boric acid and the base can be tris(hydroxymethyl)aminomethane (TRIS).

[0169] 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, salts thereof, and combinations thereof. It should be understood that the salt form of the buffer can include any suitable counter ion. For example, the salt form of an acid can include an alkali metal or alkaline earth metal counter ion.

[0170] 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 strong base (or hydrogen ions or hydroxide ions, respectively) required when added to one liter of buffer solution (standard units) to change the pH of the buffer solution by one 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 by its pK a pH ranges around the pK of a buffer a In certain embodiments, the buffer is a weak buffer, such as an alkali metal carboxylate (e.g., sodium acetate).

[0171] 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; (b) a lipophilicity value Log P of about -0.50 to about 1.5; more preferably about -0.25 to about 1.35.

[0172] 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.

[0173] The amount and identity of the buffer may be selected to achieve certain performance characteristics for 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 isotonicity 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 other embodiments, the buffer comprises an alkali metal salt of an alkyl carboxylate. In certain other embodiments, the buffer comprises an alkali metal salt of acetate. In still other embodiments, the buffer comprises sodium acetate.

[0174] 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 yet other embodiments, the solution has a pH in the range of 4.7 to 5.1.

[0175] Additional materials 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 modifiers, preservatives, antioxidants, viscosity modifiers, stabilizers, corneal permeation enhancers, and surfactants.

[0176] A. Isotonic modifiers The aqueous ophthalmic solution may optionally include one or more tonicity modifiers. The tonicity modifiers may be ionic or non-ionic. In certain embodiments, the tonicity modifiers may be salts, carbohydrates, or polyols. Exemplary tonicity modifiers include alkali metal halides 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.

[0177] It will be appreciated that the tonicity modifier may be added to the aqueous ophthalmic solution in an amount sufficient to provide a desired osmolality. In certain embodiments, the tonicity modifier 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 modifier may be present in an amount ranging from about 0.01% (w / v) to about 7% (w / v), about 0.01% (w / v) to about 5% (w / v), about 0.01% (w / v) to about 1% (w / v), about 0.1% (w / v) to about 1% (w / v), about 0.05% (w / v) to about 5% (w / v), about 0.05% (w / v) to about 0.5% (w / v), about 1% (w / v) to about 3% (w / v), or about 2% (w / v) to about 4% (w / v) of the aqueous ophthalmic solution.

[0178] B. Preservatives The aqueous ophthalmic solution may optionally include 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); alkylmercuric salts of thiosalicylic acid (such as thiomersal, phenylmercuric nitrate, phenylmercuric acetate, or germicidal disinfectant); 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.

[0179] The amount of preservative may 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.

[0180] C. Antioxidants Aqueous ophthalmic solutions may optionally include 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 hydrogen sulfate, sodium metabisulfite, sodium bisulfite, sodium sulfite, and the like); and oil-soluble antioxidants (such as ascorbyl palmitate, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like).

[0181] 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.

[0182] D. Viscosity Modifiers The aqueous ophthalmic solution may optionally include one or more viscosity modifiers. Viscosity modifiers may be used, for example, to increase the absorption of active agents or to increase the retention time of the aqueous ophthalmic solution in the eye. Exemplary viscosity modifiers include polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxpropylcellulose, carboxymethylcellulose (CMC) and its salts (e.g., CMC sodium salt), gelatin, cellulose glycolate, sorbitol, niacinamide, α-cyclodextran, polyvinyl alcohol, polyethylene glycol, hyaluronic acid, polysachcharaide, monosaccharides, and combinations thereof.

[0183] The amount of 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 with a viscosity in the range of about 30 centipoise to about 100 centipoise.

[0184] 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 the desired sustained release profile for the therapeutic agent or agents.

[0185] E. Corneal permeation enhancers The aqueous ophthalmic solution may optionally include one or more agents for facilitating 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.

[0186] 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 of 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), about 0.01% (w / v) to about 1% (w / v), about 0.1% (w / v) to about 1% (w / v), about 0.05% (w / v) to about 5% (w / v), about 0.05% (w / v) to about 0.5% (w / v), about 1% (w / v) to about 3% (w / v), or about 2% (w / v) to about 4% (w / v) of the aqueous ophthalmic solution.

[0187] 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-lower alkylene (i.e., C1-C7, straight or branched) glycol esters, fatty acid poly-lower 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, and combinations thereof.

[0188] 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.

[0189] 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. It is contemplated that stabilizers described in the pharmaceutical literature are applicable 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 (polyethylene glycol, polypropylene glycol, etc.), polyethylene glycol-nonphenol ethers, polyethylene glycol sorbitan monolaurate, polyethylene glycol sorbitan monooleate, polyethylene glycol sorbitan monooleate, polyethylene glycol sterarate, 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 mentioned above).

[0190] 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.

[0191] H. Surfactant 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, and sucrose stearate. , 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 chloline, phosphatidylserine, and combinations thereof.

[0192] The amount of surfactant may 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.

[0193] I. Demulcent Polymers The aqueous ophthalmic solution may optionally contain one or more demulcent polymers. Demulcent polymers are useful for coating and moistening the cornea of ​​the eye due to their ability to retain large amounts of water. Exemplary demulcent polymers include cellulose derivatives, dextran 40, dextran 70, gelatin, and liquid polyols.

[0194] J. Wetting Agents The aqueous ophthalmic solution may optionally include one or more wetting agents. Wetting agents may be used to moisten the ocular surface. Exemplary wetting agents include polysorbates, poloxamers, tyloxapol, and lecithin.

[0195] K. Additional materials The aqueous ophthalmic solution may optionally contain one or more additional materials, such as acetylcysteine, cysteine, sodium bisulfite, butyl-hydroxyanisole, butyl-hydroxytoluene, alpha-tocopherol acetate, thiourea, thiosorbitol, sodium dioctyl sulfosuccinate, monothioglycerol, sorbitol laurate, triethanolamine oleate, or palmitate.

[0196] Additionally, the aqueous ophthalmic solution may include a carrier, such as one or more of the exemplary carriers described 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, such as an alcohol, such as glycerin, vegetable oil, or mineral oil. Other exemplary carriers include water and a mixture of one or more of the following materials: hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, methylhydroxypropylcellulose, hydroxypropylcellulose, 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 crosslinked polyacrylic acid.

[0197] 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 illustrative only and are not intended to limit the scope of the invention in any way.

[0198] One such exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 2% (w / v) 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 salt; and (d) water; the solution has a pH in the range of 4 to 6 and does not contain a chelating agent.

[0199] 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 other embodiments, the alkali metal acetate salt 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) from about 0.25% (w / v) to about 1% (w / v) of phentolamine mesylate; (ii) from about 1% (w / v) to about 6% (w / v) of one or more polyol compounds selected from the group consisting of mannitol, glycerol, and propylene glycol; (iii) from about 1 mM to about 6 mM of an alkali metal acetate; (iv) acetic acid; and (v) water; the solution has a pH in the range of 4 to 6.

[0200] Another such 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 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 salt; and (d) water; the solution has a pH in the range of 4.5 to 5.5 and does not contain a chelating agent.

[0201] 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 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 other embodiments, the alkali metal acetate salt 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) from about 0.5% (w / v) to about 2% (w / v) phentolamine mesylate; (ii) from about 1% (w / v) to about 6% (w / v) of one or more polyol compounds selected from the group consisting of mannitol, glycerol, and propylene glycol; (iii) from about 1 mM to about 6 mM of an alkali metal acetate; (iv) acetic acid; and (v) water; the solution has a pH in the range of 4.5 to 5.5.

[0202] Another such 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 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 salt; and (d) water; the solution has a pH in the range of 4.5 to 5.5 and does not contain a chelating agent.

[0203] 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 other 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% (w / v) to about 1% (w / v) phentolamine mesylate; (ii) about 1% (w / v) to about 6% (w / v) 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; the solution has a pH in the range of 4.5 to 5.5.

[0204] Further exemplary aqueous ophthalmic solutions are provided below in Tables 1-3, in each example the solution has a pH in the range of 4.7 to 5.1. [Table 1] [Table 2] [Table 3]

[0205] Another exemplary aqueous ophthalmic solution comprises phentolamine mesylate (e.g., at 1% w / v), mannitol (e.g., at 4% w / v), dextran having a weight average molecular weight of about 70,000 g / mol (e.g., at 0.1% w / v), hydroxypropyl methylcellulose (e.g., at 0.3% w / v), potassium chloride, purified water, sodium borate, and sodium chloride; 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., at 1% w / v), mannitol (e.g., at 4% w / v), dextran having a weight average molecular weight of about 70,000 g / mol (e.g., at 0.1% w / v), hydroxypropyl methylcellulose (e.g., at 0.3% w / v), potassium chloride, purified water, sodium borate, and sodium chloride; the solution has a pH in the range of 4 to 6. In certain other embodiments, the aqueous ophthalmic solution consists essentially of phentolamine mesylate (e.g., at 1% w / v), mannitol (e.g., at 4% w / v), dextran having a weight average molecular weight of about 70,000 g / mol (e.g., at 0.1% w / v), hydroxypropyl methylcellulose (e.g., at 0.3% w / v), potassium chloride, purified water, sodium borate, and sodium chloride; the solution has a pH in the range of 4.5 to 5.1.

[0206] Another exemplary aqueous ophthalmic solution comprises phentolamine mesylate (e.g., at 1% w / v), mannitol (e.g., at 4% w / v), sodium acetate (e.g., at 3 mM), and water, wherein the solution has a pH ranging from about 4 to about 6. In certain embodiments, the solution has a pH ranging from 4.5 to 5.1. In certain embodiments, the aqueous ophthalmic solution consists essentially of phentolamine mesylate (e.g., at 1% w / v), mannitol (e.g., at 4% w / v), sodium acetate (e.g., at 3 mM), and water, wherein the solution has a pH ranging from 4 to 6. In certain embodiments, the aqueous ophthalmic solution comprises 1% w / v phentolamine mesylate, 4% w / v mannitol, 3 mM sodium acetate, and water, wherein the solution has a pH ranging from 4.5 to 5.1. In certain other embodiments, the aqueous ophthalmic solution consists essentially of phentolamine mesylate (e.g., at 1% w / v), mannitol (e.g., at 4% w / v), sodium acetate (e.g., at 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 at 1% w / v, mannitol at 4% w / v, sodium acetate at 3 mM, and water, and the solution has a pH in the range of 4.5 to 5.1.

[0207] Yet another exemplary solution is a chelating agent-free aqueous ophthalmic solution comprising: (a) about 0.1% (w / v) to about 2% (w / v) 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; the solution has a pH in the range of 4 to 6 and does not contain a chelating agent.

[0208] 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; the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0209] 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 has a pH in the range of 4.6 to 5.2 and does not contain a chelator. In certain embodiments, the aqueous ophthalmic solution is a chelator-free solution comprising about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate.

[0210] 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; the solution has a pH in the range of 4.5 to 5.2 and does not contain a chelating agent.

[0211] 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; the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0212] 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; the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0213] 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 has a pH in the range of 4.6 to 5.2 and does not contain a chelator. In certain embodiments, the aqueous ophthalmic solution is a chelator-free solution comprising about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate.

[0214] 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; the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0215] 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.

[0216] 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; the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0217] 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; the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0218] 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 has a pH in the range of 4.6 to 5.2 and does not contain a chelator. In certain embodiments, the aqueous ophthalmic solution is a chelator-free solution comprising about 0.25% (w / v) to about 1% (w / v) phentolamine mesylate.

[0219] 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; the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0220] Stability characteristics of aqueous ophthalmic solutions The aqueous ophthalmic solutions described herein may be further characterized according to their stability features, such as the percentage of phentolamine (or a pharma- ceutically acceptable salt thereof) present in the aqueous ophthalmic solution after a particular length of storage. As explained above, one of the benefits of the present aqueous ophthalmic solutions is that they retain good stability over extended periods of time, even though the ophthalmic solutions do not have a chelating agent.

[0221] Thus, in certain embodiments, the aqueous ophthalmic solution is characterized by less than 2% by weight of phentolamine or a pharma- ceutically acceptable salt thereof degrading upon storage of the solution for 12 weeks at 25° C. In certain other embodiments, the aqueous ophthalmic solution is characterized by less than 2% by weight of phentolamine or a pharma- ceutically acceptable salt thereof degrading upon storage for 24 weeks (or 36 weeks or 48 weeks) at 25° C. In yet other embodiments, less than 7% by weight of phentolamine or a pharma- ceutically acceptable salt thereof degrading upon storage for 12 weeks (or 24, 36, or 48 weeks) at 40° C. In still other embodiments, the aqueous ophthalmic solution is characterized by less than 10% by weight of phentolamine or a pharma- ceutically acceptable salt thereof degrading upon storage for 18 months, 24 months, or 36 months at 25° C. In yet another embodiment, the aqueous ophthalmic solution is characterized in that less than 10% by weight of the phentolamine or pharma- ceutically acceptable salt thereof degrades upon storage for 18 months, 24 months, or 36 months at a temperature in the range of 2-8° C. In yet another embodiment, 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 upon storage for 18 months, 24 months, or 36 months at 25° C. In yet another embodiment, less than 10% by weight of the phentolamine or pharma- ceutically acceptable salt thereof degrades upon storage for 4, 5, or 6 months at 40° C.

[0222] Polyvinylpyrrolidone artificial tears Another ophthalmic solution contemplated for use in the present invention is an ophthalmic solution comprising an α-adrenergic antagonist (e.g., phentolamine or its pharma- ceutically acceptable salt) and a polyvinylpyrrolidone artificial tear composition. Exemplary polyvinylpyrrolidone artificial tear compositions are described, for example, in U.S. Patent 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 enhances wetting and spreading, has good retention and stability on the eye, and desirably does not cause significant discomfort to the user. Thus, an exemplary polyvinylpyrrolidone artificial tear composition comprises: (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 aqueous solution having isotonic properties.

[0223] Sustained Release Delivery Systems When it is desired to have a sustained release of one or more therapeutic agents to a 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 the published literature. Exemplary sustained release delivery systems include intracanalicular inserts, sustained release contact lenses, biodegradable 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 polyethylene glycol, 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, liposomes, and silicon oxide (e.g., silicon oxide particles, silicon oxide beads, and silicon oxide porous nanoparticles). An additional exemplary sustained release delivery system is the commercially available silicon oxide sustained release delivery system (e.g., from Duxeltech).

[0224] V. 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 mydriasis, glaucoma, and other ocular conditions according to the methods described herein. EXAMPLES

[0225] The invention generally described herein will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0226] Example 1: Restoration of Mydriasis in Human Subjects by Use of Phentolamine Mesylate in Combination with Pilocarpine Hydrochloride The ability of phentolamine mesylate in combination with pilocarpine hydrochloride to restore pharmacologically induced mydriasis in the eyes of human subjects can be evaluated by clinical trials. An exemplary procedure is described below.

[0227] At least 20 subjects are enrolled and randomized 1:1 to one of two treatment sequences. All subjects are first administered a mydriatic agent (phenylephrine (2.5% w / w) or tropicamide (1% w / w)) by delivering eye drops containing the mydriatic agent to the subject's eye. Approximately 1 hour after administering the mydriatic agent, the subject is then administered the study medication according to treatment protocol 1 or treatment protocol 2.

[0228] In treatment protocol 1, subjects receive a placebo on the first treatment day (Visit 1 / Day 1) and one drop of 1% w / w phentolamine mesylate ophthalmic solution together with one drop of 0.4% w / w pilocarpine hydrochloride ophthalmic solution on the second treatment day (Visit 2 / Day 8+Day 2). In treatment protocol 2, subjects receive one drop of 1% w / w phentolamine mesylate ophthalmic solution together with one drop of 0.4% w / w pilocarpine hydrochloride ophthalmic solution on the first treatment day (Visit 1 / Day 1) and one drop of 1% w / w phentolamine mesylate ophthalmic solution together with one drop of 0.4% w / w pilocarpine hydrochloride ophthalmic solution on the first treatment day (Visit 1 / Day 1) and one placebo on the second treatment day (Visit 2 / Day 8+Day 2). The study eye is defined as the eye with the largest pupil diameter at Visit 1 (1 hour after the application of the mydriatic drops). If both eyes have the same largest pupil diameter, the study eye is the right eye.

[0229] All treatments are administered to both eyes of the subject. At each visit, pupil size, accommodation, near and far visual acuity (VA), and redness of each eye are measured before (-1 hour / baseline) and 1 hour (0 minutes / max) after mydriatic drops in each eye (i.e., administered on the right side before study treatment), and at 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after treatment dosing. Efficacy and safety, including analysis of pupil size reduction, are evaluated. [Table 4]

[0230] Efficacy analysis The primary efficacy endpoint is the change in pharmacologically induced mydriatic (maximal) pupil diameter (0 min) 2 hours after treatment in the study eye. The study eye is defined as the eye with the largest pupil diameter at Visit 1 (1 hour after mydriatic instillation). If both eyes have the same maximum pupil diameter, the study eye is the right eye. This is the study eye for both Visit 1 and Visit 2 assessments.

[0231] Secondary efficacy endpoints (for the study eye; for the non-study eye; for both eyes) include: Change (in mm) from maximum pupil diameter (at 0 min) at each rest time point (30 min, 1 hr, 4 hr, 6 hr). The percentage of subjects who achieved pre-specified reductions from maximum pupil diameter of ≧2mm, ≧3mm, and ≧4mm at each time point (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours). Percentage of subjects achieving a pupillary diameter of 0.5 mm or less above 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 acclimatization at each time point (0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours). Percentage of subjects with habituation that did not change from baseline (-1 hour) at each time point (0 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr). 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 returning 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).

[0232] Example 2: Treatment of Acute Angle-Closure Glaucoma in Human Subjects with Phentolamine Mesylate The ability of phentolamine mesylate to treat acute angle-closure glaucoma in human subjects can be evaluated through clinical trials. An exemplary procedure is described below.

[0233] At least 20 human subjects with acute angle-closure glaucoma are randomized. Subjects are randomized in a 1:1 ratio to receive one drop of phentolamine mesylate ophthalmic solution 1% w / w or a placebo eye drop. Efficacy assessments include measurements of intraocular pressure (IOP). [Table 5]

[0234] Example 3: Reduction of pupil diameter and improvement of visual performance in human subjects using phentolamine mesylate in combination with pilocarpine hydrochloride The ability of phentolamine mesylate in combination with pilocarpine hydrochloride to reduce pupil diameter and improve visual performance in human subjects was evaluated in a randomized, double-blind, placebo-controlled clinical trial. Approximately 152 subjects were enrolled and randomized into one of four treatment groups. The experimental procedures and results are provided below.

[0235] Part I: Experimental Procedure Human subjects were screened for possible enrollment and, if eligible, enrolled in the study. The inclusion and exclusion criteria used to enroll subjects selected for the study are provided below. Following the enrollment period, approximately 152 subjects were enrolled and randomized into one of four treatment groups. The four treatment groups were as follows: Group I: 1% w / w phentolamine mesylate ophthalmic solution and 0.4% w / w pilocarpine hydrochloride ophthalmic solution Group II: 1% w / w phentolamine mesylate ophthalmic solution Group III: placebo ophthalmic solution and 0.4% w / w pilocarpine hydrochloride ophthalmic solution Group IV: placebo ophthalmic solution.

[0236] During the screening / baseline visit (i.e., Visit 1), subjects were evaluated for visual assessment of corrected distance near visual acuity (mesopic and photopic conditions), best corrected distance visual acuity (mesopic and photopic conditions), best corrected intermediate visual acuity (photopic conditions), pupil size, biomicroscopy, intraocular pressure measurements, and conjunctival injection. Additionally, during Visit 1, subjects were provided with 1% w / w phentolamine mesylate ophthalmic solution or placebo ophthalmic solution and instructed to apply the above topically to the subject's eye according to treatment group at or near bedtime for 3-4 consecutive days immediately preceding Visit 2.

[0237] At Visit 2, one drop of 0.4% w / w pilocarpine hydrochloride ophthalmic solution was administered to the subject's eye for subjects in Treatment Groups I and III. All subjects were determined to have presbyopia and all treatments were administered to both eyes of the subject. At Visit 2, pupil diameter, near corrected distance visual acuity (mesopic and photopic conditions), best corrected distance visual acuity (mesopic and photopic conditions), and best corrected intermediate visual acuity (photopic conditions) were measured prior to administration of any 0.4% w / w pilocarpine hydrochloride ophthalmic solution. Following administration of any 0.4% w / w pilocarpine hydrochloride ophthalmic solution during Visit 2, subjects are assessed at multiple time points from 30 minutes to 6 hours for the following: pupil size, near corrected distance visual acuity (mesopic and photopic conditions), best corrected distance visual acuity (mesopic and photopic conditions), and best corrected intermediate visual acuity (photopic conditions), conjunctival hyperemia, adverse events, and ocular tolerability. Biomicroscopy, intraocular pressure measurements, and fundus examinations were performed 6 hours following administration of any 0.4% w / w pilocarpine hydrochloride ophthalmic solution during Visit 2. One to three days after Visit 2, subjects participated in a follow-up call to assess adverse events.

[0238] When making measurements, DCNVA reading / near vision was measured at 16 inches (approximately 40 cm) under photopic and mesopic conditions using a high-contrast near chart in a Precision Vision Small 914 Illuminator Cabinet (light box). BCDVA was measured at 4m under photopic conditions with a high-contrast Standard Early Treatment Diabetic Retinopathy Study (ETDRS) illumination chart (on a wall or on a stand). BCIVA was measured under photopic conditions at 26 inches (66 cm) with a high-contrast near chart in a Precision Vision Small 914 Illuminator Cabinet (light box). Pupil diameter (PD) was measured using a NeuroOptics pupillometer (mm). Conjunctival hyperemia was measured by CCLRU imaging using a 4-point scale (0–3). o None (0) = Normal. Few easily visible conjunctival blood vessels, which appear pale o Mild (+1) = Prominent pinkish-red color of both bulbar and palpebral conjunctiva Moderate (+2) = Light scarlet color of the bulbar and palpebral conjunctiva o Severe (+3) = Beefy red with petechiae, dark red bulbar and palpebral conjunctiva with evidence of subconjunctival hemorrhage.

[0239] Under photopic lighting conditions, the illumination chart for distance and near vision is approximately 85-160 cd / m 2 (85-160 nits). In mesopic conditions, the illumination chart for distance and near vision will have a luminance level of approximately 3 cd / m 2The lighting conditions will be at a luminance level of 100 Hz (3 nits). Ambient lighting for both photopic and mesopic vision will be at the luminance level of the light box only. Luminance reduction for mesopic conditions will be performed by a neutral density filter that reduces luminance. Subjects will be allowed to acclimate to these lighting conditions (keeping eyes open normally for a minimum of 2 minutes before the set of PD and visual acuity (VA) measurements). Subjects will be seated in an examination chair directly facing the lighting chart during the acclimatization period and for all assessments.

[0240] Room lights were turned on for the remaining scheduled safety assessments (e.g., conjunctival injection, AEs, subject questionnaires, etc.) Subjects had to be in the same room for all assessments, and every effort was made to have the same person perform measurements at all visits.

[0241] Visual acuity was measured as letters and converted to LogMAR and linear as necessary.

[0242] Inclusion criteria 1. Male or female aged ≥ 40 and ≤ 64 years.

[0243] 2. Able to independently comply with all protocol-mandated procedures and attend all scheduled clinic visits.

[0244] 3.Able and willing to give signed informed consent.

[0245] 4. Ability to self-administer study medication throughout the study period.

[0246] 5. Best corrected distance visual acuity (BCDVA) in each eye greater than or equal to 0.0 LogMAR (20 / 20 Snellen equivalent) under photopic conditions.

[0247] 6. Corrected-for-distance-near visual acuity (DCNVA) in each eye and in both eyes under photopic conditions of 0.4 LogMAR (20 / 50 Snellen equivalent) or less.

[0248] 7. Subjects who use reading glasses or bifocal glasses and have a best corrected near visual acuity of 0.1 LogMAR (20 / 25 Snellen equivalent) or better in both eyes.

[0249] Exclusion criteria Ophthalmologic conditions (in either eye): 1. Use of any topical prescription medications or OTC ophthalmic medications of any kind within 7 days of screening through study completion, with the exception of over-the-counter (OTC) eyelid scrubs (e.g., OCuSOFT® eyelid scrub, SteriLid®, baby shampoo, etc.).

[0250] 2. Use of any over-the-counter (OTC) artificial tears (preserved or unpreserved) at least once per day within 7 days of screening through study completion.

[0251] 3. Current use of any topical ophthalmic therapy for dry eye (e.g. Restasis, Xiidra, etc.).

[0252] 4. Tear film breakup time of <5 seconds or corneal fluorescein staining (≥ grade 2 in the lower zone or ≥ grade 1 in the central zone using the National Eye Institute scale).

[0253] 5. Clinically significant ocular disease that would interfere with the study as perceived by the investigator (e.g. cataract, glaucoma, corneal edema, uveitis, retinal degeneration, visual field loss, any macular pathology).

[0254] 6. Recent or current evidence of ocular infection or inflammation in either eye (such as current evidence of clinically significant blepharitis, conjunctivitis, keratitis, etc.). Subjects must be symptom-free for at least 7 days.

[0255] 7. History of herpes simplex or herpes zoster keratitis.

[0256] 8. History of diabetic retinopathy or diabetic macular edema.

[0257] 9. Known allergy, hypersensitivity, or contraindication to any component of the phentolamine, pilocarpine or vehicle formulation.

[0258] 10. History of punctal cauterization or punctal plug (silicone or collagen) insertion or removal.

[0259] 11. Ocular trauma, ocular surgery (e.g., intraocular lens), or ocular laser therapy within 6 months prior to screening. Subjects with multifocal intraocular lenses will be excluded.

[0260] 12. History of any traumatic (surgical or non-surgical) or non-traumatic condition affecting the pupil or iris (e.g., irregularly shaped pupil, neurogenic pupillary disorders, iris atrophy, iridotomy, iridectomy, iritis, etc.).

[0261] 13. Unwilling or unable to discontinue contact lens wear between screening and study completion.

[0262] 14. Conjunctival hyperemia ≥ grade 2 on the Cornea and Contact Lens Research Unit (CCLRU) 4-point scale.

[0263] systemic condition 15. Known hypersensitivity or contraindication to α-adrenergic receptor antagonists 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).

[0264] 16. Known hypersensitivity or contraindication to any systemic cholinergic parasympathomimetic agent.

[0265] 17. Clinically significant systemic disease that would interfere with the study as recognized by the investigator (e.g. uncontrolled diabetes mellitus, myasthenia gravis, cancer, hepatic, renal, endocrine, or cardiovascular disorders).

[0266] 18. Initiation of treatment with any systemic adrenergic or cholinergic medication, or change in current medication, medication, or regimen within the 7 days prior to screening or during the study.

[0267] 19. Participation in any clinical trial within 30 days prior to screening.

[0268] 20. Women of childbearing potential who are not pregnant, lactating, planning pregnancy, or using any medically acceptable form of birth control. Acceptable methods include use of at least one of the following: intrauterine device (IUD), hormonal (oral, injectable, patch, implant, ring), spermicidal barrier (condom, diaphragm), or abstinence. Women are considered of childbearing potential unless they are 1 year postmenopausal or 3 months poststerilization. All women of childbearing potential, including those with tubal ligation, must have a negative urine pregnancy test result at Visit 1 (Screening / Baseline).

[0269] 21. Resting HR outside the specified range of 50-110 beats / min after at least a 5-minute rest period in a seated position at Screening Visit 1. HR may be repeated only once after another 5-minute rest period in a seated position if outside the specified range.

[0270] 22. Hypertension with resting diastolic BP >105mmHg or systolic BP >160mmHg after at least a 5-minute rest period in a seated position at Screening Visit 1. BP may be repeated only once after another 5-minute rest period in a seated position if outside the specified ranges.

[0271] The test drugs used in the clinical trials are as shown in the table below. [Table 6]

[0272] Part II: Results Data for the observed reduction in pupil diameter is provided below in Table 2. Data for the observed improvement in best corrected distance visual acuity (BCDVA) is provided below in Table 3. Data for the observed intraocular pressure is provided below in Table 4. [Table 7] [Table 8] [Table 9]

[0273] Incorporation by Reference The entire disclosure of each of the patent documents and scientific articles referenced herein is incorporated by reference for all purposes.

[0274] Equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing embodiments are not intended to limit the invention described herein, but should be considered in all respects as illustrative. The scope of the present 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 comprising an α-adrenergic antagonist, said pharmaceutical composition comprising: (i) for use in treating mydriasis in a patient, wherein a dosage of said α-adrenergic antagonist and a dosage of a muscarinic acetylcholine receptor agonist are administered to the eye of said patient in amounts effective to treat said mydriasis; or (ii) A pharmaceutical composition for use in treating mydriasis in a patient suffering from glaucoma while reducing the risk of angle-closure glaucoma attacks, characterized in that a dosage of the alpha-adrenergic antagonist is administered to the eye of the patient in an amount effective to treat the mydriasis and reduce the risk of angle-closure glaucoma attacks.

2. 10. The pharmaceutical composition of claim 1, used to treat mydriasis in patients suffering from glaucoma while reducing the risk of angle-closure glaucoma attacks.

3. The pharmaceutical composition of claim 2 in combination with a muscarinic acetylcholine receptor agonist administered to the eye of the patient.

4. 2. The pharmaceutical composition of claim 1, wherein the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof.

5. 2. The pharmaceutical composition of claim 1, wherein the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

6. The pharmaceutical composition of any one of claims 1 or 3-5, wherein the dosage of the muscarinic acetylcholine receptor agonist is less than 0.25 mg.

7. 7. The pharmaceutical composition of claim 6, wherein the muscarinic acetylcholine receptor agonist is administered to the eye no more than once per day.

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein the patient suffers from glaucoma and has a narrow angle.

9. The pharmaceutical composition according to any one of claims 1 to 5, wherein the mydriasis is pharmacologically induced mydriasis.

10. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the mydriasis results from the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, flubiprofen, suprofen, hydroxyamphetamine, phenylephrine, ketorolac, or pharma- ceutically acceptable salts thereof.

11. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the mydriasis results from the patient receiving one or more of atropine, cyclopentolate, homatropine, scopolamine, tropicamide, or pharma- ceutically acceptable salts thereof.

12. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the mydriasis results from the patient receiving one or more of tropicamide, phenylephrine, or pharma- ceutically acceptable salts thereof.

13. 1. A pharmaceutical composition for use in combination with a muscarinic acetylcholine receptor agonist, comprising an α-adrenergic antagonist, said pharmaceutical composition comprising: (i) for use in improving visual performance under dim light conditions in a patient, characterized in that a dosage of said α-adrenergic antagonist and a dosage of said muscarinic acetylcholine receptor agonist are administered to the eye of said patient in amounts effective to improve visual performance under dim light conditions. (ii) for use in reducing pupil diameter under dim light conditions in a patient, wherein a dosage of the α-adrenergic antagonist and a dosage of the muscarinic acetylcholine receptor agonist are administered to the eye of the patient in amounts effective to reduce pupil diameter under dim light conditions; or (iii) A pharmaceutical composition for use in reducing abnormal focusing of scattered light in the eye of a patient under dim light conditions, characterized in that a dosage of said alpha adrenergic antagonist and a dosage of said muscarinic acetylcholine receptor agonist are administered to the eye of the patient in amounts effective to reduce abnormal focusing of scattered light in the eye of the patient under dim light conditions.

14. 14. The pharmaceutical composition of claim 13, wherein the combination reduces abnormal focusing of scattered light in the patient's eye under dim light conditions for at least 3 hours.

15. 14. The pharmaceutical composition of claim 13, wherein the muscarinic acetylcholine receptor agonist is pilocarpine or a pharma- ceutically acceptable salt thereof.

16. 14. The pharmaceutical composition of claim 13, wherein the muscarinic acetylcholine receptor agonist is pilocarpine hydrochloride.

17. The pharmaceutical composition of any one of claims 13 to 16, wherein the dosage of the muscarinic acetylcholine receptor agonist is less than about 0.25 mg.

18. The pharmaceutical composition of any one of claims 13 to 16, wherein said combination achieves a pupil diameter in the range of about 2.5 mm to about 5.5 mm under dim light conditions.

19. (i) the combination achieves a pupil diameter in the range of about 3 mm to about 5 mm under dim light conditions; (ii) the combination achieves a pupil diameter in the range of about 3 mm to about 4.5 mm under dim light conditions; (iii) the α-adrenergic antagonist is administered to the eye no more than once per day; (iv) the patient experiences a reduction in pupil diameter of at least 1 mm when measured under photopic conditions with the combination; (v) the patient experiences a reduction in pupil diameter of at least 2 mm when measured under photopic conditions with the combination; (vi) the patient experiences a reduction in pupil diameter of at least 3 mm when measured under photopic conditions with the combination. (vii) the patient experiences a reduction in pupil diameter ranging from about 0.5 mm to about 5 mm when measured under photopic conditions with the combination. (viii) the patient experiences a reduction in pupil diameter of at least 1 mm when measured under mesopic conditions with the combination. (ix) the patient experiences a reduction in pupil diameter of at least 2 mm when measured under mesopic conditions with the combination; (x) the patient experiences a reduction in pupil diameter of at least 3 mm when measured under mesopic conditions with the combination; or (xi) the pharmaceutical composition of any one of claims 13 to 16, wherein the patient experiences a reduction in pupil diameter ranging from about 0.5 mm to about 5 mm when measured under mesopic conditions due to the combination.

20. 1. A pharmaceutical composition comprising an α-adrenergic antagonist selected from phentolamine or a pharma- ceutical acceptable salt thereof, said pharmaceutical composition comprising: (i) for use in treating acute angle-closure glaucoma in a patient, wherein a dosage of the α-adrenergic antagonist is administered to an eye of the patient in an amount effective to treat the acute angle-closure glaucoma, and optionally the patient presents with at least two symptoms selected from the group consisting of severe eye pain, bloodshot eyes, reduced visual acuity, and blurred vision; (ii) for use in preventing angle-closure glaucoma in a patient, wherein a dosage of the α-adrenergic antagonist is administered to the eye of the patient in an amount effective to prevent the angle-closure glaucoma; or (iii) A pharmaceutical composition for use in treating or preventing narrow-angle attacks in a patient, characterized in that a dosage of the alpha-adrenergic antagonist is administered to the eye of the patient in an amount effective to treat or prevent the narrow-angle attack.

21. 21. The pharmaceutical composition according to claim 20, for use in preventing angle-closure glaucoma in a patient, wherein the alpha-adrenergic antagonist is selected from phentolamine or a pharma- ceutically acceptable salt thereof.

22. 21. The pharmaceutical composition of claim 20 for use in treating or preventing narrow angle stroke in a patient.

23. The pharmaceutical composition of any one of claims 1 to 5, 13 to 16, and 20 to 22, wherein the α-adrenergic antagonist is phentolamine or a pharma- ceutically acceptable salt thereof.

24. The pharmaceutical composition of any one of claims 1 to 5, 13 to 16, and 20 to 22, wherein the α-adrenergic antagonist is phentolamine mesylate.

25. 23. The pharmaceutical composition of any one of claims 1-5, 13-16, and 20-22, further characterized in that the α-adrenergic antagonist is in the form of an ophthalmic solution containing an aqueous pharma- ceutical acceptable carrier and phentolamine or a pharma- ceutical acceptable salt thereof.

26. 23. The pharmaceutical composition of any one of claims 1-5, 13-16, and 20-22, wherein the dosage of the alpha adrenergic antagonist comprises from about 0.5 mg to about 1.0 mg of phentolamine or a pharma- ceutically acceptable salt thereof.

27. 23. The pharmaceutical composition of any one of claims 1-5, 13-16, and 20-22, wherein the dosage of the alpha adrenergic antagonist comprises from about 0.1 mg to about 2.0 mg of phentolamine mesylate.

28. 23. The pharmaceutical composition of any one of claims 1-5, 13-16, and 20-22, wherein the dosage of the alpha adrenergic antagonist comprises from about 0.3 mg to about 0.7 mg of phentolamine mesylate.

29. 23. The pharmaceutical composition of any one of claims 1-5, 13-16, and 20-22, wherein the patient's eye has an intraocular pressure of greater than about 25 mmHg before the pharmaceutical composition is administered.

Images