Compositions and methods for treatment of presbyopia

Abstract

To provide compositions and methods for the treatment of presbyopia.SOLUTION: The compositions comprise aceclidine separately or together with a cycloplegic agent and / or with a nonionic surfactant and viscosity enhancer and / or together with low concentrations of a selective α-2 adrenergic receptor agonist.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to compositions and methods for treating presbyopia. [Background technology]

[0002] As people age, the minimum distance from the eye at which an object can be clearly seen increases if their distance vision is corrected or if their distance vision is excellent without the eye. For example, a 10-year-old person, while retaining excellent distance vision, can focus an object only 3 inches (0.072 meters) from his eye, a 40-year-old at 6 inches (0.15 meters), and a 60-year-old at an inconvenient 39 inches (1.0 meters). This long minimum focal distance condition in individuals with excellent distance vision without the eye is called presbyopia, loosely described as "farsightedness."

[0003] Excellent unaided distance vision is also known as emmetropia. The inability to focus on distant foci is known as myopia, and the inability to focus on close foci is known as hyperopia. Specifically, "distance" vision is considered a focus at or beyond one meter from the eye, while near vision is a focus less than one meter from the eye. The closest focal distance at which an object can be clearly seen is known as the "near point." The change in focus from distant to near and between is called accommodation. Accommodation is often measured in diopters. Diopters are calculated by taking the reciprocal of the focal length (in meters). For example, the decrease in accommodation from a 10-year-old eye to a 60-year-old eye is approximately 13 diopters (1 ÷ 0.072 meters = 13.89 diopters; 1 ÷ 1 meter = 1 diopter).

[0004] The highest frequency of first complaints of presbyopia occurs in people aged 42 to 44. Presbyopia results from a decline in the eye's ability to accommodate as people age—using near-distance reflexes—pupillary constriction, ocular convergence, and, especially, ciliary muscle contraction. This decline in accommodation results in insufficient change in normal thickening and the significant curvature of the anterior surface of the lens needed to shift focus from distant to near objects. Important short-focus tasks affected by presbyopia include viewing a computer screen (21 inches) and reading print (16 inches).

[0005] Presbyopia is a normal, inevitable effect of aging and is the first obvious sign for many people in their 40s. One study found that more than 1 billion people worldwide were presbyopic in 2005. This same study predicted that this number would nearly double by 2050. If everyone over the age of 45 were considered presbyopic, an estimated 122 million people in the United States alone had presbyopia in 2010. This number is likely to increase as baby boomers reach menopause.

[0006] Presbyopia is characterized by a limited ability to perform many tasks quickly, often requiring focusing on both far and near points, which was previously possible almost immediately. In presbyopic patients, these tasks can only be performed with the use of glasses, contact lenses, or after invasive surgery. One optical modification, monovision, can be performed with glasses, contact lenses, or surgery. Monovision corrects one eye for short focus and the other eye for long focus. However, monovision correction is usually accompanied by a loss of depth perception and distance vision, especially in dim light (e.g., at night). Other surgical procedures developed to alleviate presbyopia include (1) insertion of an intraocular lens (Intracor®; a registered trademark of Technolas Perfect Vision GmbH); (2) corneal reshaping (PresbyLASIK and conduction keratoplasty); (3) scleral band expansion; and (4) insertion of a corneal inlay (Flexiview Microlens®; a registered trademark of PresbyBio LLC; Kamra®; a registered trademark of AcuFocus, Inc. and Vue+). The AcuFocus Kamra® corneal inlay works by placing a pinhole on the cornea to increase depth of focus. A similar effect can be achieved with common miotics, such as pilocarpine (a nonselective muscarinic acetylcholine receptor agonist), carbachol (a nonselective muscarinic acetylcholine receptor agonist), and phospholine iodide (an acetylcholinesterase inhibitor). These common miotics trigger increased ciliary muscle contraction, adjusting for residual reserve and improving near vision at the expense of distance vision in individuals who still retain some accommodative function. While these common miotics can improve depth of focus to the extent that accommodation occurs due to the pinhole effect caused by miosis (i.e., constriction), the pinhole effect only partially offsets the induced accommodative myopia for distance vision. In some cases, such as with pilocarpine or carbachol, induced accommodation can produce up to 5 diopters or more of induced myopia, resulting in blurred distance vision during focus shifts from normal and far to near points.These common miotics also cause significant redness, severe nasal congestion, and ciliary muscle spasm, which generally induces severe and long-lasting discomfort. In extreme cases, ciliary muscle spasm can lead to retinal detachment.

[0007] Miotics have been described in various patents and patent applications for treating presbyopia. U.S. Patent Nos. 6,291,466 and 6,410,544 describe the use of pilocarpine to regulate the contraction of the ciliary muscle to return the eye to its resting state and potentially restore its ability to accommodate.

[0008] US Patent Application Publication No. 2010 / 0016395 describes the combination of pilocarpine with the nonsteroidal anti-inflammatory drug diclofenac to relieve eyelid pain resulting from ciliary muscle spasm and extend the time it takes for ciliary muscle contraction to be regulated. PCT Application Publication No. WO / 2013 / 041967 describes the combination of pilocarpine with oxymetazoline or meloxicam to temporarily relieve eye conditions such as presbyopia.

[0009] U.S. Patent No. 8,299,079 (HEK Development LLC) describes the use of direct-acting common miotics, such as pilocarpine, carbachol, and phospholipid iodide, in combination with brimonidine at concentrations of 0.05% to 3.0% w / v. However, the use of brimonidine at concentrations above 0.05% w / v increases rebound hyperemia. For example, the use of 0.20% w / v brimonidine (Alphagan®; a registered trademark of Allergan, Inc.) twice daily causes rebound hyperemia in 25% of patients.

[0010] All of these attempts at miotic treatment for presbyopia either induce transient myopia of several diopters that reduces distance vision to near legal blindness, or worsen its maximum duration of action, which typically lasts several hours, at the expense of improved near vision.

[0011] Thus, there is a need in the art for a non-invasive, convenient treatment for presbyopia with minimal side effects. Specifically, there is a need for an ophthalmic composition that enables a presbyopic patient to focus on near objects without experiencing significant side effects such as reduced distance vision, blurred vision, pain, redness, impaired night driving or inability to see in the dark, induced nasal congestion, or risk of retinal detachment. Furthermore, the treatment should provide a rapid onset of action within minutes and a maximum duration of action of several hours to achieve miosis of about 1.65 to 2.40 mm, more preferably 1.80 mm to about 2.2 mm. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] U.S. Patent No. 6,291,466 [Patent Document 2] U.S. Patent No. 6,410,544 [Patent Document 3] US Patent Application Publication No. 2010 / 0016395 [Patent Document 4] International Publication No. 2013 / 041967 [Patent Document 5] U.S. Patent No. 8,299,079 Summary of the Invention

[0013] In certain embodiments, the present invention relates to compositions and methods for treating presbyopia.

[0014] In certain embodiments, the present invention relates to compositions and methods for treating presbyopia comprising a muscarinic agonist that preferentially activates M1 and M3 muscarinic acetylcholine receptors. In even more preferred embodiments, the muscarinic agonist is more selective for M1 over M3. In most preferred embodiments, the muscarinic agonist activates only M1.

[0015] In certain embodiments, the present invention provides a method for treating a cancer cell comprising: Formula I:

[0016] [ka] Or, Formula II:

[0017] [ka] (In the above formula, R1 is H, O, CH3, alkyl, acetyl, acyl, aziridine, nitrile, imine, nitrile-imine methyl substitution, nitrile-imine methyl substitution with attached ester, aromatic ring, substituted aromatic ring, azide, acetamide, pyridine, substituted pyridine, pyrrolidine, substituted pyrrolidine, imidazole, substituted imidazole, imidazole having one or more carbon atoms substituted with O or S, substituted imidazole having one or more carbon atoms substituted with O or S, benzimidazole, substituted benzimidazole, benzimidazole having one or more carbon atoms substituted with O or S, or substituted benzimidazole having one or more carbon atoms substituted with O or S; R2 is H, O, CH3, alkyl, acetyl, acyl, nitrile, imine, nitrile-imine methyl substituted, or ester-O-alkyl; R3 is H, CH3, acyl, acetyl, or ester; R4 is acyl, acetyl, ester, CH3, alkyl, aromatic ring, substituted aromatic ring, cyclohexane, or substituted cyclohexane ring; Each of R1 and R2 independently replaces H of -CH2- on the quinuclidine ring. The present invention relates to compositions and methods for treating presbyopia comprising a muscarinic agonist of the formula:

[0018] In certain embodiments, the present invention relates to compositions and methods for treating presbyopia comprising muscarinic agonists that preferentially activate M1 and M3 muscarinic acetylcholine receptors.

[0019] In certain embodiments, the present invention relates to compositions and methods for treating presbyopia comprising a muscarinic agonist selected from the group consisting of aceclidine, talsaclidine, sabcomeline, cevimeline, WAY-132983, AFB267B (NGX267), AC-42, AC-260584, 77-LH-28-1, and LY593039, or pharmaceutically acceptable salts, esters, analogs, prodrugs, or derivatives thereof.

[0020] In certain embodiments, the present invention relates to compositions and methods for treating presbyopia comprising muscarinic agonists that activate only the M1 muscarinic acetylcholine receptor.

[0021] In certain other embodiments, the present invention relates to an ophthalmic composition for treating presbyopia comprising aceclidine.

[0022] In certain other embodiments, the present invention relates to an ophthalmic composition for treating presbyopia comprising aceclidine and a cycloplegic agent.

[0023] In certain other embodiments, the present invention relates to an ophthalmic composition for treating presbyopia comprising aceclidine and a selective alpha-2 adrenergic receptor agonist.

[0024] In certain other embodiments, the present invention relates to an ophthalmic composition for treating presbyopia comprising aceclidine, a cycloplegic agent, and a selective alpha-2 adrenergic receptor agonist.

[0025] In certain other embodiments, the present invention relates to an ophthalmic composition for treating presbyopia comprising a general miotic and a cycloplegic.

[0026] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; optionally a selective alpha-2 adrenergic receptor agonist; viscosity enhancers; and a surfactant selected from the group consisting of anionic surfactants, nonionic surfactants, and combinations thereof; The present invention relates to an ophthalmic composition comprising:

[0027] In certain other embodiments, the viscosity enhancing agent is carboxymethylcellulose; The anionic surfactant is selected from the group consisting of gamma-cyclodextrin, Captisol® (Captisol is a registered trademark of Cydex Pharmaceuticals), sodium lauryl sulfate, and sodium ester lauryl sulfate; the nonionic surfactant is selected from the group consisting of poloxamer, polysorbate, Span® 20-80 (Span is a registered trademark of Uniqema Americas Inc.), polyoxyl alkyl, cyclodextrin, and derivatives thereof.

[0028] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; Optionally, a selective alpha-2 adrenergic receptor agonist; and a surfactant selected from the group consisting of Captisol®, polyoxyl 40 stearate, and 2-hydroxypropyl β-cyclodextrin; The present invention relates to an ophthalmic composition comprising:

[0029] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; optionally a selective alpha-2 adrenergic receptor agonist; a surfactant selected from the group consisting of Captisol®, polyoxyl 40 stearate, and 2-hydroxypropyl β-cyclodextrin; and one or more additional nonionic surfactant surfactants; The present invention relates to an ophthalmic composition comprising:

[0030] In certain other embodiments, the one or more additional nonionic surfactants are selected from the group consisting of poloxamer 188, polyoxyl 40 stearate, polyoxyl 35 castor oil, polysorbate, Span® 20-80, tyloxapol, and combinations thereof.

[0031] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; and optionally a selective alpha-2 adrenergic receptor agonist; Including, The present invention relates to an ophthalmic composition of the present invention, wherein the selective alpha-2 adrenergic receptor agonist is selected from the group consisting of brimonidine, dexmedetomidine, fadolmidine and guanfacine.

[0032] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; and optionally a selective alpha-2 adrenergic receptor agonist; Including, The present invention relates to an ophthalmic composition, wherein the cycloplegic agent is selected from the group consisting of pirenzepine, tropicamide, Cyclodil® (Cyclodyl is a registered trademark of Alcon Research, Ltd.), 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), xanomeline, otenzepad, and combinations thereof. In a preferred embodiment, the cycloplegic agent is tropicamide.

[0033] In a preferred embodiment, the compositions of the present invention have a pH of about 5.5 or greater, preferably 6.0 or greater, more preferably 6.5 or greater, and most preferably 7.0 or greater.

[0034] In certain other embodiments, the present invention provides a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; Optionally, a selective alpha-2 adrenergic receptor agonist; and in situ gel; The present invention relates to an ophthalmic composition comprising:

[0035] In a preferred embodiment, the in situ gel is selected from the group consisting of Carbopol® (Carbopol is a registered trademark of Lubrizol Advanced Materials, Inc.), alginate, pectin, xanthan gum, and guar gum at a concentration of about 0.0001% to about 0.4% w / v.

[0036] In a preferred embodiment, the present invention provides aceclidine at a concentration of about 0.25% to about 2.0% w / v; tropicamide at a concentration of about 0.025% to about 0.1% w / v; Carboxymethylcellulose at a concentration of about 0.1% to about 1.2% w / v; and sodium chloride at a concentration of about 0.01% to about 1.0% w / v; The present invention relates to an ophthalmic composition for treating presbyopia, comprising:

[0037] In a preferred embodiment, the present invention provides aceclidine at a concentration of about 0.25% to about 2.0% w / v; tropicamide at a concentration of about 0.025% to about 0.1% w / v; carboxymethylcellulose at a concentration of about 0.1% to about 1.2% w / v; Sodium chloride at a concentration of about 0.01% to about 1.0% w / v; and benzalkonium chloride at a concentration of about 0.007% to about 0.01% w / v; The present invention relates to an ophthalmic composition for treating presbyopia, comprising:

[0038] In a preferred embodiment, the present invention provides aceclidine at a concentration of about 0.25% to about 2.0% w / v; tropicamide at a concentration of about 0.025% to about 0.1% w / v; carboxymethylcellulose at a concentration of about 0.1% to about 1.2% w / v; Sodium chloride at a concentration of about 0.01% to about 1.0% w / v; and a surfactant at a concentration of about 1% to about 15% w / v; The present invention relates to an ophthalmic composition for treating presbyopia, comprising:

[0039] In a preferred embodiment, the present invention provides aceclidine at a concentration of about 0.25% to about 2.0% w / v; tropicamide at a concentration of about 0.025% to about 0.1% w / v; carboxymethylcellulose at a concentration of about 0.1% to about 1.2% w / v; Sodium chloride at a concentration of about 0.01% to about 1.0% w / v; and Captisol® at a concentration of about 5.0% to about 6.0% w / v; The present invention relates to an ophthalmic composition for treating presbyopia, comprising:

[0040] In a preferred embodiment, the present invention provides aceclidine at a concentration of about 0.25% to about 2.0% w / v; tropicamide at a concentration of about 0.025% to about 0.1% w / v; carboxymethylcellulose at a concentration of about 0.1% to about 1.2% w / v; Sodium chloride at a concentration of about 0.01% to about 1.0% w / v; and Polyoxyl 40 stearate at a concentration of about 5.0% to about 6.0% w / v; The present invention relates to an ophthalmic composition for treating presbyopia, comprising:

[0041] The present invention further relates to a method for treating presbyopia comprising administering to a patient in need thereof a composition of the present invention.

[0042] The present invention further relates to a method for treating presbyopia comprising administering to a patient in need thereof a composition comprising aceclidine and optionally an alpha-2 adrenergic agonist and / or a cycloplegic, wherein the treatments may be combined in a single formulation or multiple formulations, or by simultaneous or sequential administration of an alpha-2 adrenergic agonist and / or by simultaneous or sequential administration of a cycloplegic, with simultaneous or sequential administration of both being preferred.

[0043] The present invention further relates to a method for increasing depth of field (ie, depth of focus) comprising administering to a subject in need thereof a pharmaceutically effective amount of an ophthalmic composition of the present invention.

[0044] The present invention further relates to a method for enhancing depth vision while improving unaided near vision comprising administering a pharmaceutically effective amount of the ophthalmic composition of the present invention to both eyes (binocular vision) of a subject in need thereof, wherein the binocular vision further enhances near vision beyond that of one eye separately.

[0045] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention.

[0046] The present invention further relates to a method for inducing miosis, the miosis being from about 1.40 to about 2.0 mm, comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention.

[0047] The present invention further relates to a method for inducing miosis, comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is from about 1.50 to about 1.70 mm.

[0048] The present invention further relates to a method for inducing miosis, the miosis being from about 1.80 to about 2.0 mm, comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention.

[0049] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is from about 1.50 to about 1.70 mm and the duration of miotic action is at least about 4 hours.

[0050] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is from about 1.50 to about 1.70 mm and the duration of miotic action is at least about 6 hours.

[0051] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is about 1.50 to about 1.70 mm and the duration of miotic action is at least about 7.5 hours.

[0052] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is from about 1.50 to about 1.70 mm and the duration of miotic action is at least about 9 hours.

[0053] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is from about 1.50 to about 2.50 mm and the duration of miotic action is at least about 9 hours.

[0054] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is from about 1.80 to about 2.00 mm and the duration of miotic effect is at least about 4 hours.

[0055] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is from about 1.80 to about 2.00 mm and the duration of miotic action is at least about 6 hours.

[0056] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is from about 1.80 to about 2.00 mm and the duration of miotic action is at least about 7.5 hours.

[0057] The present invention further relates to a method for inducing miosis comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein the miosis is from about 1.80 to about 2.00 mm and the duration of miotic action is at least about 9 hours.

[0058] The present invention further relates to a method for inducing miosis of about 1.35 to 2.0 mm with no accommodation or minimum accommodation of about 0.50 diopters or less such that depth of focus enhancement is achieved without significant loss of distance vision or other degradation in the quality of distance vision.

[0059] The present invention further relates to a method for inducing miosis of about 1.50 to 2.4 mm with clinically negligible accommodation such that depth of focus enhancement is achieved without significant loss of distance vision or other degradation in the quality of distance vision, and the peak minimum pupil diameter, typically about 30 to 60 minutes after instillation, can be adjusted with the addition of a cycloplegic agent without inducing irregular astigmatism, pupil dilation (i.e., dilation of the radial muscle of the iris), or substantial loss of duration of action.

[0060] The present invention further relates to a method for improving vision in a subject with refractive error (visual aberrations) comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition of the present invention.

[0061] The present invention further relates to a method for improving vision in a subject with refractive error, the refractive error being selected from the group consisting of myopia, hyperopia, regular astigmatism, irregular astigmatism, and high regular astigmatism, comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition of the present invention.

[0062] The present invention further relates to eliminating optical aberrations resulting from corneal irregularities, opacities, or significant regular astigmatism, including areas adjacent to or surrounding the central 1.5 mm optical zone, thereby inducing improvements in visual acuity and vision quality by filtering out these abnormal visual acuities in individuals suffering from irregular or significant regular astigmatism, such as occurs in conditions such as keratoconus, corneal opacities due to photokeratectomy, diffuse lamellar keratitis ("DLK") (post-LASIK DLK), cataract incisions, glaucoma filtering blebs, implanted glaucoma valves, corneal inlays with or without removal, post-corneal surgery (LASIK), and other iatrogenic corneal-induced irregularities such as secondary infectious corneal ectasia.

[0063] The present invention further relates to improving vision for existing uncorrected refractive errors. With this improved vision, patients who currently require less comfortable toric contact lenses and eyeglasses that may slip off with each blink due to astigmatism may often need only non-toric soft contact lenses, or even no contact lenses at all. Furthermore, patients who require air permeable contact lenses no longer need contact lenses, but only much more comfortable soft contact lenses. Patients who currently have high levels of astigmatism may need little or no astigmatic correction. Patients with mild or moderate myopia (farsightedness) may need little or no correction. Patients with mild or moderate hyperopia (long-sightedness) may need little or no correction.

[0064] The present invention relates to methods and ophthalmic compositions for improving vision. In a preferred embodiment, the present invention relates to methods and ophthalmic compositions for treating presbyopia. In a more preferred embodiment, the present invention relates to ophthalmic compositions comprising aceclidine. In an even more preferred embodiment, the present invention relates to ophthalmic compositions comprising aceclidine and a low dose of a cycloplegic drug. In a most preferred embodiment, the present invention relates to ophthalmic compositions comprising aceclidine, a low dose of a cycloplegic drug, and a combination of inactive ingredients that make aceclidine effective and / or enhance its effectiveness. [Brief explanation of the drawings]

[0065] [Figure 1] 1 is a graphic representation of the effect of pilocarpine and aceclidine with or without tropicamide, with or without a carrier, on near and distance visual acuity in patients 45 years of age and older. DETAILED DESCRIPTION OF THE INVENTION

[0066] The present invention relates to compositions and methods for treating presbyopia, irregular astigmatism, and / or refractive error comprising administering to a patient in need thereof a pharmaceutical composition comprising a muscarinic agonist that preferentially activates M1 and M3 muscarinic acetylcholine receptors, preferably activating M1 over M3, most preferably aceclidine or a derivative thereof. Surprisingly and unexpectedly, it has been found that aceclidine provides high daytime or nighttime presbyopic reversal (when looking at one or more direct or reflected light sources) with negligible side effects when used with the compositions of the present invention.

[0067] The compositions and methods of the present invention treat presbyopia by improving depth of focus in presbyopic patients by administering to the eye an ophthalmic composition that reduces pupil dilation in dark or dim light, produces a specific degree and duration of miosis without accommodation, imparts apparent whiteness, and / or induces anti-reduction. The compositions and methods of the present invention do not cause significant pupil rebound, tachyphylaxis, ciliary muscle spasm, induce myopia, or reduce distance visual acuity. Additionally, the compositions and methods of the present invention further improve visual acuity and depth perception in binocular (both eye) treatments. The ophthalmic compositions of the present invention surprisingly produce pupils of about 1.5 to about 2.4 mm at the anterior iris plane and about 2.0 mm at the corneal plane, with only a negligible increase in accommodative tone and reduced or eliminated the redness otherwise characteristic of miotic drug use. This miosis, with significantly reduced or nonexistent accommodative tone, is superior to the pinhole effect of Kamura® and Flexiview Microlens® corneal inlays. Miosis is superior because actual pupil constriction does not result in the concomitant severe night vision impairment caused by the light-scattering border of the anterior corneal pinhole created by the inlay. Furthermore, miosis provides a larger field of view and more focused light transmission. The use of aceclidine has minimal effect on the vertical ciliary muscle, thereby reducing the risk of retinal detachment compared to the use of common muscarinic agonists, such as pilocarpine and carbachol. The addition of a cycloplegic agent results in only a 0.04 mm anterior chamber shallowing. Aceclidine, particularly enhanced in the present invention, also has greater magnitude, duration, and control of minimum pupil diameter. The compositions of the present invention achieve these effects while having negligible effects on accommodation, avoiding the blurred distance vision typically seen in patients in response to pilocarpine- and / or carbachol-induced miosis. The effect on accommodation can be further reduced or completely eliminated in preferred embodiments using a cycloplegic agent. Aceclidine can produce the enhanced depth of focus due to miosis described herein without the need for a selective alpha-2 adrenergic receptor agonist ("alpha-2 agonist"). Use of the compositions of the present invention results in particularly high miosis, thereby allowing the use of lower concentrations of alpha-2 agonists to reduce ocular redness.Furthermore, due to the obvious and surprising selectivity of aceclidine, its administration to the eye almost exclusively affects miosis rather than ciliary muscle contraction.Therefore, administration of aceclidine causes miosis without accommodation and the accompanying blurred vision at distance.However, aceclidine may cause some redness and eyelid pain, and without strengthening the formulation of the present invention, it may cause less than optimal miosis, or at very high concentrations, may cause more than the desired peak miosis accompanied by blurred vision in dim light or in the absence of light.

[0068] Certain embodiments of the present invention enhance the desired degree of miosis by using preferred embodiments of nonionic surfactants and viscosity enhancers to achieve a consistent effect in the range of about 1.50 to 2.20 mm for most patients. Similar benefits can be achieved using other penetration enhancers, particularly Carbopol®, and various viscosity additives that extend drug residence time, such as xanthan gum, guar gum, alginate, and other in situ gels known to those skilled in the art. The present invention further prevents nasal congestion that occurs when high levels of aceclidine reach the nasal mucosa due to the rheological properties of preferred embodiments.

[0069] Combining aceclidine with low concentrations of selective alpha-2 adrenergic receptor agonists (alpha-2 agonists or alpha-2 adrenergic agonists), such as fadolmidine, brimonidine, or guanfacine, produces the desired miotic effect with little or no redness. The use of low concentrations of selective alpha-2 agonists significantly reduces redness, significantly reducing the risk of rebound redness seen at concentrations of approximately 0.06% w / v or higher. Furthermore, the use of low concentrations of selective alpha-2 agonists does not exacerbate the pupil constriction caused by aceclidine. In contrast, the use of 0.20% w / v brimonidine when applied topically to accommodate pupils for night vision results in tachyphylaxis of pupil accommodation due to alpha-2 receptor upregulation in nearly 100% of treated subjects within 4 weeks of use.

[0070] Unexpectedly, the addition of a cycloplegic agent further reduces the degree of ciliary muscle spasm upon instillation without impairing the miotic response, thereby reducing eyelid pain or associated discomfort. Because certain cycloplegic agents, such as tropicamide, have known pupillary dilation effects at concentrations as low as 0.01% w / v (Grunberger J. et al., The pupillary response test as aa method to differentiate various types of dementia, Neuropsychiatr, 2009, 23(1), p. 57), the absence of impairing the miotic response is an unexpected and surprising finding. More specifically, cycloplegic agents cause mydriasis (i.e., dilation of the radial muscles of the iris). Furthermore, the addition of a cycloplegic agent to a miotic agent unexpectedly prolongs the time during which the pupil remains within the desired size range without excessive constriction. The peak miosis at 30 to 60 minutes can be titrated inversely with the cycloplegic drug concentration. The tropicamide concentrations found in this invention apparently relax the ciliary muscles more than the radial musculature of the iris. Indeed, iris mydriasis was suppressed by adding tropicamide to compositions containing aceclidine at the concentrations used in this invention; instead, miosis was found to be at a more constant level during the miosis. Additionally, and quite surprisingly and unexpectedly, the addition of tropicamide advantageously reduces the degree of peak miosis without inducing mydriasis, thereby resulting in a more constant and ideal pupil diameter throughout drug-induced miosis. This more constant pupil diameter provides beneficial near and distance vision without blurring or loss of resolution due to diffraction limitations at very small pupil diameters (e.g., 1.25 mm) seen at peak miosis.

[0071] Common miotic drugs, such as pilocarpine, carbachol, and phosphodiesterase, can cause miosis, thereby improving near vision in presbyopic patients. However, there is a reversal decrease in distance vision associated with these common miotic drugs due to miosis and accommodation at peak effect, which is not seen with aceclidine. Co-administration of cycloplegics with aceclidine surprisingly attenuates this decrease in distance vision.

[0072] The comfort, safety, and effectiveness of preferred embodiments of the ophthalmic compositions of the present invention result from the presence of a nonionic surfactant, such as a cyclodextrin α, β, or γ chain, preferably 2-hydroxypropyl β-cyclodextrin ("HPβCD") and / or a sulfobutyl ether derivative of β-cyclodextrin (Captisol®), polyoxyl 40 stearate, or poloxamer 407; a viscosity enhancing agent, such as carboxymethylcellulose ("CMC"); a tonicity agent, such as sodium chloride; a preservative, such as benzalkonium chloride; and a pH of about 5.0 to about 8.0. Furthermore, increasing the concentration of viscosity agents and electrolytes can reduce redness. Specifically, increasing the CMC from 0.50% to 0.75% w / v (preferably 0.80% w / v) and the sodium chloride from 0.25% to 0.50% w / v reduces redness.

[0073] definition As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[0074] All numerical values ​​relating to amounts, weights, etc. used herein are defined as "about," and each specific value is ±10%. For example, the phrase "about 5% w / v" should be understood as "4.5% to 5.5% w / v." Thus, amounts within 10% of the claimed value are encompassed within the scope of the claim.

[0075] As used herein, "% w / v" refers to the weight percent of the total composition.

[0076] As used herein, the term "subject" refers to, but is not limited to, a human or other animal.

[0077] The term "muscarinic receptor agonist" ("muscarinic agonist") encompasses agonists that activate muscarinic acetylcholine receptors ("muscarinic receptors"). Muscarinic receptors are classified into five subtypes, designated M1 to M5. Muscarinic agonists of the present invention include muscarinic agonists that preferentially activate M1 and M3 receptors over M2, M4, and M5 receptors ("M1 / M3 agonists"). M1 / M3 agonists include aceclidine, xanomeline, talsaclidine, sabcomeline, cevimeline, albameline, arecoline, miramelin, SDZ-210-086, YM-796, RS-86, CDD-0102A (5-[3-ethyl-1,2,4-oxadiazol-5-yl]-1,4,5,6-tetrahydropyrimidine hydrochloride), N-aryl urea-substituted 3-morpholine arecoline, VUO255-035 (N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide ), benzylquinolone carboxylic acid (BQCA), WAY-132983, AFB267B (NGX267), AC-42, AC-260584, chloropyrazines including but not limited to L-687, 306, L-689-660, 77-LH-28-1, LY593039, and quiniclidine rings with one or more carbon substitutions, including esters, sulfur, or five- or six-carbon ring structures, including those with substituted nitrogen and / or oxygen, or pharmaceutically acceptable salts, esters, analogs, prodrugs, or derivatives thereof. A preferred M1 / M3 agonist is aceclidine. In preferred embodiments, the muscarinic agonists of the present invention include muscarinic agonists that preferentially activate M1 and M3 over M2, M4, and M5, and even more preferably muscarinic agonists that preferentially activate M1 over M3. In a more preferred embodiment, the muscarinic agonists of the present invention include muscarinic agonists that activate only M1.

[0078] The term "aceclidine" encompasses its salts, esters, analogs, prodrugs, and derivatives, including, but not limited to, aceclidine as a racemic mixture, the aceclidine (+) enantiomer, the aceclidine (-) enantiomer, aceclidine analogs including, but not limited to, highly M1 selective 1,2,5-thiadiazole substituted analogs such as those disclosed in Ward, J.S. et al., 1,2,5-Thiadiazole analogues of aceclidine as potent m1 muscarinic agonists, J. Med. Chem., 1998, Jan. 29, 41(3), 379-392, and aceclidine prodrugs including, but not limited to, carbamate esters.

[0079] The term "selective alpha-2 adrenergic receptor agonist" or "alpha-2 agonist" includes all alpha-2 adrenergic receptor agonists that have a 900-fold or greater binding affinity for alpha-2 adrenergic receptors over alpha-1 adrenergic receptors, or a 300-fold or greater binding affinity for alpha-2a or alpha-2b adrenergic receptors over alpha-1 adrenergic receptors. This term also includes pharmaceutically acceptable salts, esters, prodrugs, and other derivatives of selective alpha-2 adrenergic receptor agonists.

[0080] The term "low concentration" or "low dose" refers to a concentration of about 0.0001% to about 0.065% w / v, more preferably about 0.001% to about 0.035% w / v, even more preferably about 0.01% to about 0.035% w / v, and even more preferably about 0.03% to about 0.035% w / v.

[0081] The term "brimonidine" includes, but is not limited to, brimonidine salts and other derivatives, including, but not limited to, brimonidine tartrate, 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, and Alphagan®.

[0082] The terms "treat" and "treatment" refer to reversing, alleviating, inhibiting or slowing the progression of the disease, disorder or condition to which the term applies, or one or more symptoms of said disease, disorder or condition.

[0083] The term "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable (i.e., does not produce unacceptable levels of undesirable biological effects or interact in a deleterious manner).

[0084] As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to exert a desired biological effect, such as, but not limited to, the prevention, reduction, alleviation, or elimination of signs or symptoms of a disease or disorder. Thus, the total amount of each active ingredient of a pharmaceutical composition or method is sufficient to provide a meaningful subject benefit. Thus, the "pharmaceutically effective amount" depends on the circumstances in which it is administered. A pharmaceutically effective amount can be administered in one or more prophylactic or therapeutic administrations.

[0085] The term "prodrug" refers to compounds that have cleavable groups and become pharmaceutically active compounds in vivo under physiological conditions, including, but not limited to, monomers and dimers of the compounds of the present invention.

[0086] As used herein, "salt" refers to salts that retain the biological effectiveness and properties of the parent compound and that are not biologically or otherwise harmful in the amounts administered. Salts of the compounds of the present invention can be prepared from inorganic or organic acids or bases.

[0087] The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids or bases. The phrase "pharmaceutically acceptable salts" means salts that are suitable for use in contact with the tissues of humans and lower animals without causing excessive toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known to those skilled in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1 et seq.

[0088] The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate salts. In addition, basic nitrogen-containing groups can be quaternized with materials such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long-chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aryl alkyl halides, such as benzyl and phenethyl bromides; etc. Thus, water- or oil-soluble or dispersible products can be obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids, such as hydrochloric acid, hydrobromic acid, hyaluronic acid, malic acid, sulfuric acid, and phosphoric acid; organic acids, such as oxalic acid, malic acid, maleic acid, methanosulfonic acid, succinic acid, and citric acid.

[0089] Base addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting the carboxylic acid-containing moiety with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, or ammonia, or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, among others; non-toxic quaternary ammonia and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0090] As used herein, the term "ester" refers to an ester of the formula -OC(O)A 1 or -C(O)OA 1 (In the formula, A 1 may be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl group, or other suitable substituent.

[0091] Compositions of the Invention In one embodiment, the present invention relates to an ophthalmic composition comprising aceclidine. In a preferred embodiment, aceclidine is present at a concentration of about 0.25% to about 2.0% w / v, more preferably about 0.50% to about 1.90% w / v, even more preferably about 1.25% to about 1.85% w / v, and most preferably about 1.35% to about 1.65% w / v. Because aceclidine is a chiral tertiary amine, both + and - optical isomers exist (some studies suggest that the (+) is more potent, while others suggest that the (-) may be more potent). At these concentrations, polarimetry showed an exactly equal ratio of the (+) and (-) isomers. Therefore, altering this ratio will alter this concentration range proportionally.

[0092] The present invention further relates to an ophthalmic composition comprising a muscarinic agonist, preferably a nonionic surfactant above the critical micelle concentration of the composition, and a viscosity enhancing agent or in situ gelling agent. In a preferred embodiment, the initial viscosity of the composition upon topical application is greater than 20 cp at low shear (1 / s), preferably greater than 50 cp, and more preferably greater than 70 cp.

[0093] Nonionic surfactants suitable for the present invention include cyclodextrins, polyoxyl alkyls, poloxamers, or combinations thereof, and may also include combinations with other nonionic surfactants, such as polysorbates. Preferred embodiments include polyoxyl 40 stearate, and optionally poloxamer 188, poloxamer 407, polysorbate 20, polysorbate 80, ionically charged (e.g., anionic) β-cyclodextrin (Captisol®), 2-hydroxypropyl β-cyclodextrin ("HPβCD"), α-cyclodextrin, γ-cyclodextrin, polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil, or combinations thereof. Additionally, substitution of other ophthalmically compatible nonionic surfactants may provide similar formulation benefits, including one or more nonionic surfactants such as poloxamer, poloxamer 103, poloxamer 123 and poloxamer 124, poloxamer 407, poloxamer 188 and poloxamer 338, poloxamer analogs or derivatives, polysorbate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate analogs or derivatives, cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated β-cyclodextrin, β-cyclodextrin sulphate ... sulphate, hydroxypropyl-β-cyclodextrin sulphate, hydroxypropyl-γ-cyclodextrin sulphate, hydroxypropyl-β-cyclodextrin sulphate, hydroxypropyl-γ-cyclodextrin sulphate, hydroxypropyl-β-cyclodextrin sulphate, hydroxypropyl-γ-cyclodextrin sulph butyl ether, gamma-cyclodextrin sulfobutyl ether or glucosyl-beta-cyclodextrin, cyclodextrin analog or derivative, polyoxyethylene, polyoxypropylene glycol, polysorbate analog or derivative, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (200), polyoxypropylene glycol (70), polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, polyoxyl, polyoxyl stearate, nonoxynol, octylphenol ethoxylate, nonylphenol ethoxylate, capryol, lauroglycol, PEG, Brij(R) 35 (Brij is a product of Uniqema Americas)LLC), glyceryl laurate, lauryl glycoside, decyl glucoside, or cetyl alcohol; zwitterionic surfactants, such as palmitoyl carnitine, cocamide DEA, cocamide DEA derivatives, cocamidopropyl betaine, or trimethylglycine betaine, N-2(2-acetamido)-2-aminoethanesulfonic acid (ACES), N-2-acetamidoiminodiacetic acid (ADA), N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid Sulfonic acid (BES), 2-[bis-(2-hydroxyethyl)-amino]-2-hydroxymethyl-propane-1,3-diol (bis-tris), 3-cyclohexylamino-1-propanesulfonic acid (CAPS), 2-cyclohexylamino-1-ethanesulfonic acid (CHES), N,N-bis(2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid (DIPSO), 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) , N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 2-(N-morpholino)-ethanesulfonic acid (MES), 4-(N-morpholino)-butanesulfonic acid (MOBS), 2-(N-morpholino)-propanesulfonic acid (MOPS), 3-morpholino-2-hydroxypropanesulfonic acid (MOPSO), 1,4-piperazine-bis-(ethanesulfonic acid) (PIPES), piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) Acid) (POPSO), N-tris(hydroxymethyl)methyl-2-aminopropanesulfonic acid (TAPS), N-[tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropanesulfonic acid (TAPSO), N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES), 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris), tyloxapol, and Span® 20-80. In certain embodiments, the addition of an anionic surfactant, such as sodium lauryl sulfate and / or sodium ester lauryl sulfate, may be preferred.

[0094] Ophthalmic in situ gels that may be used in place of or in addition to one or more nonionic surfactants include, but are not limited to, gelatin, carbomers of various molecular weights, including carbomer 934P and 974P, xanthan gum, alginic acid (alginate), guar gum, locust bean gum, chitosan, pectin, and other gelling agents known to those skilled in the art.

[0095] In a preferred embodiment, the nonionic surfactant is polyoxyl 40 stearate at a concentration of about 1 to about 15% w / v, more preferably about 5.5% w / v.

[0096] In the preferred embodiment described above, polyoxyl 40 stearate is found to preferentially enhance decongestant activity relative to aqueous solutions and other nonionic surfactants, such as poloxamer 407, particularly in the presence of an alpha-2 agonist.

[0097] Viscosity enhancing agents suitable for the present invention include, but are not limited to, carboxymethylcellulose ("CMC"), methylcellulose, methylcellulose 4000, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose 2906, carboxypropylmethylcellulose, hydroxyethylcellulose or hydroxyethylcellulose, hyaluronic acid, dextran, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, gellan, carrageenan, alginic acid, carboxyvinyl polymers, or combinations thereof. In a preferred embodiment, the viscosity enhancing agent has an equilibrium viscosity between 10 centipoise ("cp") and 100 cp between blinks, and an equilibrium viscosity during a single blink of 30 cp or less, preferably 20 cp or less, and more preferably 15 cp or less. In a preferred embodiment, the viscosity enhancer is 0.62% to 1.25% w / v CMC, more preferably 0.75% to 0.87% w / v CMC (1%=2,500 centipoise), most preferably 0.80% w / v CMC (1% in water=2,500 centipoise).

[0098] Without being bound by any particular theory, it appears that the combination of a nonionic surfactant and a viscosity enhancer produces nanometer-sized particles, such as spheroids, or other geometric shapes such as rods or ellipsoids that aggregate into bilayers. These particles have low surface tension and can have relatively high viscosity, which allows tears leaving the lacrimal puncta to remain for a long time with minimal flow, thereby better penetrating the lacrimal mucosa and cornea, reducing nasal mucosa penetration and local effects, and reducing systemic absorption. Once applied topically, an initial viscosity of more than 20 cp prevents nasolacrimal drainage and nasal congestion caused by aceclidine, a direct vasodilatory cholinergic drug that may otherwise cause some degree of nasal congestion. This comfort is achieved without causing systemic side effects resulting from nasolacrimal vessels entering the circulation, and suppresses the direct action of the aceclidine aqueous composition on the nasal mucosa, which results in nasal congestion.

[0099] A selective alpha-2 agonist may be incorporated into the compositions of the present invention, or may be applied topically, preferably just a few minutes before, or less preferably just a few minutes after, if an additional measure to reduce nasal congestion or congestion is desired for sensitive subjects. Selective alpha-2 agonists suitable for the present invention have minimal alpha-1 agonist activity at low concentrations. For example, in the case of brimonidine or fadolmidine, 1% to 2% w / v is considered very high, while 0.5% to 1.0% w / v highly induces alpha-1 receptors and is toxic for purposes of the present invention. Furthermore, 0.10% to 0.5% w / v is too high, and 0.070% to 0.10% w / v is associated with a higher than desirable incidence of rebound hyperemia (although in the case of dexmedetomidine, its high lipophilicity and intraocular penetration reduce the risk of rebound in this range). Although only 0.065% w / v or less is potentially tolerable, for many alpha-2 agonists, 0.050% w / v, and even more preferably 0.035% w / v or less, is desirable depending on selectivity. While some useful activity may occur at concentrations further reduced by an order of magnitude or more, preferred embodiments of the present invention, brimonidine, fadolmidine, and guanfacine, preferentially stimulate alpha-2 adrenergic receptors, and even more preferably alpha-2b adrenergic receptors, such that alpha-1 adrenergic receptors are not stimulated sufficiently to cause excessive large-vessel arteriolar narrowing and vasoconstrictive ischemia. Additionally, preventing or suppressing hyperemia in the case of drugs that otherwise directly induce hyperemia, such as the acetylcholine agonist aceclidine, has been found to increase compliance in sensitive subjects who may experience hyperemia or nasal congestion even with the alpha-2 agonist-free formulations of the present invention. However, because alpha-2 agonists shift their ionization equilibrium, the acidic pH is somewhat offset by the fact that the agonists are more effective at neutral or alkaline pH. Thus, each alpha-2 agonist has a preferred pH range depending on its pKa value and lipophilicity when added to the present compositions containing aceclidine. In the present invention, a pH range of 5.0 to 8.0 is acceptable, but the preferred embodiment is pH 5.5 to 7.5, more preferably 6.5 to 7.0.Furthermore, it has been found that the use of cyclodextrin and / or polyoxyl 40 stearate as a nonionic surfactant component or as the sole nonionic surfactant results in a greater whitening effect when an alpha-2 agonist is included in the composition rather than poloxamer 407. While an alpha-2 agonist is occasionally not required except in sensitive subjects, an alpha-2 agonist can optionally be applied separately or, in certain preferred embodiments, together with formulations of the present invention that do not contain an alpha-2 agonist, such as formulations having 5.5% w / v polyoxyl 40 stearate as the nonionic surfactant. Fadolmidine represents the alpha-2 agonist with the highest hydrophilicity and, therefore, high surface retention in the present invention. Guanfacine is also highly selective and hydrophilic. Brimonidine is highly selective and moderately lipophilic. Finally, dexmedetomidine is highly selective and highly lipophilic, and can be used with low efficacy to reduce congestion for the purposes of the present invention (although it may cause fatigue as a side effect in some patients). In a preferred embodiment, polyoxyl 40 stearate 5.5% w / v, CMC 0.80% w / v, NaCl 0.037% w / v, EDTA 0.015% w / v, borate buffer 5 mM, and BAK 0.007% w / v produces hyperemia of about 1.0 to 1.5 out of 4, which lasts transiently for about 10 minutes and returns to near baseline by 30 minutes.

[0100] In one embodiment, the selective alpha-2 adrenergic receptor agonist is a compound having a binding affinity of about 900 or greater, even more preferably about 1000-fold or greater, and most preferably about 1500 or greater.

[0101] The selective alpha-2 adrenergic receptor agonist may be present at a concentration of about 0.0001% to about 0.065% w / v, more preferably about 0.001% to about 0.035% w / v, even more preferably about 0.01% to about 0.035% w / v, and even more preferably about 0.020% to about 0.035% w / v.

[0102] In one embodiment, the selective alpha-2 adrenergic receptor agonist is selected from the group consisting of brimonidine, guanfacine, fadolmidine, dexmedetomidine, (+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione, 1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds. Analogs of these compounds that function as highly selective alpha-2 agonists can also be used in the compositions and methods of the invention.

[0103] In a more preferred embodiment, the selective alpha-2 agonist is selected from the group consisting of fadolmidine, guanfacine, and brimonidine. In an even more preferred embodiment, the selective alpha-2 agonist is brimonidine in the form of a salt at a concentration of 0.025% to 0.065% w / v, more preferably 0.03% to 0.035% w / v. In a preferred embodiment, the salt is the tartrate salt.

[0104] In another even more preferred embodiment, the selective alpha-2 agonist is fadolmidine in the form of its hydrochloride ("HCl") salt at a concentration of about 0.005% to about 0.05% w / v, more preferably 0.02% to about 0.035% w / v.

[0105] In another even more preferred embodiment, the selective alpha-2 agonist is guanfacine in the form of its HCl salt at a concentration of about 0.005% to about 0.05% w / v, more preferably 0.02% to about 0.035% w / v.

[0106] In another even more preferred embodiment, the selective alpha-2 agonist is dexmedetomidine in the form of its HCl salt at a concentration of about 0.005% to about 0.05% w / v, more preferably 0.04% to about 0.05% w / v.

[0107] In another preferred embodiment, it is recognized that a pH lower than physiological pH, preferably pH 4.5 to 6.5, more preferably pH 5.5 to 6.0, enhances the whitening effect of brimonidine. However, while reduction of hyperemia is achieved at all pHs, enhanced absorption of aceclidine occurs at alkaline pH, resulting in greater effectiveness from a given concentration. Thus, although effective in the pH range of 4.5 to 8.0, a pH range of 6.5 to 7.5 is preferred for the present invention, with a pH range of 7.0 to 7.5 being most preferred.

[0108] The present invention further relates to ophthalmic compositions containing a cycloplegic agent. A surprising and entirely unexpected finding of the present invention is that certain cycloplegic agents can be combined with miotic agents, particularly aceclidine in the present case, without reducing the onset, degree, or duration of miosis, and further blunt the normally associated spike in miotic effect that coincides with the peak absorption time in aqueous formulations to provide consistent miosis versus time after onset ranging from 15 to 30 minutes to 6 to 10 hours, depending on the desired formulation. The addition of a cycloplegic agent also reduces any residual associated discomfort that would otherwise occur shortly after instillation, possibly as a result of cyclospasm or excessive miosis.

[0109] Cycloplegic agents suitable for the present invention include, but are not limited to, atropine, Cyclodil®, hyoscine, pirenzepine, tropicamide, atropine, 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin (Vesicare), tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium (Spiriva), and otenzepad (also known as AF-DX 116, or 11-{[2-(diethylamino)methyl]-1-piperidinyl}acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepin-6-one). In a preferred embodiment, the cycloplegic agent is tropicamide at a concentration of about 0.01% to about 0.10% w / v, more preferably about 0.025% to about 0.080% w / v, and even more preferably about 0.04% to about 0.06% w / v, hi another preferred embodiment, the cycloplegic agent is tropicamide at a concentration of about 0.04% to about 0.07% w / v, or a mixture of pirenzepine or otenzepad at a concentration of about 0.002% to about 0.05% w / v.

[0110] In a preferred embodiment, tropicamide at 0.01% w / v was found to slightly reduce eyelid pain, at 0.030% w / v further reduced eyelid pain, and at 0.04% to about 0.07% w / v completely eliminated eyelid pain without reducing the mean miosis diameter during the duration of action. In a preferred embodiment, tropicamide demonstrated a completely unexpected sensitivity of effect, unexpectedly and very effectively reducing or eliminating eyelid pain and ciliary muscle spasm pain at about 0.04% w / v, with very significant further reduction at 0.042% w / v, and (surprisingly, due to its common use as a mydriatic) abolishing it at 0.044% w / v in the preferred embodiment without ciliary muscle spasm. Furthermore, tropicamide did not reduce the mean degree of miosis, the time to onset of miosis, or subsequent visual benefit. In contrast, tropicamide blunted the peak miosis seen with aqueous formulations to produce a smooth, consistent miotic effect over time. The peak miosis was adjusted to achieve a more uniform effect over time without the mydriasis observed with previous use. Specifically, tropicamide, in some embodiments, is useful for preventing transient constriction of 1.50 mm or less 30 to 60 minutes after aceclidine, reducing the transient, excessive, and undesirable blurring of vision that may otherwise occur at a peak onset of approximately 30 minutes. For example, ophthalmic compositions containing 1.53% w / v aceclidine, 5% w / v HPβCD, 0.75% w / v CMC, 0.25% w / v NaCl, 0.01% w / v BAK, and phosphate buffer at pH 7.0; or 1.45% w / v aceclidine, 5.5% w / v polyoxyl 40 stearate, 0.80% w / v CMC, 0.037% w / v NaCl, 0.015% w / v EDTA, 0.007% w / v BAK, and 5 mM phosphate buffer at pH 7.0 were changed from 0.040% w / v tropicamide, which caused moderate blurring, to 0.044% w / v tropicamide, which caused barely detectable blurring except in very dim light conditions. Further adjustment of pupil diameter with a cycloplegic agent produces sufficient aceclidine concentrations for long-term action while blunting the undesirable associated peak hyperconstriction and uncomfortable eyelid pain. Surprisingly, because of its short duration of action, tropicamide achieves this blunting effect without causing mydriasis.Furthermore, in preferred embodiments, it has been found that 0.014% w / v tropicamide reduces blepharitis, 0.021% w / v reduces blepharitis further, and 0.028% to 0.060%, and in some embodiments up to 0.09% w / v, completely eliminates blepharitis without causing cycloplegia (i.e., paralysis of the ciliary muscles of the eye).

[0111] It has been found that in a racemic 50:50 mixture of the (+) and (-) aceclidine enantiomers (the (+) is believed to be more potent in some studies, and the (-) in others), tropicamide efficacy can vary depending on the ratio of aceclidine to tropicamide. For example, in an ophthalmic composition of the present invention containing 1.55% w / v aceclidine, 5.5% w / v HPβCD, or in a preferred embodiment, polyoxyl 40 stearate, 0.75% w / v CMC (1% = 2,500 centipoise), 0.25% w / v NaCl, and 0.01% w / v BAK at pH 7.5, 0.042% w / v tropicamide can be distinguished from 0.035% w / v, the former exhibiting normal indoor night vision and the latter exhibiting slight blurring that becomes more pronounced at lower concentrations. At higher concentrations, such as about 0.075% to about 0.090% w / v tropicamide, loss of pupil constriction begins in the preferred range of 1.50 mm to 1.80 mm, and at higher concentrations, obvious mydriasis begins to occur. Because the isomer ratio alters the effective concentration, this must be a factor in the clinical effect expected with aceclidine. For the preferred embodiment of the present invention, a polarimeter (personal communication, Toronto Research Chemicals) was used to determine the exact 50:50 isomer ratio.

[0112] Figure 1 shows the effect of miotics with or without cycloplegics and with or without vehicle. Subjects were emmetropic individuals aged 45 years or older with baseline near visual acuity of 20.100 and distance visual acuity of 20.20. Topical administration of 1% w / v pilocarpine in saline to the eye improved near visual acuity to 20.40 (8a), but this improvement occurred at the expense of a decrease in distance visual acuity to 20.100 (8b). The addition of 0.015% w / v tropicamide improved near visual acuity to 20.25 (9a) and reduced the decrease in distance visual acuity to 20.55 (9b), although some irregular astigmatism was induced (a slightly blotchy area in the reading field) in some cases. Topical application of 1.55% w / v aceclidine in saline solution results in a prolonged improvement of near visual acuity to 20.40 over a 6-hour period (10a) without affecting baseline distance visual acuity (10b). Figures 10c and 10d show the effect of administering aceclidine in a vehicle consisting of 5.5% w / v 2-hydroxypropyl β-cyclodextrin, 0.75% w / v CMC (1% = 2,500 centipoise), 0.25% w / v NaCl, and 0.01% w / v BAK. As seen in 10c, the vehicle enhances the effective effect of aceclidine, resulting in near visual acuity of 20.20 or greater. As seen in 10d, a similar improvement in distance visual acuity occurs. Figures 10e and 10f show the effect of adding 0.042% w / v tropicamide to aceclidine in the vehicle. As seen in 10e, near visual acuity improves to 20.15 with a rapid onset of maximum visual acuity. As seen in Figure 10f, a similar improvement in distance vision is observed. Taken together, Figure 1 demonstrates that aceclidine can temporarily correct near vision in presbyopic subjects without affecting baseline distance vision. Similar results can be achieved with a different miotic drug, pilocarpine, plus a cycloplegic drug such as tropicamide. An appropriate drug carrier may also have beneficial effects.

[0113] The present invention further relates to an ophthalmic composition comprising a tonicity agent and a preservative.

[0114] The tonicity agent can be, but is not limited to, a salt such as sodium chloride ("NaCl"), potassium chloride, mannitol, or glycerin, or another pharmaceutically or ophthalmically acceptable tonicity agent. In certain embodiments, the tonicity agent is 0.037% w / v NaCl.

[0115] Preservatives that may be used in the present invention include, but are not limited to, benzalkonium chloride ("BAK"), chlorobutanol, thimerosal, phenylmercuric acetate, disodium ethylenediaminetetraacetic acid, phenylmercuric nitrate, perborate, or benzyl alcohol. In a preferred embodiment, the preservative is BAK at a concentration of about 0.001% to about 1.0% w / v, more preferably at a concentration of about 0.007% w / v. In another preferred embodiment, the preservative is perborate at a concentration of 0.01% to about 1.0% w / v, more preferably at a concentration of about 0.02% w / v.

[0116] Various buffers and means for adjusting pH may be used to prepare the ophthalmic compositions of the present invention. These buffers include, but are not limited to, acetate buffer, citrate buffer, phosphate buffer, and borate buffer. It is understood that acids or bases may be used, preferably at concentrations of 1 to 10 mM, more preferably about 5 mM, to adjust the pH of the composition as needed. In a preferred embodiment, the pH is about 4.0 to about 8.0, and in a more preferred embodiment, the pH is about 5.0 to about 7.0.

[0117] The present invention also relates to ophthalmic compositions further comprising an antioxidant. Antioxidants that can be used in the present invention include, but are not limited to, disodium ethylenediaminetetraacetic acid at a concentration of about 0.005% to about 0.50% w / v, citrate at a concentration of about 0.01% to about 0.3% w / v, and dicalcium diethylenetriaminepentaacetic acid ("CaDTPA") at a concentration of about 0.001% to about 0.2% w / v, preferably CaDTPA at a concentration of about 0.01% w / v, which can be prepared by adding 0.0084% w / v Ca(OH) and 0.0032% w / v pentetic acid to the formulation and slowly mixing. Additional combinations of antioxidants can be used. Other antioxidants that can be used in the present invention include those known to those skilled in the art, such as ethylenediaminetetraacetic acid at a concentration of about 0.0001% to about 0.015% w / v.

[0118] It is a surprising and unexpected finding that the topical formulations of the present invention, particularly one of the preferred embodiments comprising 1.35% to 1.55% w / v aceclidine, 5.5% w / v polyoxyl 40 stearate, 0.80% w / v CMC, 0.037% w / v NaCl, 0.015% w / v EDTA, 0.007% w / v BAK, and 5 mM phosphate buffer at pH 7.0, provide significantly longer contact lens wear and comfort after once-daily instillation. Once-daily use of the preferred embodiment allows dry eye subjects to sleep in their lenses for up to a week, even though they previously had to wear film-covered contact lenses that blurred night vision and required removal, cleaning, and replacement (see Example 7).

[0119] The following exemplary embodiments are offered for illustrative purposes only and are not intended to limit the invention in any way.

[0120] Representative Embodiments In certain embodiments, the present invention provides compounds of formula I:

[0121] [ka] Or, Formula II:

[0122] [ka] (In the above formula, R1 is H, O, CH3, alkyl, acetyl, acyl, aziridine, nitrile, imine, nitrile-imine methyl substitution, nitrile-imine methyl substitution with attached ester, aromatic ring, substituted aromatic ring, azide, acetamide, pyridine, substituted pyridine, pyrrolidine, substituted pyrrolidine, imidazole, substituted imidazole, imidazole having one or more carbon atoms substituted with O or S, substituted imidazole having one or more carbon atoms substituted with O or S, benzimidazole, substituted benzimidazole, benzimidazole having one or more carbon atoms substituted with O or S, or substituted benzimidazole having one or more carbon atoms substituted with O or S; R2 is H, O, CH3, alkyl, acetyl, acyl, nitrile, imine, nitrile-imine methyl substituted, or ester-O-alkyl; R3 is H, CH3, acyl, acetyl, or ester; R4 is acyl, acetyl, ester, CH3, alkyl, aromatic ring, substituted aromatic ring, cyclohexane, or substituted cyclohexane ring; Each of R1 and R2 independently replaces H of -CH2- on the quinuclidine ring. The present invention relates to compositions and methods for treating presbyopia comprising a muscarinic agonist of the formula:

[0123] In certain embodiments, the present invention relates to compositions and methods for treating presbyopia comprising muscarinic agonists that preferentially activate M1 and M3 muscarinic acetylcholine receptors.

[0124] In certain embodiments, the present invention relates to compositions and methods for treating presbyopia comprising muscarinic agonists that activate only the M1 muscarinic acetylcholine receptor.

[0125] In certain other embodiments, the present invention relates to an ophthalmic composition for treating presbyopia comprising aceclidine.

[0126] In certain other embodiments, the present invention relates to an ophthalmic composition for treating presbyopia comprising aceclidine and a cycloplegic agent.

[0127] In certain other embodiments, the present invention relates to an ophthalmic composition for treating presbyopia comprising aceclidine, a cycloplegic agent and a selective alpha-2 adrenergic receptor agonist.

[0128] In certain other embodiments, the present invention relates to an ophthalmic composition for treating presbyopia comprising a general miotic and a cycloplegic.

[0129] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; optionally a selective alpha-2 adrenergic receptor agonist; viscosity enhancers; and a surfactant selected from the group consisting of anionic surfactants, nonionic surfactants, and combinations thereof; The present invention relates to an ophthalmic composition comprising:

[0130] In certain other embodiments, The viscosity enhancer is carboxymethyl cellulose; The anionic surfactant is selected from the group consisting of gamma-cyclodextrin, Captisol®, sodium lauryl sulfate and sodium ester lauryl sulfate, and the nonionic surfactant is selected from the group consisting of poloxamer, polysorbate, Span® 20-80, polyoxyl alkyl, cyclodextrin and its derivatives.

[0131] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; Optionally, a selective alpha-2 adrenergic receptor agonist; and a surfactant selected from the group consisting of Captisol®, polyoxyl 40 stearate, and 2-hydroxypropyl β-cyclodextrin; The present invention relates to an ophthalmic composition comprising:

[0132] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; optionally a selective alpha-2 adrenergic receptor agonist; a surfactant selected from the group consisting of Captisol®, polyoxyl 40 stearate, and 2-hydroxypropyl β-cyclodextrin; and one or more additional nonionic surfactants selected from the group consisting of poloxamer 188, polyoxyl 40 stearate, polyoxyl 35 castor oil, polysorbate, Span® 20-80, tyloxapol, and combinations thereof; The present invention relates to an ophthalmic composition comprising:

[0133] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; and optionally a selective alpha-2 adrenergic receptor agonist; Including, the selective alpha-2 adrenergic receptor agonist is selected from the group consisting of brimonidine, dexmedetomidine, fadolmidine, and guanfacine; The present invention relates to an ophthalmic composition.

[0134] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; and optionally a selective alpha-2 adrenergic receptor agonist; Including, the cycloplegic agent is selected from the group consisting of pirenzepine, tropicamide, cyclodyl®, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), xanomeline, otenzepad, and combinations thereof; The present invention relates to an ophthalmic composition.

[0135] In a preferred embodiment, the compositions of the present invention have a pH of about 5.5 or greater.

[0136] In certain other embodiments, the present invention provides a method for treating a cancer cell comprising: a general miotic, a compound of Formula I or II, a muscarinic agonist, or aceclidine; Possibly cycloplegics; Optionally, a selective alpha-2 adrenergic receptor agonist; and an in situ gel selected from the group consisting of Carbopol®, alginate, pectin, xanthan gum, and guar gum at a concentration of about 0.0001% to about 0.4% w / v; The present invention relates to an ophthalmic composition comprising:

[0137] In a preferred embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.53% w / v; Tropicamide at a concentration of approximately 0.044% w / v; carboxymethylcellulose at a concentration of approximately 0.80% w / v; sodium chloride at a concentration of approximately 0.75% w / v; Benzalkonium chloride at a concentration of about 0.01% w / v; and phosphate buffer at a concentration of about 5 millimolar; Including, The pH is approximately 8.0.

[0138] In another preferred embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.53% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Brimonidine at a concentration of approximately 0.042% w / v; carboxymethylcellulose at a concentration of approximately 0.80% w / v; sodium chloride at a concentration of approximately 0.75% w / v; Benzalkonium chloride at a concentration of about 0.01% w / v; and phosphate buffer at a concentration of about 5 millimolar; Including, The pH is approximately 8.0.

[0139] In a most preferred embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.45% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Polyoxyl 40 stearate at a concentration of approximately 5.5% w / v; carboxymethylcellulose at a concentration of approximately 0.8% w / v; sodium chloride at a concentration of approximately 0.37% w / v; Disodium ethylenediaminetetraacetic acid at a concentration of approximately 0.015% w / v; Benzalkonium chloride at a concentration of about 0.007% w / v; and phosphate buffer at a concentration of about 5 millimolar; Including, The pH is about 7.0 Optionally, 0.40% w / v brimonidine may be added to slightly reduce transient hyperemia approximately during the first 10 to 20 minutes after instillation.

[0140] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Captisol® at a concentration of about 5.0% to about 6.0% w / v; carboxymethylcellulose at a concentration of about 0.90% to about 1.2% w / v; Sodium chloride at a concentration of about 0.025% to about 0.50% w / v; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0141] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Captisol® at a concentration of about 5.0% to about 6.0% w / v; carboxymethylcellulose at a concentration of about 0.90% to about 1.2% w / v; sodium chloride at a concentration of about 0.025% to about 0.50% w / v, preferably about 0.037% to about 0.05% w / v; Benzalkonium chloride, optionally at a concentration of about 0.007% w / v or greater; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0142] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Captisol® at a concentration of about 5.0% to about 6.0% w / v; carboxymethylcellulose at a concentration of about 0.90% to about 1.2% w / v; sodium chloride at a concentration of about 0.025% to about 0.50% w / v; Mannitol at a concentration of about 4.0% w / v; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0143] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Captisol® at a concentration of about 5.0% to about 6.0% w / v; carboxymethylcellulose at a concentration of about 0.90% to about 1.2% w / v; sodium chloride at a concentration of about 0.025% to about 0.50% w / v; an antioxidant selected from the group consisting of disodium ethylenediaminetetraacetic acid at a concentration of about 0.005% to about 0.50% w / v, citrate at a concentration of about 0.01% to about 0.3% w / v, CaDTPA at a concentration of about 0.001% to about 0.2% w / v, and combinations thereof, preferably ethylenediaminetetraacetic acid at a concentration of about 0.0001% to about 0.015% w / v; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0144] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Captisol® at a concentration of about 5.0% to about 6.0% w / v; carboxymethylcellulose at a concentration of about 0.90% to about 1.2% w / v; sodium chloride at a concentration of about 0.025% to about 0.50% w / v; an alpha-2 adrenergic receptor agonist selected from the group consisting of brimonidine, fadolmidine, and guanfacine at a concentration of about 0.025% to about 0.045% w / v; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0145] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% w / v; Tropicamide at a concentration of approximately 0.044% w / v; about 5.0% to about 6.0% w / v polyoxyl 40 stearate; carboxymethylcellulose at a concentration of approximately 0.80% w / v; Sodium chloride at a concentration of about 0.025% to about 0.05% w / v, preferably about 0.037% to about 0.05% w / v; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0146] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Polyoxyl 40 stearate at a concentration of about 1% to 10%, more preferably about 5.0% to about 6.0% w / v; carboxymethylcellulose at a concentration of about 0.80% to 0.90% w / v; sodium chloride at a concentration of about 0.025% to about 0.90%, more preferably 0.05% w / v; optionally cocamidopropyl betaine at a concentration of about 0.1% w / v; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0147] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Polyoxyl 40 stearate at a concentration of about 5.0% to about 6.0% w / v; carboxymethylcellulose at a concentration of approximately 0.80% w / v; sodium chloride at a concentration of about 0.025% to about 0.05% w / v; Benzalkonium chloride at a concentration of about 0.007% w / v; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0148] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Polyoxyl 40 stearate at a concentration of about 5.0% to about 6.0% w / v; carboxymethylcellulose at a concentration of approximately 0.80% w / v; sodium chloride at a concentration of about 0.025% to about 0.05% w / v, preferably about 0.037% to about 0.05% w / v; an antioxidant selected from the group consisting of disodium ethylenediaminetetraacetic acid at a concentration of about 0.005% to about 0.50% w / v, citrate at a concentration of about 0.01% to about 0.3% w / v, CaDTPA at a concentration of about 0.001% to about 0.2% w / v, and combinations thereof, preferably ethylenediaminetetraacetic acid at a concentration of about 0.0001% to about 0.015% w / v; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0149] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.35% to 1.45% w / v; Tropicamide at a concentration of approximately 0.044% w / v; Polyoxyl 40 stearate at a concentration of about 5.0% to about 6.0% w / v; carboxymethylcellulose at a concentration of approximately 0.80% w / v; sodium chloride at a concentration of about 0.025% to about 0.05% w / v, preferably about 0.037% to about 0.05% w / v; an alpha-2 adrenergic receptor agonist selected from the group consisting of brimonidine, fadolmidine, and guanfacine at a concentration of about 0.025% to about 0.045% w / v; and a buffer selected from the group consisting of phosphate buffer and borate buffer at a concentration of about 4.0 millimolar to about 5.0 millimolar; Includes.

[0150] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of about 1.40 to 1.45% w / v; Tropicamide at a concentration of approximately 0.044% w / v; carboxymethylcellulose at a concentration of about 0.85% w / v; sodium chloride at a concentration of approximately 0.75% w / v; Including, The composition further comprises borate buffer at a concentration of about 10 millimolar; benzalkonium chloride at a concentration of approximately 0.01% w / v; Polyoxyl 40 stearate at a concentration of approximately 5.5% w / v; citrate at a concentration of about 0.2% w / v; Including, the composition has a pH of about 7.0; w / v indicates weight / volume.

[0151] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 1.40% w / v; Tropicamide at a concentration of approximately 0.044% w / v; carboxymethylcellulose at a concentration of about 0.80% to about 0.85% w / v; sodium chloride at a concentration of approximately 0.05% w / v; Including, The composition further comprises borate buffer at a concentration of about 10 millimolar; benzalkonium chloride at a concentration of approximately 0.01% w / v; Polyoxyl 40 stearate at a concentration of approximately 5.5% w / v; Dicalcium diethylenetriaminepentaacetic acid (“Ca2DTPA”) in concentrations from about 0.01% w / v; Including, the composition has a pH of about 7.0; w / v indicates weight / volume.

[0152] In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of approximately 0.5% w / v; approximately 0.1% w / v poloxamer 188; approximately 0.2% w / v poloxamer 407; approximately 5% w / v polyoxyl stearate; approximately 0.25% w / v polyoxyl 35 castor oil; carboxymethylcellulose at a concentration of about 0.80% to about 0.85% w / v; sodium chloride at a concentration of approximately 0.25% w / v; perborate at a concentration of approximately 0.02% w / v; a citrate buffer at a concentration of about 15 to about 75 mM; and optionally, guanfacine at a concentration of about 0.03% w / v; Including, the composition has a pH of about 5.0 to about 8.0, preferably about 5.9 to about 6.2; w / v indicates weight / volume.

[0153] The following examples are offered for illustrative purposes only and are not intended to limit the invention in any way. [Example]

[0154] Example 1: Effect of Aceclidine on Visual Acuity in Subjects Aged 47 to 67 Table 1 shows the effects on short-focus ability of presbyopic subjects before and after instillation of compositions containing aceclidine. Each composition contained the specified concentrations of aceclidine, 5.5% w / v HPβCD, 0.75% w / v CMC, 0.25% w / v NaCl, and 0.01% w / v BAK. In addition, the composition administered to subjects 4 and 5 contained 0.125% w / v tropicamide. Because aceclidine is an enantiomer, clinical efficacy may vary with different ratios. In this study, a nearly exact 50:50 ratio of stereoisomers was determined to be best by polarimetry.

[0155] [Table 1]

[0156] As shown in Table 1, all subjects had less than perfect near vision (20.20) (object held 15 inches from the eye) in both the left and right eyes, and many subjects had less than perfect distance vision before administration of the composition. After administration of the composition, all subjects experienced an improvement in near vision that lasted 7 to 12 hours. Surprisingly, the majority of subjects also experienced an improvement in distance vision over the same period. Even more surprising was the improvement in near vision, which was significantly closer than the 16 inches typically required for comfortable reading, in some cases improving to approximately 8.5 inches, which is more common in individuals under 30 years of age. The addition of the cycloplegic drug tropicamide had no additive or adverse effect on the vision correction.

[0157] Example 2

[0158] [Table 2]

[0159] Abbreviations: (C) indicates corrected visual acuity; (m) indicates minutes; (hr) indicates hours; mm indicates millimeters; BD indicates baseline distance visual acuity; BN indicates baseline near visual acuity; BP indicates baseline pupil diameter; OD indicates right eye; OS indicates left eye; OU indicates both eyes.

[0160] All percentages are w / v. "pt" refers to print size, 4 equals 20 / 20 vision, and 3 equals 20 / 15 vision.

[0161] "Time" refers to the duration of the effect.

[0162] As shown in Table 2, aceclidine at a concentration of at least 1.1% w / v was able to reduce pupil size to 1.63 mm one hour after instillation, and near and distance visual acuity was corrected for at least 10 hours. Reducing the aceclidine concentration to 0.75% w / v (Formulation #3) reduced the miotic effect to 2.0-2.5 mm one hour later, and visual acuity correction lasted only 6.5 hours. Adding 0.03% w / v brimonidine reduced ocular redness to 1.5 out of 4 within 30 minutes of instillation (4 out of 4 without brimonidine, not shown) and maintained this throughout the duration of visual acuity correction. Changing the nonionic surfactant to HPβCD (Formulations #2-6) further reduced ocular redness. Lowering the concentration of aceclidine to 0.75% w / v (Formulation #3) further reduced ocular redness, but also shortened the duration of visual field correction for the formulation as described above.

[0163] With Formulations #1-3, eyelid pain and stinging were noticeable, with a pain level of 2 out of 4, accompanied by mild nausea, stomach upset, and fatigue. Surprisingly, the addition of the cycloplegic tropicamide reduced eyelid pain and stinging to 0.5 out of 4 and 0 out of 4, respectively, and eyelid pain disappeared after 60 minutes (Formulation #4). Furthermore, increasing the aceclidine concentration to 1.1% w / v restored corrected visual acuity for a longer period than seen with Formulations #1-2 without increasing ocular redness. However, re-instillation of Formulation #4 at the end of 10 hours caused significant eyelid pain. Instillation of Formulation #5, which has a higher tropicamide concentration after Formulation #4 (OD and OS), alleviated the eyelid pain experienced with re-instillation of Formulation #4. At the end of Formulation #5's shelf life, a third instillation of Formulation #5 again caused significant eyelid pain. Again, increasing the concentration of tropicamide in Formulation #6 was able to resolve the eyelid pain. Additionally, unexpectedly, despite being a cycloplegic, tropicamide had no effect on miosis or vision correction. Surprisingly, the addition of tropicamide resulted in optimal pupil diameter constriction for a prolonged period.

[0164] To examine the effect of brimonidine on miosis, Formulation #7 was administered. Administration of Formulation #7 resulted in a slight reduction in miosis to 1.70 mm, with the same improvement in distance and near visual acuity as with Formulation #5. 2-3+ conjunctival hyperemia was observed.

[0165] All baseline visual acuity data was based on vision corrected with distance contact lenses. Near vision was perceived by the subject as projecting horizontally from 8 inches 1.5 hours after instillation. A Marco autorefractometer with an infrared camera and on-board pupillary scale was used for all pupil diameter measurements. Once an image was selected, it was left on the screen to allow for accurate calibration.

[0166] Example 3

[0167] [Table 3]

[0168] All percentages are w / v. Scores out of 4 are given for nasal congestion, initial stinging, stinging after 3 minutes, initial congestion, congestion after 15 minutes, whitening, pain and overall assessment.

[0169] "pt" refers to the size of the print, with 4 equaling 20 / 20 vision and 3 equaling 20 / 15 vision.

[0170] Baseline visual acuity was 20.20 in both eyes for distance vision, 20.70 in the right unaided eye and 20.80 in the left eye for near vision (best @ 16”).

[0171] D / C indicates discontinuation after rinsing due to intolerable stinging.

[0172] Aceclidine at a concentration of 1.55% w / v was able to reduce pupil size to approximately 1.63 mm 30 minutes after instillation, with no significant effects lasting approximately 7.5 hours, as shown in Table 3, thereby correcting near and distance visual acuity to 20.20 or better for at least 6 hours. Lowering the aceclidine concentration to 1.25% w / v (not shown) produced a useful improvement in near visual acuity to approximately 20.25-20.30, but was less effective than alkaline pH, which produced a more rapid onset, longer duration, and greater effect in the higher dose range. The addition of 0.037% w / v brimonidine reduced ocular redness (4 out of 4 without brimonidine, not shown) to baseline within 15 minutes of instillation, a reduction that was maintained throughout the approximate correction of visual acuity. The addition of 0.10% w / v glycerin significantly reduced stinging. However, the alternative addition of 0.05% w / v poloxamer 188 and 0.05% w / v polyoxyl 40 stearate further reduced the initial stinging but was more viscous. The combination of 0.1% w / v glycerin and 0.1% w / v poloxamer 188 at pH 6.5 significantly reduced onset, duration, comfort, and efficacy. AB11T, which did not contain glycerin, poloxamer 188, or polyoxyl 40 stearate, caused severe stinging immediately after instillation, leading to eye flushing and discontinuation of the experiment. Substituting 0.037% w / v guanfacine for brimonidine in AB12T resulted in minimal initial redness, prolonged reduction in redness, and some whitening, and appeared to provide the best overall cosmetic results, although a slightly higher aceclidine concentration was required for optimal effectiveness.

[0173] All baseline visual acuity data were based on visual acuity corrected with distance contact lenses. Near visual acuity was perceived by the subjects as projecting horizontally from 8 to 10 inches 30 minutes after instillation for AB4T and AB6T.

[0174] Both AB4T and AB6T were repeated monocularly and binocularly. When both eyes were treated, there was a substantial improvement in depth perception, near visual acuity to 3 pt (20.15), and near point distance (8", 20.20) compared to monocular treatment. Monocular treatment resulted in worsening visual acuity with both eyes open compared to when only the treated eye was tested.

[0175] Example 4

[0176] [Table 4]

[0177] As shown in Table 4, increasing the brimonidine to 0.42% w / v in formulations #8-9 reduced congestion to 0.5, and 0.75% w / v CMC produced a watery consistency. Unexpectedly, increasing the CMC from 0.75% w / v to the range of 0.80% w / v to 0.87% w / v and increasing the NaCl from 0.25% w / v to 0.75% w / v in formulations #10-11 produced a thicker consistency, extended the residence time from 7 hours to 10-12 hours, and reduced the amount of drug flushed into the nasolacrimal duct. This reduced drug delivery to the nostrils reduces nasal congestion.

[0178] In formulations #13-18, decreasing the amount of aceclidine from 1.61% to 1.53% w / v resulted in a pupil diameter range of 1.8 to 2.0 mm. Blurred vision as a result of pupil constriction decreased linearly from 1.5 to 0.5 with decreasing aceclidine dose. Specifically, pupils with a diameter of 1.8 to 2.0 mm received 41% more light than pupils with a diameter of 1.5 to 1.7 mm. Surprisingly, pupils with a diameter of 1.8 to 2.0 mm experienced a near depth gain of 1.75 D. This is only a 0.25 D loss from the effective 2.00 D seen in the 1.5 to 1.7 mm range. Thus, while individuals under 60 years of age received the full benefit of improved near vision, the 1.80 to 2.0 mm range received 41% more light. In contrast, individuals over 60 years of age still experienced a high computer benefit and a slightly higher near vision benefit.

[0179] Increasing the tropicamide concentration from 0.042% w / v (Formulations #8-#11) to 0.044% w / v (Formulations #13-#18) reduced pain to negligible amounts. The amount of pain may also be correlated with the age of the individual. For individuals under 45 years of age, it may be preferable to increase the tropicamide concentration to the range of 0.046% to 0.060% w / v.

[0180] Furthermore, Table 4 shows the unexpected result seen in formulations #13 and #17, where increasing NaCl from 0.25% w / v to the range of 0.50 to 0.75% w / v resulted in an acceptable hyperemia score of only 1.0 without the addition of the decongestant brimonidine.

[0181] Formulations #15, #16, and #17 each achieve a maximum overall rating of 5 by combining the following benefits: (1) a low aceclidine concentration improved light exposure without significantly affecting the near vision benefit seen with formulations #8-#12; (2) a high NaCl concentration further reduced redness even in the absence of brimonidine; and (3) a high CMC concentration extended residence time on the eye.

[0182] Formulation #19 is a good alternative for the small number of individuals who are high responders to Formulations #15-#17 and who experience significant blurring of vision with 1.53% w / v aceclidine. Formulation #20 is a good alternative for the small number of individuals who are low responders to Formulation #19. Finally, Formulation #21 is a good alternative for the small number of individuals who are low responders and who experience poor pupillary response with Formulation #20.

[0183] Example 5

[0184] [Table 5]

[0185] Clinical Protocol: Twenty well-corrected presbyopic patients each received one of the above formulations (#22-#23). All patients underwent pre- and post-instillation distance and near visual acuity measurements using Zeiss Visante® (Visante is a registered trademark of Carl Zeiss Meditec AG), optical coherence tomography, axial length, and contrast visual acuity testing (i.e., Colenbrander-Michelson 10% Lum target), with the following results: 1) All patients achieved miosis of 1.5 to 2.20 mm; 2) the patient did not experience cyclomyalgia, ciliary muscle spasm, or induced accommodation; 3) All patients achieved 20 / 30+ or ​​better visual acuity at 14" and were very satisfied with their high contrast near vision results, with no obvious complaints of burning or throbbing; 4) In both cases, the duration of action lasted 6 to 8 hours; 5) binocular visual acuity gave all patients 1 to 1.5 additional lines of near visual acuity compared with monocular testing; 6) the last 10 patients were tested at 20” (i.e., computer distance, cell phone distance) and all achieved near visual acuity of 20 / 25 or better; 7) Unaided presbyopic patients with moderate presbyopia (approximately +2.25 spheres) were very satisfied with improved distance vision to 20 / 25 or better and near vision in the 20 / 30 range; and 8) Uncorrected distance visual acuity was often improved in patients who chose not to correct small refractive errors.

[0186] As shown in Table 5, the use of polyoxyl 40 stearate resulted in the most comfortable aceclidine formulation, exhibiting the least amount of blurred and bloodshot eyes. To achieve results similar to those of formulation #22, formulation #23 required a nonionic surfactant concentration of 10-15% or greater, and formulation #24 required a nonionic surfactant concentration of 15-20% or greater. HPβCD induced a color change over time, likely indicative of oxidation. Substitution with Captisol® yielded similar findings.

[0187] Example 6 Adjustment of Aceclidine Concentration in Preferred Embodiments Preferred embodiment: Aceclidine 1.35%-1.55% w / v; Polyoxyl 40 stearate 5.5% w / v; NaCl 0.037% w / v; CMC 0.80%w / v; EDTA 0.015% w / v; BAK 0.007%w / v; phosphate or borate buffer 5mM; and pH 7.0.

[0188] 1.35% w / v aceclidine 1) Stinging pain when instilling: 0.25 / 4.0 (lasts approximately 2-5 seconds); 2) Hyperemia induced at 10 minutes: 1.0 to 1.5 / 4.0; 3) induced hyperemia at 30 minutes: 0.0 to 0.25 / 4.0; 4) Comfort: Very high; 5) Wetness: Very high. The eyes maintained an improved wetness sensation for most of the 24 hours after a single instillation; 6) Long depth of focus: Excellent; 7) Short focal depth: Excellent.

[0189] Testing of the above formulations in several subjects revealed that there was a small range in clinical efficacy depending on the concentration of aceclidine, with 1.35% to 1.55% w / v aceclidine being preferred, and 1.35% w / v and 1.45% w / v providing the desired benefit in most subjects.

[0190] Furthermore, it has been found that the clinical efficacy of 1.35% w / v aceclidine can be improved when administered as follows: 1) Baseline effect: 1 drop in each eye. 2) Strengthening effect: 2 drops in each eye. 3) For greater effect: Repeat step 1) above after step 2). 4) Maximum effect: After step 2), repeat step 2 above.

[0191] Example 7 Use of Preferred Embodiments to Prolong Contact Lens Wear Preferred embodiment: Aceclidine 1.45%w / v; Polyoxyl 40 stearate 5.5% w / v; NaCl 0.037% w / v; CMC 0.80%w / v; EDTA 0.015% w / v; BAK 0.007%w / v; phosphate or borate buffer 5mM; pH 7.0.

[0192] As a baseline, subjects who normally wore continuous-wear lenses (Air Optix®; Air Optix is ​​a registered trademark of Novartis AG) wore the lenses for one day and slept overnight. Each morning, upon waking, the subjects' vision was blurred, and the contact lenses had to be cleaned to remove the film and haze that had formed overnight. Mean distance visual acuity upon waking was 20.60 on the Michelson contrast chart; mean near visual acuity was 20.80.

[0193] The formulation was then instilled once daily between 7:00 AM and 10:00 AM for 7 days of continuous wear. The subject wore the Air Optix® lenses throughout the day and slept in them overnight. Upon waking each morning, the subject's distance visual acuity was 20.20+ and unaided near visual acuity was 20.40 (matching the subject's baseline presbyopia when the subject did not wear lenses overnight and instead wore the lenses upon waking).

[0194] Example 8

[0195] [Table 6]

[0196] As shown in Table 6, when polyoxyl 40 stearate is used as the surfactant, elimination of EDTA in the polyoxyl 40 stearate composition reduces congestion and yields the best overall rating (Formulations #25 and #26). Addition of cocamidopropyl betaine ("CAPB") further reduces congestion but produces noticeable pain (Formulation #31). Replacing polyoxyl 40 stearate with Captisol® and adding mannitol reduces congestion as does the addition of CAPB to polyoxyl 40 stearate, but yields the best overall rating among aceclidine compositions without any associated pain (Formulation #32). After several weeks, the formulation with Captisol® had an orange hue, likely indicating oxidation.

[0197] Example 9 Use of the Preferred Embodiment Compositions tested: aceclidine at a concentration of approximately 0.5% w / v; approximately 0.1% w / v poloxamer 188; approximately 0.2% w / v poloxamer 407; approximately 5% w / v polyoxyl stearate; approximately 0.25% w / v polyoxyl 35 castor oil; carboxymethylcellulose at a concentration of about 0.80% to about 0.85% w / v; sodium chloride at a concentration of approximately 0.25% w / v; optionally BAK at a concentration of about 0.01% w / v; citrate buffer at a concentration of approximately 0.02%; with or without guanfacine at a concentration of about 0.03% w / v, the composition has a pH of about 5.0 to about 8.0, preferably about 5.9 to about 6.2; w / v indicates weight / volume.

[0198] The above composition was administered to a 61-year-old subject, followed by a second instillation one hour later. A 1.6mm pupil, 20.20+ reading visual acuity, and 20.20+ distance visual acuity were observed. Cyclospasm did not result in loss of distance visual acuity. Without guanfacine, a transient redness of approximately 2+ on a 4-point scale was observed for approximately 20 minutes, whereas with guanfacine, a transient redness of approximately 0.5+ on a 4-point scale lasting less than 5 minutes was observed. Otherwise, clinical results were identical. The presence or absence of BAK had no clinical effect and was used to provide an optional preservative.

Claims

1. An ophthalmic composition for treating presbyopia comprising aceclidine.

2. 10. The ophthalmic composition of claim 1, further comprising a cycloplegic agent.

3. 10. The ophthalmic composition of claim 1, further comprising a selective alpha-2 adrenergic receptor agonist.

4. 3. The ophthalmic composition of claim 2, wherein the cycloplegic agent is tropicamide.

5. 4. The ophthalmic composition of claim 3, wherein the selective alpha-2 adrenergic receptor agonist is brimonidine.

6. An ophthalmic composition for treating presbyopia comprising a general miotic and a cycloplegic.

7. 7. The ophthalmic composition of claim 6, further comprising a viscosity enhancer and a surfactant selected from the group consisting of anionic surfactants, nonionic surfactants, and combinations thereof.

8. the viscosity enhancer is carboxymethyl cellulose; the anionic surfactant is selected from the group consisting of gamma-cyclodextrin, Captisol®, sodium lauryl sulfate, and sodium ester lauryl sulfate; The nonionic surfactant is selected from the group consisting of poloxamer, polysorbate, Span® 20-80, polyoxyalkyl, cyclodextrin and derivatives thereof; The ophthalmic composition of claim 7.

9. 8. The ophthalmic composition of claim 7, wherein the surfactant is selected from the group consisting of Captisol®, polyoxy 40 stearate, and 2-hydroxypropyl β-cyclodextrin.

10. 8. The ophthalmic composition of claim 7, further comprising one or more additional non-ionic surfactants selected from the group consisting of poloxamer 188, polyoxyethylene 40 stearate, polyoxyethylene 35 castor oil, polysorbate, Span® 20-80, tyloxapol, and combinations thereof.

11. 7. The ophthalmic composition of claim 6, wherein the cycloplegic agent is selected from the group consisting of pirenzepine, tropicamide, cyclodyl(R), 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin, tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium, otenzepad, and combinations thereof.

12. 12. The ophthalmic composition of claim 11, wherein the cycloplegic agent is tropicamide.

13. 7. The ophthalmic composition of claim 6, wherein the general miotic is selected from the group consisting of pilocarpine, carbachol, and phosphorine iodide.

14. Aceclidine at a concentration of about 0.25% to about 2.0% w / v; and Tropicamide at a concentration of about 0.025% to about 0.1% w / v; Including, Ophthalmic composition for treating presbyopia, where w / v indicates weight / volume.

15. further carboxymethylcellulose (1% = 2,500 cp) at a concentration of about 0.1% to about 1.2% w / v; and sodium chloride at a concentration of about 0.01% to about 1.0% w / v; Including, 15. The ophthalmic composition of claim 14, wherein w / v indicates weight / volume.

16. aceclidine is present at a concentration of about 1.40-1.45% w / v; Tropicamide is present at a concentration of about 0.044% w / v; Carboxymethylcellulose is present at a concentration of about 0.85% w / v; sodium chloride is present in a concentration of about 0.05% to 0.90% w / v; The composition further comprises: Borate buffer at a concentration of about 10 millimolar; benzalkonium chloride at a concentration of about 0.01% w / v; Polyoxy 40 stearate at a concentration of about 5.5% w / v; Citrate at a concentration of about 0.2% w / v; Including, the composition has a pH of about 7.0; 16. The ophthalmic composition of claim 15, wherein w / v indicates weight / volume.

17. Aceclidine is present at a concentration of about 1.40 w / v; Tropicamide is present at a concentration of about 0.044% w / v; Carboxymethylcellulose is present in a concentration of about 0.80% to about 0.85% w / v; sodium chloride is present at a concentration of about 0.05% w / v; The composition further comprises: Borate buffer at a concentration of about 10 millimolar; benzalkonium chloride at a concentration of about 0.01% w / v; Polyoxy 40 stearate at a concentration of about 5.5% w / v; Dicalcium diethylenetriaminepentaacetic acid ("Ca2DTPA") at a concentration from about 0.01% w / v; Including, the composition has a pH of about 7.0; 16. The ophthalmic composition of claim 15, wherein w / v indicates weight / volume.

18. Aceclidine is present at a concentration of about 0.5% w / v; The composition further comprises: Poloxamer 188 at about 0.1% w / v; Poloxamer 407 at about 0.2% w / v; about 5% w / v polyoxystearate; about 0.25% w / v Polyoxy 35 Castor Oil; Carboxymethylcellulose at a concentration of about 0.80% to about 0.85% w / v; containing sodium chloride at a concentration of about 0.25% w / v; may contain perborate at a concentration of about 0.02% w / v; may include a citrate buffer at a concentration of about 4 to about 75 mM; and may comprise guanfacine at a concentration of about 0.03% w / v; said composition having a pH of about 5.0 to about 8.0; The ophthalmic composition of claim 1 , wherein w / v indicates weight / volume.

19. Aceclidine is present at a concentration of about 1.35% w / v; Tropicamide is present at a concentration of about 0.044% w / v; Carboxymethylcellulose is present at a concentration of about 0.80% w / v; sodium chloride is present in a concentration of about 0.025% to about 0.50% w / v; The composition further comprises Polyoxy 40 stearate at a concentration of about 5.0% to about 6.0% w / v; and a buffer selected from the group consisting of a phosphate buffer and a borate buffer; Including, the buffer has a concentration of about 4.0 millimolar to about 5.0 millimolar; 16. The ophthalmic composition of claim 15, wherein w / v indicates weight / volume.

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