Compositions and methods for the treatment of presbyopia

Abstract

To provide compositions and methods for the treatment of presbyopia.SOLUTION: The methods preferably comprise storing an aceclidine composition in a container having a headspace at a temperature from about 2 to about 8°C. The methods further comprise filling the container under an inert gas overlay and / or enclosing the container an anti-leaching material or disposing the container in a second container containing an anti-leaching material.SELECTED DRAWING: Figure 1

Description

Background Art

[0001] As people age, the minimum distance from the eye at which an object can be focused increases if the person has corrected distant vision or excellent unaided distant vision. For example, a 10-year-old child can focus on an object as close as 3 inches (0.072 meters) from the eye, i.e., the "focal point", while maintaining excellent distant vision. However, at 40 years of age, this distance is 6 inches (0.15 meters), and at 60 years of age, it becomes 39 inches (1.0 meters), which is inconvenient. This condition in which the minimum focal distance increases for individuals with excellent unaided distant vision is called presbyopia and is roughly translated as "aging eyes".

[0002] Excellent unaided distant vision is also known as emmetropia. The inability to focus on distant objects is known as myopia, and the inability to focus on nearby objects is known as hyperopia. Specifically, "distant" vision is considered to be a focus more than 1 meter away from the eye, and near vision is considered to be a focus less than 1 meter away from the eye. The minimum focal distance at which an object can be focused is called the "near point". The change in focus from a distant point to the near point and the foci in between is called accommodation. Accommodation is often measured in diopters. Diopters are calculated by taking the reciprocal of the focal distance (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).

[0003] The highest incidence of the first complaints of presbyopia occurs in people aged 42 to 44 years. Presbyopia occurs because the eye's ability to accommodate using near reflex pupillary constriction decreases as a person ages, and the eye's convergence, particularly the contraction of the ciliary muscle, decreases. This decrease in accommodation results in inappropriate changes in the normal thickness and an increase in the curvature of the front surface of the lens, which is necessary for the shift in focus from distant objects to nearby objects. Important near-focus tasks affected by presbyopia include viewing a computer screen (21 inches) and reading printed materials (16 inches).

[0004] Presbyopia is a normal and inevitable part of aging, and for many people in their 40s, it's the unmistakable first sign of aging. According to one study, more than one billion people worldwide had presbyopia in 2005. This same study predicted that number would nearly double by 2050. If we consider everyone over 45 to have presbyopia, an estimated 122 million people in the United States alone had it in 2010. This number is only going to increase as the baby boomer generation reaches menopause.

[0005] Presbyopia is characterized by a limitation in the ability to perform many tasks that require focusing quickly and almost instantaneously, tasks that previously required focusing at both far and near points. In people with presbyopia, these tasks may only be possible with the use of eyeglasses, contact lenses, or after invasive surgery. One such optical correction, monovision, can be performed with the use of eyeglasses, contact lenses, or surgery. Monovision corrects one eye for near vision and the other eye for far vision. However, monovision correction usually comes with a decrease in depth perception and distance vision, especially in dim light (e.g., at night). Other surgical procedures developed to alleviate presbyopia include: (1) insertion of intraocular lenses (INTRACOR®; registered trademark of Technolas Perfect Vision GMBH); (2) corneal reshaping (PresbyLASIK and conductive keratoplasty); (3) dilation of scleral bands; and (4) insertion of corneal inlays (FlexivueMicrolens®; registered trademark of PresbiBio LLC, Kamra®; registered trademark of AcuFocus, Inc. and Vue+). Kamra® corneal inlays, manufactured by AcuFocus, function by inserting pinholes into the cornea to increase depth of focus.

[0006] Similar effects can be achieved using common miotics such as pilocarpine (a non-selective muscarinic acetylcholine receptor agonist), carbachol (a non-selective muscarinic acetylcholine receptor agonist), and phosphorine iodide (an acetylcholinesterase inhibitor). These common miotics can induce pinhole pupils at concentrations sufficient to achieve pupils smaller than 2.0 mm and may extend the depth of focus like an inlay, but at concentrations sufficient to cause pinhole pupil diameters of 2.0 mm or less, these drugs cause increased ciliary muscle contraction, inducing remaining reserve accommodation and improving near vision at the expense of distance vision in individuals who still retain accommodative function. Side effects of ciliary spasm, as seen with pilocarpine, can induce migraines such as supraorbital ridge pain, as well as blurred hyperopia resulting from myopia induced beyond the ability of the pinhole pupil to correct, so weaker concentrations with much shorter durations of action and more marginal effects should be used. In such cases, even a slight hyperopia can help offset the induced myopia, but, as is very common, even a very small increase in myopia can worsen it. In extreme cases, such ciliary muscle spasms can be associated with shallowing of the anterior chamber, pulling on the serrated edge of the retina and potentially leading to retinal tears and / or retinal detachment.

[0007] Miotics are described in various patents and patent applications for the treatment of presbyopia. U.S. Patents 6,291,466 and 6,410,544 describe the use of pilocarpine to modulate the contraction of the ciliary muscle to return the eye to a resting position and potentially restore its accommodative ability.

[0008] U.S. Patent No. 8,299,079 (HEK Development LLC) describes the use of direct-acting general miotics such as pilocarpine, carbachol, and phosphorine iodide, and the alpha-2 selective vasoconstrictor brimonidine at concentrations of 0.05% to 3.0% w / v. However, the use of brimonidine concentrations of approximately 0.20% (or 0.05% or higher) w / v often induces ciliary spasms accompanied by supraglottic pain and / or headache of migraine severity, and often results in increased rebound congestion. For example, rebound congestion occurs in 25% of patients using brimonidine 0.20% w / v (Alphagan®, Allergan, Inc. registered trademark) twice daily.

[0009] U.S. Patent Application Publication 2014 / 0113946 describes the use of the vasoconstrictors oxymetazoline and pilocarpine, which are alpha-1 and mild alpha-2 agonists, and shows limitations in distance clarity and duration (Table 1). Of the 16 eyes treated, only 3 were between -0.25 and -0.50 diopters, and 8 eyes were mild hyperopia. Of the -0.50 diopter eyes, 2 showed a reduction to a distance of 20.40. Furthermore, the duration was limited as the full effect began to diminish after approximately 4 hours. The pupil size range was 2.0 mm to 2.7 mm, and there was little improvement in near-field effect from depth of focus or in distance sharpness.

[0010] All these attempts at treating presbyopia miosis induce a transient myopia of several diopters, worsening distance vision to near statutory blindness or worse, at the expense of improved near vision for the entire duration of their effect (usually lasting several hours). This myopic effect is amplified by an exponential decline in distance vision, even by a small increment of nominal myopia with respect to untreated uncorrected vision. For example, a patient with mild myopia with respect to distance vision without glasses (e.g., -0.25D, -0.50D equivalent spherical power) will typically experience a loss of several lines of distance vision after instilling 1% pilocarpine (i.e., -0.75D equivalent spherical power).

[0011] Other miotics used to treat glaucoma, particularly acezine, are associated with ciliary spasm, supraorbital pain and / or headache, as well as myopic blurring. Furthermore, acezine is unstable in solution. Typically, acezine is stored in a two-bottle system (the first bottle containing lyophilized acezine, and the second bottle containing the diluent needed to reconstitute the lyophilized acezine before topical application). However, the main problem with its use as a presbyopic miotic is that it is painful and, in some cases, can induce distance blurring.

[0012] U.S. Patent No. 9,089,562 describes a composition comprising acekidine in combination with a ciliary muscle paralyzer, in a preferred embodiment, acekidine 1.45% is combined with tropicamide 0.042%. The addition of a ciliary muscle paralyzer at very low concentrations (less than 0.10%) surprisingly induces pupillary constriction and allows for useful improvement in distance and near vision without ciliary muscle spasms (a migraine-like pain in the supraorbital rim that can be extremely painful and incapacitating), which is induced by the use of acekidine alone. Furthermore, aceline and ciliary muscle paralyzers require specific, narrowly defined ratios and concentration ranges that are interrelated, as are complex factors in the manufacturing and regulatory processes, particularly the need for lyophilization of aceline to enable stable storage, and the associated effects of antifreeze / lyophilization protectants (hereinafter referred to as "antifreezes"). In the case of the present invention, the addition of antifreezes such as polyols in mannitol in preferred embodiments results in a reduction of the effectiveness of the defined ranges and concentration ratios of U.S. Patent No. 9,089,562. Due to these medical and practical inefficiencies, aceline compositions have been discovered that require the same or slightly higher concentrations of aceline as in U.S. Patent No. 9,089,562, and much lower concentrations, or in some cases, do not require ciliary muscle paralyzers. On the other hand, allowing for modifications to the formulation for lyophilization of aceline would be desirable for the treatment of presbyopia with the necessary commercially stable formulations. However, to date, acezine compositions containing less ciliary muscle paralyzing agent than the amounts claimed in the United States have not been effective, as described above, in treating presbyopia alone, particularly in young and middle-aged individuals (45-58 years old) with severe ciliary spasms. Furthermore, in some subjects, it may cause accommodatively induced hyperopic blurring. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] U.S. Patent No. 6,291,466 [Patent Document 2] U.S. Patent No. 6410544 [Patent Document 3] U.S. Patent No. 8299079 [Patent Document 4] U.S. Patent Application Publication No. 2014 / 0113946 [Patent Document 5] U.S. Patent No. 9089562 [Overview of the project] [Problems that the invention aims to solve]

[0014] Therefore, there is a need in the art for a convenient, non-invasive treatment of presbyopia with minimal side effects. Specifically, there is a need for an ophthalmic composition that enables patients with presbyopia to focus on near objects without serious side effects such as decreased visual acuity, blurred vision, pain, redness, difficulty driving at night or reduced vision in dim light, induction of nasal congestion, or the risk of retinal detachment. Furthermore, there is a need in the art for a reduction or elimination of the need for ciliary muscle paralyzing agents used with aceline to potentially enhance duration and efficacy, as well as a stable storage method for aceline compositions, such compositions preferably enhancing both near focal distance and depth of focus, and reducing pupillary constriction to the range of 1.50–2.0 mm without clinically significant side effects. [Means for solving the problem]

[0015] In certain embodiments, the present invention relates to compositions and methods for the treatment of presbyopia.

[0016] In certain embodiments, the present invention relates to compositions and methods for the treatment of presbyopia comprising a muscarinic agonist, wherein the muscarinic agonist preferentially activates M1 and M3 muscarinic acetylcholine receptors. In more preferred embodiments, the muscarinic agonist is more highly selective for M1 than for M3. In certain embodiments, the present invention relates to compositions and methods for the treatment of presbyopia comprising a muscarinic agonist that preferentially activates M1 and M3 muscarinic acetylcholine receptors.

[0017] In certain embodiments, the present invention relates to compositions and methods for the treatment of presbyopia comprising a muscarinic agonist selected from the group consisting of aceline, talsacridine, subcomerine, 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.

[0018] In certain embodiments, the present invention relates to compositions and methods for the treatment of presbyopia comprising a muscarinic agonist that activates only the M1 muscarinic acetylcholine receptor.

[0019] In certain other embodiments, the present invention relates to an ophthalmic composition comprising aceline for the treatment of presbyopia.

[0020] In certain preferred embodiments, the present invention relates to an ophthalmic composition for the treatment of presbyopia, preferably comprising aceline in a concentration of about 0.25% to about 2.0% w / v, and a ciliary muscle paralyzing agent, preferably tropicamide.

[0021] In certain preferred embodiments, the present invention is directed to an ophthalmic composition for the treatment of presbyopia comprising acridine, preferably at a concentration of about 0.25% to about 2.0% w / v and a cryoprotectant, preferably a polyol, preferably mannitol at a concentration of about 1.0% to about 10.0% w / v, more preferably 2.5% w / v. In certain preferred embodiments, the present invention relates to an ophthalmic composition for the treatment of presbyopia comprising about 1.75% w / v acridine; about 2.5% w / v mannitol; and optionally, about 0.004% to 0.015% w / v tropicamide.

[0022] In certain preferred embodiments, the present invention relates to an ophthalmic composition for the treatment of presbyopia comprising about 1.75% w / v acridine; about 2.5% w / v mannitol; about 1.0% to about 6.0% w / v nonionic surfactant; about 0.1% to about 2.25% w / v hydroxypropylmethylcellulose; and optionally, about 0.004% to 0.015% w / v tropicamide.

[0023] In certain preferred embodiments, the present invention relates to an ophthalmic composition for the treatment of presbyopia comprising about 1.75% w / v acridine; about 2.5% w / v mannitol; about 1.0% to about 6.0% w / v nonionic surfactant, preferably the nonionic surfactant is selected from polysorbate, tyloxapol, poloxamer, cyclodextrin, vitamin E TPGS and polyoxyl, more preferably polysorbate 80, even more preferably about 1.0% to about 5.0% w / v polysorbate 80, most preferably about 2.0% to about 4.0% w / v polysorbate 80; about 0.1% to about 2.25% w / v hydroxypropylmethylcellulose, more preferably about 0.75% to about 1.5% w / v hydroxypropylmethylcellulose, most preferably about 1.0% to about 1.25% w / v hydroxypropylmethylcellulose; about 0.10% to about 0.12% w / v sorbic acid; about 0.005% to about 0.02% w / v benzalkonium chloride; and optionally, about 0.004% to 0.015% w / v tropicamide.

[0024] In certain preferred embodiments, the present invention relates to an ophthalmic composition for the treatment of presbyopia comprising about 1.75% w / v acridine; about 2.5% w / v mannitol; a nonionic surfactant, preferably the nonionic surfactant is selected from polysorbate, tyloxapol, poloxamer, cyclodextrin, vitamin E TPGS, and polyoxyl, more preferably polysorbate 80, even more preferably about 1.0% to about 5.0% w / v of polysorbate 80, most preferably about 2.0% to about 4.0% w / v of polysorbate 80; about 0.1% to about 2.25% w / v of hydroxypropylmethylcellulose, more preferably about 0.75% to about 1.5% w / v of hydroxypropylmethylcellulose, most preferably about 1.0% to about 1.25% w / v of hydroxypropylmethylcellulose; about 0.10% to about 0.12% w / v of sorbic acid; about 0.005% to about 0.02% w / v of benzalkonium chloride; one or more antioxidants selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), ethylenediaminetetraacetic acid dihydrate, sodium citrate, and citrate buffer, preferably selected from the group consisting of ethylenediaminetetraacetic acid dihydrate and sodium citrate or citrate buffer; and optionally about 0.004% to 0.015% w / v of tropicamide.

[0025] In certain preferred embodiments, the present invention relates to an ophthalmic composition for the treatment of presbyopia comprising about 1.75% w / v acridine; optionally about 0.004% to 0.015% w / v of tropicamide; about 1.0% to about 6.0% w / v of a nonionic surfactant; about 0.1% to about 2.25% w / v of hydroxypropylmethylcellulose; about 0.10% to about 0.12% w / v of sorbic acid; and about 0.005% to about 0.02% w / v of benzalkonium chloride, wherein the composition is maintained at a temperature of about 2°C to about 8°C.

[0026] In certain preferred embodiments, the present invention relates to an ophthalmic composition for the treatment of presbyopia comprising about 1.75% w / v aceline; about 2.5% w / v mannitol; about 4.0% w / v polysorbate 80; about 1.25% w / v hydroxypropyl methylcellulose; about 0.12% w / v sorbic acid; about 0.1% w / v ethylenediaminetetraacetic acid dihydrate; about 0.02% w / v benzalkonium chloride; and about 0.1% w / v sodium citrate or citrate buffer.

[0027] In certain preferred embodiments, the present invention relates to an ophthalmic composition for the treatment of presbyopia comprising about 1.75% w / v aceline; about 2.5% w / v mannitol; about 4.0% w / v polysorbate 80; about 1.25% w / v hydroxypropyl methylcellulose; about 0.12% w / v sorbic acid; about 0.1% w / v ethylenediaminetetraacetic acid dihydrate; about 0.02% w / v benzalkonium chloride; about 0.1% w / v sodium citrate or citrate buffer; and about 0.01% w / v tropicamide.

[0028] In preferred embodiments, the concentration of hydroxypropyl methylcellulose is about 0.1% to about 2.25% w / v, more preferably about 0.75% to about 1.5% w / v, and most preferably about 1.0% to about 1.25% w / v. Preferably, the concentration of hydroxypropyl methylcellulose is such that the viscosity before drip infusion is about 1 to about 10,000 cps, more preferably about 200 to about 500 cps, and most preferably about 400 cps.

[0029] In another preferred embodiment, the ophthalmic composition of the present invention comprises one or more antioxidants selected from the group consisting of ethylenediaminetetraacetic acid ("EDTA"), ethylenediaminetetraacetic acid dihydrate, sodium citrate, and citrate buffer, preferably 0.1% w / v ethylenediaminetetraacetic acid dihydrate; and 0.1% w / v sodium citrate or citrate buffer.

[0030] In another preferred embodiment, the nonionic surfactant is selected from polysorbate, tyroxapole, poloxamer, cyclodextrin, vitamin E TPGS, and polyoxyl, preferably polysorbate 80, more preferably 4.0% w / v polysorbate 80.

[0031] In another preferred embodiment, the ophthalmic composition of the present invention has a pH of about 4.0 to about 8.0 for compositions without tropicamide, about 4.0 to about 6.0 for compositions containing tropicamide, and more preferably 5.0 for compositions regardless of the tropicamide content.

[0032] In another preferred embodiment, the present invention preferably comprises aceline in a concentration of about 0.25% to about 2.0% w / v, an antifreeze agent, preferably a polyol, preferably mannitol in a concentration of about 1.0% to about 10.0% w / v, more preferably 2.5% w / v, and a nonionic surfactant (preferably the nonionic surfactant being polysorbate, polyoxyl castor oil, polyoxyl stearate, poloxamer, polyethylene glycol, polyoxyl The present invention relates to an ophthalmic composition for the treatment of presbyopia comprising ethylene glycol alkyl ether, tyroxapol, and 2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxy]ethanol, more preferably selected from the group consisting of polysorbate 80 or polyoxyl 35 castor oil.

[0033] In another preferred embodiment, the present invention includes: aceline, preferably at a concentration of about 0.25% to about 2.0% w / v, more preferably at 1.75% w / v; an antifreeze, preferably a polyol, preferably mannitol, preferably at a concentration of about 1.0% to about 10.0% w / v, more preferably at 2.5% w / v; tropicamide, preferably at a concentration of about 0.004% to about 0.025% w / v, more preferably at about 0.005% to about 0.007%; a nonionic surfactant, preferably polysorbate 80, more preferably at a concentration of about 0.5% to about 10.0% w / v, more preferably at about 2.0% to about 6.0% w / v, even more preferably at about 2.5% to about 4.0% w / v; and preferably a cellulose derivative, hyaluronic acid, carbomer, and gum, more preferably high molecular weight carboxymethylcellulose. The present invention relates to an ophthalmic composition for the treatment of presbyopia, comprising a viscous agent selected from the group consisting of or carbomer 940, preferably at a concentration of about 1.0% to about 2.0% w / v, more preferably about 1.35% to 1.45% w / v, and even more preferably about 1.42% w / v, or another viscous agent such as hydroxypropyl methylcellulose, preferably at a concentration of about 1.0% to about 2.0%, more preferably about 0.50% to 1.95%, wherein the initial viscosity of the composition before instillation into the eye may be in the range of about 25 to about 10,000 centipoise, more preferably about 100 to about 5,000 centipoise, and which is a non-Newtonian fluid or may induce tear secretion to produce minimal blurring or may result in minimal blurring with high shear (during one blink) versus low shear (between blinks) after instillation.

[0034] In certain preferred embodiments, the present invention provides an antifreeze agent, preferably a polyol, preferably mannitol, preferably a polyol Onoactive surfactant, preferably polysorbate 80, more preferably at a concentration of about 0.5% to about 10.0% w / v, more preferably about 2.0% to about 6.0% w / v, and even more preferably at a concentration of about 2.5% to about 4.0% w / v, preferably a viscosity agent selected from the group consisting of cellulose derivatives, hyaluronic acid, carbomer 940, and gum, more preferably high molecular weight carboxymethylcellulose or carbomer 940, preferably about 1.0 At a concentration of approximately 2.0% w / v, more preferably approximately 1.35% to 1.45% w / v, even more preferably approximately 1.42% w / v, or at a concentration of other viscous agents such as hydroxypropyl methylcellulose, preferably approximately 0.5% to approximately 1.75%, more preferably approximately 0.75% or 1.5%, most preferably approximately 1.0% to approximately 1.5%, and most preferably approximately 1.05% to 1.25%, where the initial viscosity of the composition before instillation into the eye is The present invention relates to an ophthalmic composition for the treatment of presbyopia, which has a power of approximately 25 to approximately 10,000 centipoise, more preferably in the range of approximately 100 to approximately 5,000 centipoise, is a non-Newtonian fluid, minimizes blurring at high shear (during one blink) and low shear (between blinks) after instillation, and preferably comprises a preservative selected from the group consisting of benzalkonium chloride ("BAK"), sorbic acid, and oxychloro complexes.

[0035] In certain other embodiments, the present invention relates to a method for stabilizing an acelyne-containing composition, comprising storing the composition in a container having headspace at a temperature of about 2°C to about 8°C, preferably about 5°C.

[0036] In certain other embodiments, the composition of the present invention is filled into a container having a headspace under an inert gas overlay, preferably nitrogen, and preferably the headspace is purged with an inert gas overlay, preferably nitrogen.

[0037] In certain other embodiments, the present invention relates to a method for stabilizing a composition comprising aceline, a viscous agent, and a nonionic surfactant, comprising storing the composition in a container having a headspace at a temperature of about 2°C to about 8°C, wherein the composition is filled into the container under a nitrogen overlay, the headspace is purged with nitrogen, and the composition provides low shear (1:1000 / sec) viscosities of about 50 to about 1000 centipoise and high shear (1:1000 / sec) viscosities of about 0.5 centipoise or less.

[0038] In certain other embodiments, the container of the present invention includes a closure and a container, the portion of which the closure and the portion of which the container are sealed with a leaching-proof material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene and aluminum foil, preferably biaxially oriented polyethylene terephthalate.

[0039] In certain other embodiments, the container of the present invention is placed inside a second container formed or lined with a leaching-resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil, preferably biaxially oriented polyethylene terephthalate.

[0040] In certain other embodiments, the present invention relates to a method for stabilizing an acelydin-containing composition, comprising storing the composition in a container having headspace at a temperature of about 22°C to about 25°C, wherein the container comprises a closure and a container, the portion of which the closure and the portion of which the container are sealed with a leaching-proof material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene and aluminum foil, and / or the container is placed in a second container formed of or lined with biaxially oriented polyethylene terephthalate, polytetrafluoroethylene and aluminum foil.

[0041] In certain other embodiments, the second container includes a second closure, which provides an airtight seal.

[0042] In certain other embodiments, the airtight seal is resealable.

[0043] In certain other embodiments, the aceline is at a concentration of approximately 0.25% to approximately 4.0% w / v.

[0044] In certain other embodiments, the method of the present invention provides at least 90% stability of asecidine for at least 7 months, at least 8 months, at least 12 months, at least 15 months, at least 18 months, at least 20 months, or at least 22 months.

[0045] In certain other embodiments, the composition of the present invention further comprises a viscous agent, a polysorbate, an antifreeze agent, and a preservative.

[0046] In certain other embodiments, the viscous agent provides a viscosity of at least 50 centipoise, at least 100 centipoise, or at least 200 centipoise.

[0047] In certain other embodiments, the antifreeze agent is selected from the group consisting of polyols, sugars, alcohols, lower alkanols, lipophilic solvents, hydrophilic solvents, fillers, solubilizers, surfactants, antioxidants, cyclodextrins, maltodextrins, colloidal silicon dioxide, polyvinyl alcohols, 2-methyl-2,4-pentanediol, cellobiose, gelatin, polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), formamide, antifreeze protein 752, or combinations thereof.

[0048] In certain other embodiments, the preservative is selected from the group consisting of benzalkonium chloride, sorbates, antioxidants, and combinations thereof.

[0049] In certain other embodiments, the antioxidant is selected from the group consisting of sodium ascorbate, sodium bisulfate, sodium metabisulfite, n-acetylcysteine, or a combination thereof.

[0050] In certain other embodiments, the present invention relates to a method for stabilizing a composition comprising aceline, hydroxypropyl methylcellulose, polysorbate 80, mannitol, sorbate, and an antioxidant selected from the group consisting of sodium ascorbate, sodium bisulfite, sodium metabisulfite, n-acetylcysteine, or a combination thereof, comprising storing the composition in a container having a headspace at a temperature of about 2 degrees Celsius to about 8 degrees Celsius, wherein the composition is filled into the container under an inert gas overlay, preferably nitrogen, and the headspace is purged with an inert gas, preferably nitrogen.

[0051] In certain other embodiments, aceline is present at a concentration of approximately 0.25% to approximately 4.00% w / v, hydroxypropyl methylcellulose at a concentration of approximately 0.75% to approximately 1.25% w / v, polysorbate 80 at a concentration of approximately 2% to approximately 4% w / v, mannitol at a concentration of approximately 2% to approximately 4% w / v, sorbate at a concentration of approximately 0.10% to approximately 0.12% w / v, and antioxidant at a concentration of approximately 0.10% to approximately 0.25% w / v.

[0052] In certain other embodiments, the present invention relates to a container containing aceline prepared by a process comprising the following steps. a) Provide a container. b) Fill the container with a composition containing acelyne under an inert gas overlay, preferably under nitrogen. c) Purge the headspace created during step b) with an inert gas, preferably nitrogen. d) Put a lid on the container. and e) Optionally, store the container at a temperature of approximately 2 to 8°C.

[0053] In certain other embodiments, the present invention relates to one or more means of stabilizing a composition selected from the group consisting of about 0.25% to about 4.0% w / v acelineidine, filling the composition into a container under an inert gas overlay and purging the headspace generated during the filling of the inert gas, making the total viscosity of the composition at least 50 centipoise, and adding a preservative to the composition selected from the group consisting of sorbates, benzalkonium chloride, sodium ascorbate, sodium bisulfate, sodium metabisulfite, n-acetylcysteine ​​and combinations thereof, wherein the composition is stored at a temperature of about 2 to about 8°C, and w / v represents the weight by total volume of the composition.

[0054] In certain other embodiments, the present invention relates to a method for treating presbyopia, comprising administering a composition of the present invention to a subject in need thereof.

[0055] In certain other embodiments, the present invention relates to a method for treating presbyopia, comprising administering an ophthalmic composition of the present invention to a subject in need thereof. Here, the subject's near visual acuity, if the addition of a nonionic surfactant of 0.50% to 10%, more preferably 1.0% to 6.0%, and even more preferably 3.0% to 5.0%, is detected, is measured by a resolution of at least 4 lines for at least 8 hours; and, Optionally, improvement can be achieved by one or more of the following: In a preferred embodiment, hydroxypropyl methylcellulose is used at 1.25% to increase viscosity to about 400 cps; And, Addition of a combination of BAK preservatives, sorbates, and one or more antioxidants such as EDTA and citrates; This will result in one or more further improvements; i) Reduction of congestion; ii) Increased line definition with almost no blurring of distance; iii) Excellent comfort; and iv) Extension of the period.

[0056] In certain other embodiments, the present invention relates to a method for treating a refractive error of the eye in a subject requiring such treatment, comprising administering a pharmaceutically acceptable amount of the composition of the present invention to the subject requiring such treatment, wherein the refractive error of the eye is selected from presbyopia, myopia, hyperopia, astigmatism, or a combination thereof.

[0057] In certain other embodiments, the present invention relates to a method for treating refractive errors of the eye, comprising administering a pharmaceutically acceptable amount of the composition of the present invention to a patient in need thereof. Here, the pupil size is reduced to approximately 1.5 to 2.5 millimeters, preferably approximately 1.7 to 2.2 millimeters. Furthermore, here, refractive errors are selected from the following group: The range of distance-corrected visual acuity is, Mild to moderate hyperopia of 3.0D or less; Mild to moderate myopia of -5.0D or less; Regular astigmatism of 3.0D or less; Uncorrected distance visual acuity when normal vision is +0.50 to -0.50 spheq and regular astigmatism is 0.75 D or less; Irregular corneal astigmatism, corneal irregularities induced by diastema, transparent-induced corneal irregularities, higher-order aberrations, and higher-order aberrations induced by refractive surgery.

[0058] The present invention further relates to a method for increasing the visual depth of field (i.e., depth of focus) secondary to pupillary constriction, comprising administering a pharmaceutically effective amount of the ophthalmic composition of the present invention to a subject in need thereof.

[0059] The present invention further relates to a method for reducing side effects of ophthalmic aceciloid administration by modulating the agonist effect on the ciliary body of the eye so that ciliary spasms, ciliary-induced eyebrow pain, and / or ciliary-induced headache are substantially reduced or eliminated.

[0060] The present invention further relates to a method for enabling physiological local presymptomatic correction of both eyes.

[0061] The present invention further relates to a method for eliminating the need for monocular limitation due to distance blurring or for reducing the treatment of mild hyperopia to alleviate induced myopic blurring, and typically relates to pilocarpine, or a combination of pilocarpine and an alpha agonist.

[0062] The present invention further relates to a method for improving near vision by increasing accommodation without reducing the clarity of distance vision. This is achieved by simultaneously increasing modulated incremental accommodation, which is sufficient to provide additional near vision enhancement, while maintaining the induction rate and overall degree of accommodation such that the associated myopic blurring does not impair the ability of the simultaneously induced pupillary constriction pinhole effect to filter out refractive errors and maintain distance clarity.

[0063] The present invention further relates to a method for increasing visual depth perception in improving near visual acuity without assistance, comprising administering a pharmaceutically effective amount of the ophthalmic composition of the present invention to a subject in need of it, in both eyes (binocular vision), wherein such binocular vision further enhances myopia beyond that of either eye separately.

[0064] The present invention further relates to a method for improving vision in a subject having refractive errors (visual abnormalities), comprising administering a pharmaceutically effective amount of the composition of the present invention to a subject in need thereof.

[0065] The present invention relates to a method for improving vision in a subject with a refractive error, further comprising administering a pharmaceutically effective amount of the composition of the present invention to a subject in need thereof, wherein the refractive error is selected from the group consisting of myopia, hyperopia, regular astigmatism, irregular astigmatism and high regular astigmatism.

[0066] The present invention further relates to eliminating optical aberrations induced by corneal irregularity (astigmatism), opacity, or very high degree of regular astigmatism, including areas adjacent to or peripheral to the central 1.5 mm optical zone, and thereby inducing improvements in visual acuity and visual quality by filtering out these aberrational visual properties in people suffering from irregular astigmatism or higher degree of regular astigmatism, such as keratoconus, photorefractive keratoconus induced by optical refraction, interlaminar keratitis ("DLK") (post-LASIK DLK), and other iatrogenic induced corneal irregularities such as ectasia after cataract incision, glaucoma filtering bleb, transplanted glaucoma bulb, corneal inlay with or without removal, corneal surgery (LASIK), and corneal ectasia due to infection.

[0067] The present invention further aims to improve visual acuity compared to existing uncorrected refractive errors. This improvement in visual acuity means that patients who currently require toric contact lenses for astigmatism, which are often uncomfortable and prone to shifting with each blink, may now only need non-toric soft contact lenses or no contact lenses at all. Furthermore, those who require air-permeable contact lenses may no longer need contact lenses or may only need much more comfortable soft contact lenses. Patients with high astigmatism may no longer require correction or may need reduced astigmatism correction. Patients with mild to moderate myopia may require less correction or no correction at all. Patients with mild to moderate hyperopia may not require correction or may need reduced correction.

[0068] The present invention relates to a method and an ophthalmic composition for improving visual acuity. In a preferred embodiment, the present invention relates to a method and an ophthalmic composition for treating presbyopia. In a more preferred embodiment, the present invention relates to an ophthalmic composition comprising aceline.

[0069] The present invention relates to a method and an ophthalmic composition for improving visual acuity. In a preferred embodiment, the present invention relates to a method and an ophthalmic composition for treating presbyopia. In a more preferred embodiment, the present invention relates to an ophthalmic composition comprising aceline.

[0070] The present invention relates to a method for treating irregular astigmatism, corneal ectasia, and mild myopia or hyperopia, with or without astigmatism, and includes administering the ophthalmic composition of the present invention to a subject in need of such treatment.

[0071] The present invention further relates to a method for stabilizing aceline, comprising: a first chamber containing about 1.75% w / v aceline and about 2.5% w / v mannitol; and a second chamber containing about 0.01% w / v tropicamide, about 4.0% w / v polysorbate 80, about 1.25% w / v hydroxypropyl methylcellulose, about 0.10% to 0.12% w / v sorbic acid, about 0.1% w / v ethylenediaminetetraacetic acid dihydrate, about 0.02% w / v benzalkonium chloride, and about 0.1% w / v sodium citrate or citrate buffer, wherein the potency of aceline is maintained for at least one month after mixing the first and second compositions.

[0072] The present invention further relates to a method for stabilizing aceline, comprising storing the composition of the present invention at 0 to 8 degrees Celsius.

[0073] The present invention further, A step of providing an ophthalmic composition comprising approximately 1.75% w / v acelinezine, approximately 2.5% w / v mannitol, approximately 0.01% w / v tropicamide, approximately 4.0% w / v polysorbate 80, and approximately 1.25% w / v hydroxypropyl methylcellulose; The step of adding approximately 0.10% to 0.12% w / v sorbic acid; and The step of adding approximately 0.1% w / v ethylenediaminetetraacetic acid dihydrate and one or more of approximately 0.1% w / v sodium citrate or citrate buffer. This relates to a method for inhibiting the growth of microorganisms and fungi, including [specific microorganisms]. [Brief explanation of the drawing]

[0074] [Figure 1] This graph shows the effects of pilocarpine and aceline on near and far visual acuity in patients aged 45 and older, with and without tropicamide and carriers. [Figure 2] This graph shows the effects of adding nonionic surfactants and viscous agents on near vision and the duration of the effect. The "Line-Hours" line indicates the line showing improved duration of the effect. [Figure 3] This graph shows the effectiveness index for prescriptions #L33 to #L94. The box colors indicate comfort levels: white is good, cross-hatching is average, and black is poor. [Figure 4] This graph shows the stability percentage of aceline refrigerated compositions over 30 months at 5 degrees Celsius and 25 degrees Celsius. [Modes for carrying out the invention]

[0075] Detailed description of the invention The present invention relates to compositions and methods for treating presbyopia, irregular astigmatism and / or refractive errors, comprising administering a pharmaceutical composition comprising a muscarinic agonist that preferentially activates M1 and M3 muscarinic acetylcholine receptors, preferably M1 rather than M3, most preferably acelinezine or a derivative thereof, to a patient in need. Surprisingly and unexpectedly, acelinezine has been found to provide an enhancement of presbyopia reversal with negligible side effects, during the day or at night (including one or more direct or reflected light sources when viewing).

[0076] Aceclidine has traditionally been used as a treatment for glaucoma. When aceclidine is used to treat glaucoma, it is typically stored in a two-bottle system; one bottle contains lyophilized aceclidine, and the second bottle contains the diluent necessary to reconstitute the lyophilized aceclidine before topical instillation. Romano JH, Double-blind cross-over comparison of aceclidine and pilocarpine in open-angle glaucoma, Brit J Ophthal, Aug 1970, 54(8), 510-521. Providing an aqueous aceclidine composition that is stable in combination with cold chain storage is a further aspect of the present invention. Providing a method for stabilizing aqueous aceclidine by combining effective excipients, pH ranges and temperature ranges is yet another aspect of the present invention.

[0077] The present invention provides a composition and method for treating presbyopia by improving depth of focus in patients with presbyopia, by administering an ophthalmic composition to the eye that reduces pupillary dilation in dark or dim light, produces a particular degree and duration of miosis without accommodation, provides whitening, and / or induces anticonjunctival hyperemia. Moreover, the composition and method of the present invention does not cause significant pupillary rebound, tachyphylaxis, ciliary spasm, induction of myopia, or decrease in distance visual acuity. Furthermore, the composition and method of the present invention allows for further improvement in visual acuity and depth perception in bilateral (both eyes) treatment. The ophthalmic composition of the present invention remarkably produces pupils of approximately 1.5 mm to 2.4 mm on the anterior surface of the iris and approximately 2.0 mm on the corneal surface. While we do not wish to be bound by any particular theory, the clinical effect appears to involve both a modulated increase in accommodative tension and a pinhole enhancement near the depth of focus for improved near visual acuity estimated to be approximately -1.25 D or less. However, the power is limited to remain within the range of hyperopia pinhole correction, and has been found to be approximately -1.00D or less, so the total increases, and in some cases, myopia of +2.00D or more may be added without hyperopia blurring. This is accompanied by a reduction or elimination of redness, which is otherwise characteristic of the use of miotics. The pupillary constriction of the present invention with such modulation and limitation of peak accommodative tone is superior to the pinhole effect of Kamra® and FlexivueMicrolens® corneal inlays and enables bilateral treatment without peak accommodative tone. The pupillary constriction of the present invention with modulated accommodation is also superior to inlays because the actual pupillary constriction does not result in the severe night vision impairment caused by the light scattering boundary of the corneal pinhole created by the inlay. Further pupillary constriction provides a wider field of view and more focused light transmission, resulting in negligibly mild and highly tolerable photochromic and enhanced contrast, improved distance vision, reduced nighttime glare, and improved near vision within the optimal pupillary range found to be approximately 1.5 mm to 2.1 mm using the formulation discovery of the present invention.

[0078] The use of acezine has minimal impact on the longitudinal ciliary muscle, thus reducing the risk of retinal detachment compared to the use of common muscarinic agonists such as pilocarpine and carbachol. Further inclusion of a ciliary muscle paralyzer resulted in an anterior chamber being only 0.04 mm shallower. Acezine, especially as enhanced for this invention, also offers greater control over size, duration, and minimum pupil diameter than conventional pilocarpine, with or without an alpha agonist, and results in less anterior chamber inflammation with chronic use. The compositions of this invention achieve these advantages by enabling both the benefits of pinhole myopic depth perception and a moderate accommodative increase below the threshold of myopic distance blur induced through pupillary constriction, thereby, in a preferred embodiment, the rate of pupillary constriction and the rate of accommodative increase maintain a synchronous balance, allowing for pinhole correction of accommodative blur otherwise induced in the conventional application of pupillary constriction for presbyopia correction. Therefore, this combination has been found to prevent, without the discovery of the formulation of the present invention, distance blurring typically seen in patients in response to pilocarpine and / or carbachol-induced miosis, as well as excessive accommodative myopia and ciliopspasm that manifest as headaches such as headache or systemic migraine.

[0079] Such conventional formulations of pilocarpine to provide a reasonable duration of effect, while minimizing but not eliminating distance-induced myopic blurring and ciliary spasms due to the high accommodation ratio for pupillary constriction, require a minimum concentration of approximately 1.0% pilocarpine, and are still limited to about 4 hours or less in most cases. Furthermore, pilocarpine needs to be instilled monocularly to minimize unbearable distance blurring and even more troublesome 2-3 line distance blurring. Even when injected monocularly, pilocarpine can still cause troublesome accompanying distance blurring and should be limited to about 1.0%. Instilling 1.0% pilocarpine results in pupil size of approximately 2.3 mm or more in most subjects, thereby limiting not only the pinhole filtering of induced myopic light but also the important benefit of pinhole depth perception. The restriction of pilocarpine to approximately 1.0% of these conventional formulations, while accompanied by a short and still problematic duration, attempts to prevent the very strong 5D to 11D accommodation that is well known to occur at higher concentrations of pilocarpine, by reducing distance blurring in emmetropia or myopia (and slightly neutralizing it in low hyperopia).

[0080] In preferred embodiments, by combining a miotic agent and a ciliary muscle paralyzer in a narrow, specific ratio of miosis to ciliary muscle paralysis, such as the ratio found in U.S. Patent No. 9,089,562, for example, about 35:1 in preferred embodiments, any effect on accommodation can be further reduced or completely eliminated, and in the present invention, this is significantly increased by about 300% to 700% in the presence of an antifreeze. Acecilyne can result in increased depth of focus by both pupillary miosis of less than 2.3 mm and moderate accommodation as described in the present invention. Particularly enhanced miosis results from the use of the compositions of the present invention. This enhanced miosis allows the use of α-2 agonists at very low concentrations when necessary to alleviate mild conjunctival hyperemia. Other combinations of inactive components reduce or effectively eliminate conjunctival hyperemia without such agonists. Furthermore, due to the evident and remarkably selective nature of acezidine, and the discovery of a commercially stable acezidine formulation of the present invention, administration of the composition of the present invention to the eye results in a net strongly enhanced near vision from both a pupillary pinhole effect and moderately accommodated ciliary accommodation. These beneficial effects are accompanied by a filtering pupillary effect that eliminates distance blurring from accommodation and corrects any residual refractive errors and optical aberrations that may be present, often improving distance vision as well.

[0081] Certain embodiments of the present invention enhance the preferred degree of pupillary constriction found by providing an effect within a certain range of about 1.50–2.20 mm for most patients using preferred embodiments of nonionic surfactants and viscosity enhancers. Similar benefits can be achieved using other penetration enhancers, particularly Carbopol® (polyacrylic acid or carbomer), as well as various viscous additives that extend drug retention time, such as xanthan gum, guar gum, alginates, and other in situ gels well known to experts in the art. It is well known to experts in the art that the precise concentration of a particular viscosity enhancer depends on both the molecular weight and concentration of the selected drug, and that the same viscosity can be obtained even if the concentration decreases as the molecular weight increases. The present invention further prevents nasal congestion that occurs when large levels of aceline reach the nasal mucosa, due to the rheological properties of the preferred embodiments.

[0082] The combination of aceline and low concentrations of selective α-2 adrenergic receptor agonists (α-2 agonists or α-2 adrenergic agonists) such as fadolmidine, brimonidine, or guanfacine reduces or eliminates conjunctival hyperemia, enabling the desired miosis. The use of low concentrations of selective α-2 agonists results in a substantial reduction in conjunctival hyperemia and significantly reduces the risk of rebound hyperemia found at concentrations above approximately 0.06% w / v. Furthermore, the use of low concentrations of selective α-2 agonists does not adversely alter the pupillary constriction caused by aceline. In contrast, the use of 0.20% w / v brimonidine, when applied topically for night vision pupillary accommodation, results in tachyphylaxis of pupillary accommodation due to α-2 receptor upregulation in nearly 100% of patients within 4 weeks of use.

[0083] Unexpectedly, the addition of a ciliary muscle paralyzing agent reduces supraorbital pain or associated discomfort by further decreasing the degree of ciliary spasm with topical instillation without losing the miotic response. Even more unexpectedly and surprisingly, the ratio of 1.40% aceline and about 0.040% tropicamide in the preferred embodiment of U.S. Patent No. 9,089,562 (35:1) becomes about 1.75% aceline to about 0.004% to 0.010% tropicamide (350:1 and 175:1, respectively) in the presence of mannitol, and 2.5% provides a better effect than 4.0%.

[0084] Since certain ciliary muscle paralyzers, such as tropicamide, exhibit known pupillary dilation at concentrations as low as 0.01% w / v, this absence of a miotic response is an unexpected and surprising finding (Grunberger J. et al., Thepupillaryresponsetestasamethodtodifferentiatevarioustypesofdementia, Neuropsychiatr, 2009, 23(1), pg57). More specifically, ciliary muscle paralyzers cause pupillary dilation (i.e., dilation of the radial muscles of the iris). Furthermore, the addition of a ciliary muscle paralyzer to a miotic agent unexpectedly prolongs the time the pupil maintains the desired size range without excessive restriction. The peak miotic effect at 30-60 minutes can be titrated inversely proportional to the ciliary muscle paralyzer concentration. The tropicamide concentration found in this invention clearly induces more relaxation of the ciliary muscle than of the radial muscle system of the iris. In fact, iris dilation is suppressed by the addition of tropicamide to a composition containing aceline at the concentrations used in the present invention, and instead, pupillary constriction is found to be at a more consistent level throughout the duration of the miotic effect. Furthermore, quite surprisingly, unexpectedly, and beneficially, the addition of tropicamide can reduce the degree of peak pupillary constriction without inducing pupillary dilation, thereby resulting in a more consistent and ideal pupil size throughout the drug-induced miosis. This more consistent pupil size allows for beneficial near and distance visual acuity without the harmful blurring or loss of resolution due to diffraction limits at the very reduced pupil size (e.g., 1.25 mm) seen with peak pupillary constriction.

[0085] Previously, in U.S. Patent No. 9,089,562, it was surprisingly found that the addition of at least 0.04% w / v of a ciliary muscle paralyzing agent resulted in a reduction of ciliary side effects caused by administration of aceline (1.40%) to the eye, in a preferred embodiment. However, such formulations are not sufficiently stable for commercial use and typically have a duration of action of up to about 5-6 hours.

[0086] Several additional discoveries of the present invention enable commercially stable aceline formulations with enhanced efficacy and duration of action.

[0087] Equally, or even more surprising than, the synergistic effect of 0.040% thyroplezic added to 1.40% acelinezine, is the discovery of the present invention that a combination of 1.50% to 2.0% (preferably about 1.75%) acelinezine with an antifreeze, preferably a polyol, and in a preferred embodiment, particularly 0.5% to 4.0%, most preferably about 2.5% mannitol, can achieve a similar pupillary range with reduced or no ciliary side effects. Furthermore, the combination of an antifreeze with acelinezine allows for freeze-drying without degrading acelinezine, and at the same time, the present invention can further reduce or eliminate the need for ciliary paralytic agents in relation to the teaching of the ciliary paralytic concentration range required by U.S. Patent No. 9,089,562. Therefore, optionally, the addition of an antifreeze can be used to further eliminate the mild but potentially troublesome ciliary muscle side effects, particularly in young presbyopia, and to significantly reduce the concentration of ciliary muscle paralyzer required to further modulate pupillary constriction than the combination of aceline and antifreeze alone (i.e., 0.025% w / v or less, preferably 0.004% to 0.015%, most preferably 0.005% to 0.010% of the ciliary muscle paralyzer). As seen in preferred embodiments of the present invention, troublesome peak concentration adjustments are reduced and, in most cases, eliminated. In preferred embodiments, it has been found that about 1.50% to 2.0%, more preferably 1.75%, of aceline and about 0.5% to 4.0%, more preferably 2.5%, of mannitol provide the optimal concentration combination for the present invention, but while the discovery of additive formulations can further enhance the clinically desirable degree and duration of general improvement, an effective topical presbyopia composition requires, but does not have, a desirable general improvement of about 3 lines and a duration of 5 hours or more.

[0088] Surprisingly, while adding a viscous agent to the composition a. above only slightly improves size and duration, it was discovered that when a nonionic surfactant such as polyoxyl stearate or polysorbate 80 is added first, an optimal concentration is found that provides a significantly improved size and duration in the present invention, and its viscosity can provide a much more substantial duration of addition than when added alone. When the concentration of polysorbate 80 or polyoxyl 40 stearate is between 1.0% and 10.0%, it was found that a more preferable concentration of about 2.5% to 5.0% w / v is beneficial.

[0089] Combining the formulation improvements of a. and b. above results in preferred embodiments such as 1.75% aceline, 2.5% mannitol, and 2.75% polysorbate 80. Surprisingly, viscosities such as high-viscosity carboxymethylcellulose ("CMC") have been found to moderately increase size and significantly increase duration, unlike the formulations described above alone. Combinations of high molecular weight CMC concentrations of 0.75% to 1.75%, most preferably about 1.40%, or about 0.25% to 2.0%, more preferably about 0.50% or 1.50%, most preferably about 1.0% to 1.25% hydroxypropyl methylcellulose ("HPMC") resulted in an improvement in near visual acuity of about +3 lines or more, with a duration of 5 to 10 hours, averaging about 7 hours or more, which is longer than 1.0% pilocarpine, which is less than about 4 hours.

[0090] While we do not wish to be bound by any particular theory, citrate combined with EDTA as a buffer in a preferred embodiment appears to reduce congestion, extend the shelf life of sorbate preservatives, and, when combined with BAK, at a concentration of 0.005% to 0.02% (0.02% is preferred), further enhances near line of sight to approximately 4 lines and duration to approximately 8 to 12 hours.

[0091] Furthermore, in a preferred embodiment, 0.5% or 1.5% sodium chloride is added. Optionally, the sodium chloride may be replaced, preferably, with 0.35% boric acid, or preferably, with 0.47% potassium borate.

[0092] While we do not wish to be bound by any particular theory, the addition of a nonionic surfactant at an optimized concentration of approximately 2.5% to 5.0% appears to enhance the penetration of aceline into the eye, which may be related in particular to the optimal micelle size, in the micromicelle or nanomicelle range. This increased penetration coincides with a desired increase in size and duration, and in the presence of mannitol, though not in the presence of tropicamide, ciliary sensation and photoregulation are slightly increased. Therefore, if an enhanced combination of formulations a-d above exists, a ciliary muscle paralyzer is no longer necessary in a-d above, and the addition of a nonionic surfactant at a concentration found to be preferable may be further improved with much lower concentrations of ciliary muscle paralyzer than those found in U.S. Patent No. 9,089,562, such as the use of approximately 0.042% tropicamide and 1.40% aceline. In the present invention, a preferred embodiment includes about 1.75% aceline, 2.5% mannitol, about 2.5% to 5.0% polysorbate 80, about 1.42% CMC, or about 1.8% HPMC, and about 0.004% to 0.010%, more preferably about 0.005% to 0.007%, most preferably about 0.005% to 0.006% tropicamide. Micelle formation above the critical micelle concentration may allow micelles to spread across the entire tear film surface and cover this surface at low concentrations, whereas at high concentrations, these micelles increasingly contract and are “compressed” along the surface.

[0093] While we do not wish to be bound by any particular theory, in a preferred composition of 1.75% acelinezine, 2.5% mannitol, 0.01% tropicamide, and citrate buffer (1–100 mM, preferably 3–5 mM), the addition of approximately 0.10% sorbate and approximately 0.10% EDTA, along with 0.02% BAK, exceeds the critical micelle concentration of BAK. When an ionic micelle gradient is created with the cationic surfactant BAK and the +charged NH4 + quaternary nitrogen, the polar head aggregates outward and the lipophilic alkyl chain aggregates inward to the hydrophobic tail. BAK micelles can cause significant similar acelysine alignments due to the dipole between the quaternary NH3 nucleophilic or NH4 protonated nitrogen oriented along the outer polar head and the more hydrophobic carbonyl C=O along the hydrophobic BAK micelle tail. These prevent, significantly reduce, or moderately reduce collisions of nonionic acelysine molecules (nucleophiles) and, if oriented in solution to randomly collide with another acelysine carbonyl, result in the chemical transformation of that acelysine via nucleophilic attack on its target carbonyl, re-entering from such nucleophiles into other acelysines thus repeatedly oriented, via 0.005%, preferably 0.01% to 0.02%, most preferred micelles, without BAK orientation, leading to a loss of stability. Although the concentration of such nonionic nucleophiles at the preferred pH in the preferred embodiment is relatively low, these nonionic nucleophiles have a high ability to repeatedly destabilize adjacent acekidine without degrading themselves. As a result, upon opening the dual-chamber bottle, mixing occurs between the lyophilized acekidine / mannitol and the remaining formulation in the diluent, which may improve the potency of the mixed solution for more than one month and / or improve the stability in the solution sufficient for commercialization at room temperature or in a cold chain.

[0094] While BAK alone does not provide sufficient antimicrobial and antifungal effects, it has been found that BAK and sorbate, or sorbate alone, provide sufficient preservation of the diluent and / or mixed solution of the present invention.

[0095] While we do not wish to be bound by any particular theory, preferred embodiments of the present invention, such as those containing 1.25% hydroxypropyl methylcellulose, may have a viscosity of approximately 400 cps before infusion, unlike conventional high-viscosity artificial tear formulations such as Celluvisc®, which has a viscosity of approximately 400 cps. This may blur vision for 10–20 minutes, or blur Liquigel® at approximately 100 cps, resulting in a similar, but slightly, reduction in blur, with approximately 60 seconds of blur rapidly dissipating with the influx of tear secretion. This may be due to both a decrease in non-Newtonian viscosity at high shear (e.g., approximately 1 / 1000 of a second during blinking) and a parasympathetic trigger for tear secretion as a siarogen.

[0096] Common miotics such as pilocarpine, carbachol, and phospholine diesterase can cause pupillary constriction and improve near vision in presbyopic patients. However, distance vision associated with these common miotics is conversely reduced due to the peak effect and accommodative miosis not seen with acezine. Surprisingly, the co-administration of ciliary muscle paralyzers and acezine results in a reduction of this decline in distance vision.

[0097] The comfort, safety, and efficacy of preferred embodiments of the ophthalmic compositions of the present invention are due to the presence of nonionic surfactants such as cyclodextrin alpha, beta, or gamma chains, preferably 2-hydroxypropyl beta-cyclodextrin ("HPβCD"), sulfobutyl ether derivatives of β-cyclodextrin (Captisol®), polyoxyl alkyls such as polyoxyl 40 stearate and polyoxyl 35 castor oil, or poloxamers such as poloxamer 108 and poloxamer 407, polysorbates such as polysorbate 80 or Brij® 35 (Brij® is a registered trademark of Uniqema Americas LLC); viscous agents such as carboxymethylcellulose ("CMC"); tonicity modifiers such as sodium chloride; preservatives such as benzalkonium chloride; and a pH of about 5.0 to about 8.0. Furthermore, increasing the concentration of nonionic surfactants may result in a reduction of redness. Specifically, increasing the polysorbate concentration from 0.10% to 0.50-1.0% reduces redness. Furthermore, increasing the CMC or Carbopol® 940 concentration to 0.50-1.5% w / v (preferably 1.40-1.43% w / v) improves near vision in both quantitative and duration of improvement.

[0098] The viscosity of the composition of the present invention, which contains a viscous agent, may be about 1 to about 10,000 cps before topical instillation into the eye. As a result of the shear force applied to the composition when it exits the device used for administration, the viscosity decreases to a range of about 1 to about 25 cps at high shear during blinking and to a range of 50 to 200 cps at low shear between blinks. This allows for greater droplet retention, reducing spillage, nasolacrimal duct drainage, and systemic absorption during topical instillation.

[0099] definition As used herein, the term “composition” is intended to encompass products containing specific amounts of specific components, and products obtained directly or indirectly by combining specific amounts of specific components.

[0100] As used herein, the term “stabilization” refers to any process that facilitates and / or enables the retention of an activator in a solution. As used herein, the term “stabilization” also refers to any means or process that inhibits and / or reduces the tendency of a muscarinic agonist, including acecilidine, to degrade.

[0101] Where used herein, all numerical values ​​relating to quantities, weights, etc., defined as "about" each specific value are plus or minus 10%. For example, the phrase "about 5% w / v" should be understood as "4.5% w / v to 5.5% w / v". Thus, quantities within 10% of the claimed value are covered by the scope of the claim.

[0102] As used herein, "%w / v" refers to the percentage weight of the total composition.

[0103] As used herein, the term “subject” refers to, but is not limited to, a person or another animal.

[0104] As used herein, the term “container” refers to a pharmaceutically acceptable container that includes a chamber suitable for containing a liquid drug product. Containers include, for example, vials, syringes, capsules, and ampoules.

[0105] As used herein, “headspace” refers to the area within the chamber of the container between the composition and the cap when the cap is oriented away from gravity.

[0106] As used herein, the terms “cap” or “closure” refer to any article that can prevent a composition from coming out of its container.

[0107] The term muscarinic receptor agonist ("muscarinic agonist") encompasses agonists that activate muscarinic acetylcholine receptors ("muscarinic receptors"). Muscarinic receptors are divided into five subtypes, designated M1-M5. The muscarinic agonists of this invention include muscarinic agonists that preferentially activate M1 and M3 receptors over M2, M4, and M5 receptors ("M1 / M3 agonists"). M1 / M3 agonists include, but are not limited to, aceline, xanomeline, talsacridine, subcomerine, cevimeline, albameline, arecoline, mirameline, SDZ-210-086, YM-796, RS-86, CDD-0102A (5-[3-ethyl-1,2,4-oxadiazole-5-yl]-1,4,5,6-tetrahydropyrimidine hydrochloride), N-arylurea-substituted 3-morpholine arecoline, and VUO255-035 (N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiazia This includes chloropyrazines, including, but not limited to, L-687, 306, L-689-660, 77-LH-28-1, and LY593039, as well as esters, sulfur, or quinicliidine rings having one or more carbon substitutions, including 5 or 6 carbocyclic structures, including substituted nitrogen and / or oxygen, or pharmaceutically acceptable salts, esters, analogs, prodrugs, or derivatives thereof. A preferred M1 / M3 agonist is acequinidine. In preferred embodiments, the muscarinic agonists of the present invention include muscarinic agonists that preferentially activate M1 and M3 over M2, M4, and M5; more preferably, muscarinic agonists that activate M1 over M3. In a more preferred embodiment, the muscarinic agonists of the present invention include those muscarinic agonists that activate only M1.

[0108] The term "acekidine" encompasses acekidine as a racemic mixture, acekidine(+) ​​enantiomers, acekidine(-) enantiomers, acekidine(-) enantiomers, acekidine analogs including highly M1-selective 1,2,5-thiadiazole-substituted analogs, such as those disclosed in Ward, JS et al., 1,2,5-Thiadiazole analogue soface clidine aspotent m1 muscarinicagonists, J.MedChem, 1998, Jan. 29, 41(3), 379-392, as well as acekidine prodrugs including carbamate esters, salts, esters, analogs, prodrugs and derivatives thereof.

[0109] The terms “selective α-2 adrenergic receptor agonist” or “α-2 agonist” encompass all α-2 adrenergic receptor agonists having a binding affinity of 900 times or more to α-2 than to α-1 adrenergic receptors, or 300 times or more to α-2a or α-2b than to α-1 adrenergic receptors. The terms also encompass pharmaceutically acceptable salts, esters, prodrugs, and other derivatives of selective α-2 adrenergic receptor agonists.

[0110] The term "inert gas" refers to a gas that is chemically inert and does not react with other compounds. Inert gases include, but are not limited to, helium, neon, argon, krypton, xenon, radon, and nitrogen.

[0111] The terms “low concentration” or “low dose” of alpha-2 adrenergic receptor agonists refer to concentrations of approximately 0.0001% to approximately 0.065% w / v, more preferably approximately 0.001% to approximately 0.035% w / v; even more preferably approximately 0.01% to approximately 0.035% w / v; and even more preferably approximately 0.03% to approximately 0.035% w / v.

[0112] The term "brimonidine" encompasses, without limitation, brimonidine salts and other derivatives, and specifically includes, but is not limited to, brimonidine tartrate, 5-bromo-6-(2-imidazoline-2-ylamino)quinoxaline D-tartrate, and Alphagan®.

[0113] The terms “to treat” and “treatment” refer to the reversal, alleviation, suppression or delay of the progression of a disease, disorder or condition to which such terms apply, or one or more symptoms of such disease, disorder or condition.

[0114] The term "pharmaceutically acceptable" describes materials that are not biologically or otherwise undesirable (i.e., do not cause undesirable biological effects at unacceptable levels or interact in an adverse manner).

[0115] As used herein, the term “pharmaceutically effective amount” means, without limitation, a quantity sufficient to produce a desired biological effect, such as a beneficial outcome, including the prevention, reduction, remission, or elimination of signs or symptoms of a disease or disorder. Thus, the total amount or method of each active component of a pharmaceutical composition is sufficient to demonstrate a meaningful target benefit. Therefore, “pharmaceutically effective amount” will depend on the context in which it is administered. A pharmaceutically effective amount may be administered in one or more prophylactic or therapeutic doses.

[0116] The term "prodrug" refers to compounds, including monomers and dimers of the compounds of the present invention, that have cleavable groups and become pharmaceutically active compounds in vivo under physiological conditions, but are not limited to the following.

[0117] As used herein, “salt” refers to a salt that retains the biological efficacy and properties of the parent compound and is not biologically or otherwise harmful at the administered dose. Salts of the compounds of the present invention can be prepared from inorganic or organic acids or bases.

[0118] The term "higher-order aberration" refers to aberrations in the field of view selected from starburst, halo (spherical aberration), diplopia, multiple images, blemishes, coma aberration, and trefoil aberration.

[0119] The term "cold chain" refers to storage at a temperature of approximately 2 to 8°C from manufacturing to immediately before administration.

[0120] The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids or bases. The phrase "pharmaceutically acceptable salt" means a salt that, within the bounds of sound medical judgment, is free from excessive toxicity, irritation, and allergic reactions, is suitable for use in contact with human and lower animal tissues, and corresponds to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1 et seq.

[0121] The salt can be prepared in situ during the final isolation and purification of the compound of the present invention, or separately by reacting the free basic functional group with a suitable organic acid. Typical acid addition salts include, but are not limited to, acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, 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. Furthermore, the basic nitrogen-containing group can be quaternized with agents 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 sulfate; long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and arylalkyl halides such as benzyl and phenethyl bromide and others. Water- or oil-soluble or dispersible products are obtained thereby. 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, as well as organic acids such as oxalic acid, malic acid, maleic acid, metanosulfonic acid, succinic acid, and citric acid.

[0122] Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the present invention by reacting the carboxylic acid-containing portion with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal-based cations such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts, as well as non-toxic quaternary ammonia and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and especially ethylammonium. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0123] The term "ester" as used herein refers to formula -OC(O)A 1 or -C(O)OA 1 It is expressed by, in the formula, A 1 This can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl group, or other suitable substituent.

[0124] Composition of the present invention In one embodiment, the present invention relates to an ophthalmic composition comprising acelyzine. In a preferred embodiment, the acelyzine is present at a concentration of about 0.25% w / v to about 2.0% w / v, more preferably about 0.50% w / v to about 1.90% w / v, even more preferably about 1.65% w / v to about 1.85% w / v, and most preferably about 1.75% w / v. Since acelyzine is an asymmetric tertiary amine, both + and - optical isomers exist (in some studies, the (+) is thought to be potent, and in others, the (-) is thought to be potent). For the above concentrations, optical rotation analysis has demonstrated that the ratio of (+) and (-) isomers is exactly equal for these concentrations. Therefore, changing this ratio may change this concentration range proportional to the change in the ratio.

[0125] The present invention further relates to an ophthalmic composition comprising a muscarinic agonist, preferably a nonionic surfactant exceeding its critical micelle concentration for the composition, and a viscous agent; or, as an alternative, an in situ gelling agent. In a preferred embodiment, the initial viscosity of the composition upon topical application is greater than 20 cps at low shear (1 / s), preferably greater than 50 cps, and more preferably greater than 70 cps.

[0126] Antifreezing agents are compounds that prevent freezing or prevent damage to compounds during freezing. As used herein, the terms “antifreezing agent” or “antifreezing agent (plural)” include cryoprotectants. Antifreezing agents suitable for use in the present invention include, but are not limited to, polyols, sugars, alcohols, lower alkanols, lipophilic solvents, hydrophilic solvents, fillers, solubilizers, surfactants, antioxidants, cyclodextrins, maltodextrins, colloidal silicon dioxide, polyvinyl alcohol, glycine, 2-methyl-2,4-pentanediol, cellobiose, gelatin, polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), formamide, antifreeze protein 752, or combinations thereof.

[0127] As used herein, the term “polyol” refers to a compound having multiple hydroxyl functional groups available for organic reactions, such as monomer polyols including glycerin, pentaerythritol, ethylene glycol, and sucrose. Furthermore, polyol may refer to a polymer polyol containing glycerin, pentaerythritol, ethylene glycol, and propylene oxide or sucrose reacted with ethylene oxide. In preferred embodiments, the polyol is selected from the group consisting of mannitol, glycerol, erythritol, lactitol, xylitol, sorbitol, isosorbide, ethylene glycol, propylene glycol, maltitol, treitol, arabitol, and ribitol. In more preferred embodiments, the polyol is mannitol.

[0128] Suitable sugars for use as antifreeze agents in the present invention include, but are not limited to, glucose, sucrose, trehalose, lactose, maltose, fructose, and dextran.

[0129] In another preferred embodiment, the alcohol includes, but is not limited to, methanol.

[0130] In one embodiment, the present invention excludes each antifreeze agent individually from the definition of an antifreeze agent.

[0131] The antifreeze agent can currently be present in the composition of the present invention at a concentration of about 0.1% to about 99% w / v, preferably about 1% to about 50% w / v, and more preferably about 1% to about 10% w / v.

[0132] Lower alkanols suitable for use in the present invention include, but are not limited to, amyl alcohol, butanol, sec-butanol, t-butyl alcohol, n-butyl alcohol, ethanol, isobutanol, methanol, isopropanol, and propanol.

[0133] Suitable bulking agents for use in the present invention include, but are not limited to, sugars, polyvinylpyrrolidone, cyclodextrin, and trehalose.

[0134] Suitable solubilizers for use in the present invention include, but are not limited to, cyclic amides, gentisic acid, and cyclodextrins.

[0135] In preferred embodiments, surfactants suitable for use in the present invention include, but are not limited to, nonionic surfactants, more preferably surfactants having a hydrophilic-lipophilic balance ("HLB") value of 1 to 18.

[0136] In preferred embodiments, antioxidants suitable for use in the present invention include, but are not limited to, bisulfites, ascorbic acid, disodium ethylenediaminetetraacetate or tetrasodium ethylenediaminetetraacetate, citrates, butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), sulfoxylates, propyl gallate, amino acids containing a thio group, and thiols.

[0137] Suitable nonionic surfactants 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 108, poloxamer 188, poloxamer 407, polysorbate 20, polysorbate 80, cyclodextrins with or without ionically charged (e.g., anionic) beta-butyric acid (Captisol®), 2-hydroxypropyl beta-cyclodextrin ("HPβCD"), alpha-cyclodextrin, gamma-cyclodextrin, polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil, or combinations thereof. Furthermore, substitution with other nonionic surfactants compatible with ophthalmic use allows for the benefits of similar formulations, including, but not limited to, poloxamer, poloxamer 103, poloxamer 123, and poloxamer 124, poloxamer 407, poloxamer 188, and poloxamer 338, any poloxamer analog or derivative, polysorbate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, any polysorbate analog or derivative, cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated β-cyclodextrin, β-cyclodextrin sulfo Butyl ether, γ-cyclodextrin sulfobutyl ether or glucosyl-β-cyclodextrin, any 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, octiphenol ethoxylate, nonylphenol ethoxylate, capriol, lauroglycol, polyethylene glycol ("PEG"), Brij® 35, 78, 98,700 (polyoxyethylene glycol alkyl ether), glyceryl laurate, lauryl glucoside, decyl glucoside, or cetyl alcohol; or amphoteric surfactants such as palmitoyl carnitine, cocamide DEA, cocamide DEA derivative cocamidopropyl betaine, or trimethylglycine betaine, N-2(2-acetamide)-2-aminoethanesulfonic acid (ACES), N-2-acetamidoiminodiacetic acid (ADA), N,N-bis(2-Hydro) (Roxyethyl)-2-aminoethanesulfonic 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-P Perazine propanesulfonic 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) (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), Tyroxapol, Solulan, TMThe present invention may include one or more nonionic surfactants such as C-24 (2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxy]ethanol) and Solulan® 20-80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, and sorbitan monooleate). In certain embodiments, the addition of an anionic surfactant such as sodium lauryl sulfate and / or sodium lauryl sulfate ester may be preferred. In other embodiments, the addition of polysorbate 80 is preferred. In addition to the above nonionic surfactants, any nonionic surfactant is suitable for use in the present invention, as long as the concentration of the nonionic surfactant exceeds the critical micelle concentration of that nonionic surfactant. Preferably, the nonionic surfactant used in the present invention achieves submicron diameter micelles, more preferably less than 200 nanometers, and more preferably less than 150 nanometers in diameter.

[0138] In ophthalmic in situ gels, which may be added in place of or in addition to one or more nonionic surfactants, include, but are not limited to, gelatin, carbomers 934P and 974P of various molecular weights, carbopol, xanthan gum, alginic acid (alginate), guar gum, locust bean gum, chitosan, pectin, and other gelling agents well known to experts in the art.

[0139] 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.

[0140] In these preferred embodiments, polyoxyl 40 stearate is found to preferentially enhance the hyperemia-reducing effect, particularly in the presence of an α-2 agonist, compared to aqueous solutions and other nonionic surfactants such as poloxamer 407 and β-cyclodextrin.

[0141] In other preferred embodiments, the nonionic surfactant is polysorbate 80 in a concentration of about 0.5% to about 10% w / v, more preferably about 1% to about 7% w / v, and even more preferably about 2% to about 5% w / v, even more preferably about 2.5% to about 4% w / v, and most preferably about 2.5%, 2.75%, 3%, 4%, or 5% w / v.

[0142] Suitable viscous agents for the present invention include, but are not limited to, guar gum, hydroxypropyl guar ("hp guar"), xanthan gum, alginate, chitosan, gellite, hyaluronic acid, dextran, Carbopol (registered trademark) (polyacrylic acid or carbomer), including the Carbopol (registered trademark) 900 series including Carbopol (registered trademark) 940 (carbomer 940), Carbopol (registered trademark) 910 (carbomer 910) and Carbopol (registered trademark) 934 (carbomer 934), cellulose derivatives such as carboxymethylcellulose ("CMC"), methylcellulose, methylcellulose 4000, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose 2906, carboxypropyl methylcellulose, hydroxypropyl ethylcellulose, and hydroxyethylcellulose, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, gellan, carrageenan, aloic acid, carboxyvinyl polymer, or combinations thereof.

[0143] In a preferred embodiment, the viscous agent will have an equilibrium viscosity of less than 100 cps, preferably about 15 to about 35 cps, most preferably about 30 cps. In a preferred embodiment, the viscous agent is Carbopol® 940 (carbomer 940) at a concentration of about 0.05% to about 1.5% w / v, preferably about 0.09% to about 1.0% w / v, more preferably 0.09%, 0.25%, 0.5%, 0.75%, 0.9%, or 1.0% w / v. In such circumstances, particularly in the case of polyoxyl, in a preferred embodiment, polyoxyl 40 stearate, and in the case of cellulose derivatives, particularly hydroxypropyl methylcellulose, the use of non-polysaccharide derivatives for viscosity enhancement, such as polyacrylic acid derivatives (carbomer, carbomer 934, or 940 in a preferred embodiment), may hinder such separation. Alternatively, a non-polyoxyl nonionic surfactant such as polysorbate 80, which contains either a cellulose derivative or a non-cellulose derivative viscosity agent, may be used as a substitute.

[0144] In another preferred embodiment, the viscous agent is carboxymethylcellulose in a concentration of about 1% to about 2% w / v, more preferably 1.35% to about 1.45% w / v, and most preferably 1.42% w / v or 1.40% w / v.

[0145] In another preferred embodiment, the viscous agent is hydroxypropyl methylcellulose in a concentration of about 0.5% to about 1.75%, more preferably about 0.75% or 1.5%, even more preferably about 1.0% to about 1.5%, and most preferably about 1.25%.

[0146] While I don't particularly want to get bogged down in theory, the quinuclidine nucleus of the heterocyclic nitrogen on acekidine appears to be very electron-rich, and therefore readily attacks not only itself but also surrounding compounds.

[0147] To enhance the preservation of cold chain stability, in addition to the preferred embodiments, several modifications may be used individually or in combination, including 1.40% to 1.75% aceline, 0.025% to 0.10% tropicamide, and optionally, preferably 5.5% or 0.5% to 10% of non-ioin surfactants such as polyoxyl 40 stearate (see Table 1). This is a discovery of the present invention.

[0148] The acidic pH is preferably less than 5.5, preferably less than 5.0, and most preferably about 4.75.

[0149] The viscous agent preferably has a viscosity of about 15 to 50 cps, more preferably 20 to 45 cps at 25°C, where a preferred embodiment is 0.09% to 1.5% carbomer 940.

[0150] In preferred embodiments, the antifreeze is a polyol, preferably 2.5% to 4.0% mannitol.

[0151] When a buffer solution is added, if an acetate buffer or phosphate buffer is preferred, the amount is preferably in the range of 3 to 5 mmol and 2 to 100 mmol, and

[0152] The preservative added is preferably 0.015% BAK.

[0153] Selective α-2 agonists may be incorporated into the compositions of the present invention, or, if additional means to reduce nasal congestion or congestion are desired for sensitive subjects, they may be applied topically, preferably just a few minutes prior, or less preferably just a few minutes later. Selective α-2 agonists suitable for the present invention have minimal α-1 agonist activity at low concentrations. For example, in the case of brimonidine or fadorumidine, 1%–2% w / v is considered very high, and 0.5%–1.0% w / v highly induces α-1 receptors and is toxic for the purposes of the present invention. Furthermore, 0.10%–0.5% w / v is too high, and 0.070%–0.10% w / v is associated with a higher incidence of rebound hyperemia than the preferred incidence (however, in the case of dexmedetomidine, its high lipophilicity and intraocular penetration reduce the risk of rebound in this range). Only concentrations of 0.065% w / v or less are potentially acceptable, but for many α-2 agonists, concentrations of 0.050% w / v, and more preferably 0.035% w / v or less, are desirable depending on selectivity. On the other hand, some useful activity can be achieved at further reductions of more than an order of magnitude in concentration. The brimonidine, fadorumidine, and guanfacine of preferred embodiments of the present invention preferentially stimulate α-2 adrenergic receptors, and more preferably α-2b adrenergic receptors, so that α-1 adrenergic receptors are not sufficiently stimulated to cause excessive arteriolar stenosis and vasoconstrictive ischemia. In addition, it has been found that preventing or suppressing congestion with drugs that would otherwise directly cause congestion, such as acetylcholine agonists and aceline, improves compliance in sensitive subjects who might otherwise experience congestion or nasal congestion even with formulations of the present invention that do not contain α-2 agonists. However, since the α-2 agonist shifts to its ionization equilibrium, the acidic pH is somewhat offset by the fact that the agonist exhibits a higher effect at neutral or alkaline pH. Therefore, each α-2 agonist has a preferred pH range depending on its pKa value and lipophilicity when added to the composition of the present invention containing aceline. In the present invention, a pH range of 5.0 to 8.0 is acceptable, but the pH of a preferred embodiment is 5.5 to 7.5, more preferably 6.5 to 7.0.Furthermore, it has been discovered that a higher whitening effect is produced when an α-2 agonist is incorporated into the composition instead of poloxamer 407, either as a nonionic surfactant component or as a single nonionic surfactant, by using cyclodextrin and / or polyoxyl 40 stearate. Although the α-2 agonist is not necessary except for occasionally sensitive subjects, the α-2 agonist may be applied separately or, in certain preferred embodiments, together with formulations of the present invention that do not contain an α-2 agonist, such as formulations having 5.5% w / v polyoxyl 40 stearate as a nonionic surfactant. Fadolmidine corresponds to an α-2 agonist with the highest hydrophilicity, and therefore, in the case of the present invention, high surface retention. Guanfacine is also highly selective and hydrophilic. Brimonidine is highly selective and has moderate lipophilicity. Finally, dexmedetomidine is highly selective and lipophilic and can be used with low efficacy to reduce hyperemia for the purposes of the present invention (however, it may cause fatigue as a side effect in some patients). In a preferred embodiment, using 5.5% w / v polyoxyl 40 stearate, 0.80% w / v CMC, 0.037% w / v NaCl, 0.015% w / v EDTA, 5 mM borate buffer and 0.007% w / v BAK results in hyperemia of about 1.0 to 1.5 out of 4 points, which lasts temporarily for about 10 minutes and returns to near baseline by 30 minutes.

[0154] In one embodiment, the selective α-2 adrenergic receptor agonist is a compound having a binding affinity of about 900 or more, more preferably about 1000 times or more, and most preferably about 1500 or more.

[0155] Selective α-2 adrenergic receptor agonists may be present at concentrations of approximately 0.0001% to approximately 0.065% w / v, more preferably approximately 0.001% to approximately 0.035% w / v, even more preferably approximately 0.01% to approximately 0.035% w / v, and even more preferably approximately 0.020% to approximately 0.035% w / v.

[0156] In one embodiment, the selective α-2 adrenergic receptor is selected from the group consisting of brimonidine, guanfacine, fadorumidine, dexmedetomidine, (+)-(S)-4-[1-(2,3-dimethylphenyl)-ethyl]-1,3-dihydroimidazole-2-thione, 1-[(imidazolidine-2-yl)imino]indazole, and mixtures of these compounds. Analogues of these compounds that function as highly selective α-2 agonists may also be used in the compositions and methods of the present invention.

[0157] In a more preferred embodiment, the selective α-2 agonist is selected from the group consisting of fadorumidine, guanfacine, and brimonidine. In an even more preferred embodiment, the selective α-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 a tartrate.

[0158] In another, even more preferred embodiment, the selective α-2 agonist is a fadorumidine in the form of a hydrochloric acid ("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.

[0159] In another, even more preferred embodiment, the selective α-2 agonist is guanfacine in the form of an 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.

[0160] In another, even more preferred embodiment, the selective α-2 agonist is dexmedetomidine in the form of an 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.

[0161] In another preferred embodiment, a pH lower than physiological pH has been found to enhance the whitening effect of brimonidine, preferably pH 4.5 to 6.5, more preferably pH 5.5 to 6.0. However, a reduction in congestion is achieved at all pH levels, and the enhancement of aceline absorption occurs at alkaline pH levels, with more effect occurring from certain concentrations onwards. Therefore, while the pH range of 4.5 to 8.0 is effective, in the present invention a pH range of 6.5 to 7.5 is preferred, with 7.0 to 7.5 being most preferred.

[0162] The present invention further relates to an ophthalmic composition further comprising a ciliary muscle paralyzer. The surprising and entirely unexpected discovery of the present invention is that certain ciliary muscle paralyzers can be combined with miotics without reducing the onset, magnitude, or duration of pupillary constriction, particularly in the present invention, and further blunt the spikes usually associated with the miotic effect, which coincide with the time of peak absorption in aqueous formulations, to provide a constant pupillary constriction from 15-30 minutes to 6-10 hours with respect to the time after onset, depending on the desired formulation. The addition of a ciliary muscle paralyzer also reduces discomfort associated with residual effects that may occur immediately after topical instillation, possibly as a result of ciliary spasm or excessive pupillary constriction.

[0163] Suitable ciliary muscle paralyzing agents for the present invention include, but are not limited to, atropine, Cyclogyl® (cyclopentolate hydrochloride), hyostine, pirenzepine, tropicamide, atropine, 4-diphenylacetoxy-N-methylpiperidine metobromide (4-DAMP), AF-DX384, metoctramine, tripitramine, dalifenacin, solifenacin (Vesicare), tolterodine, oxybutynin, ipratropium, oxytropium, tiotropium (Spriva), and otenzepad (also known as AF-DX116 or 11-{[2-(diethylamino)methyl]-1-piperidinyl}acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepine-6-one). In a preferred embodiment, the ciliary muscle paralyzer is tropicamide at a concentration of about 0.004% to about 0.025% w / v. More preferably, about 0.005% to about 0.015% w / v, and even more preferably, about 0.005% to about 0.011% w / v, about 0.005% to about 0.007% w / v, and about 0.005% to about 0.006% w / v. In another preferred embodiment, the ciliary muscle paralyzer is tropicamide at a concentration of about 0.04% to about 0.07% w / v, or a mixture of pirenzepine or otensepad at a concentration of about 0.002% to about 0.05% w / v.

[0164] In preferred embodiments, 0.01% w / v tropicamide slightly reduced supraorbital pain, 0.030% w / v further reduced supraorbital pain, and 0.04% w / v to approximately 0.07% w / v completely eliminated supraorbital pain, with no decrease in mean pupillary constriction diameter over the duration of the effect. Tropicamide in preferred embodiments demonstrated entirely unexpected efficacy sensitivity, here, at approximately 0.04% w / v unexpectedly and very effectively reduced or eliminated supraorbital pain and ciliary spasm pain, at 0.042% w / v it was reduced very significantly further, and (surprisingly, due to its common use as a pupillary dilator) there was no cycloplegia at 0.044% w / v in preferred embodiments. Furthermore, tropicamide did not reduce the mean degree of pupillary constriction, the time of onset of pupillary constriction, or subsequent visual benefits. On the contrary, tropicamide produced a smooth, consistent miotic effect over time by blunting the peak miosis seen in aqueous formulations. This allowed the modulation of peak pupillary constriction to achieve greater effectiveness over time without the dilution seen in its conventional use. Specifically, tropicamide is useful in some embodiments to prevent transient constriction of less than 1.50 mm in 30–60 minutes following aceline, and to reduce transient, excessive, and undesirable blurring of vision that may otherwise occur with a peak onset of approximately 30 minutes. For example, an ophthalmic composition containing 1.53% w / v aceline, 5% w / v HPβCD, 0.75% w / v CMC, 0.25% w / v NaCl, 0.01% w / v BAK, and pH 7.0 phosphate buffer; or 1.45% w / v aceline; 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 pH 7.0 5 mM phosphate buffer was changed from 0.040% w / v tropicamide, which caused moderate blurring, to 0.044% w / v tropicamide, which made the blurring almost undetectable except in extremely dim light conditions.This additional pupil size adjustment using a ciliary muscle paralyzer allows for a sufficient acecilyne concentration for a prolonged effect while numbing undesirable associated peak hyperconstriction, as well as unpleasant supraorbital pain. Surprisingly, and due to its short-acting nature, tropicamide achieves this numbing effect without causing pupillary dilation. Furthermore, in preferred embodiments, 0.014% w / v tropicamide reduced supraorbital pain, 0.021% w / v further reduced it, and 0.028% w / v to 0.060% w / v, and in some embodiments, up to 0.09% w / v, were found to completely eliminate supraorbital pain without cycloplegia (i.e., paralysis of the ciliary muscle of the eye).

[0165] In the case of a racemic 50:50 mixture of (+) and (-) acekidine optical isomers (some studies suggest (+) is more potent, while others suggest (-) is more potent), it has been found that the tropicamide effect may differ depending on the acekidine to tropicamide ratio. For example, in the ophthalmic composition of the present invention comprising 1.55% w / v acekidine, 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 may be distinguished from 0.035% w / v, the former exhibiting normal indoor night vision, and the latter exhibiting slight blurring, which becomes more pronounced at lower concentrations. At higher concentrations, such as tropicamide at approximately 0.075% to 0.090% w / v, a loss of pupillary constriction in the preferred range of 1.50 mm to 1.80 mm begins, and at even higher concentrations, obvious mydriasis starts. Since the isomer ratio changes the effective concentration, this must be a factor in the clinical effect predicted with aceline. In the preferred embodiment of the present invention, a polarimeter (Toronto Research Chemicals) was used to determine the exact 50:50 isomer ratio.

[0166] Figure 1 shows the effects of miotics with and without ciliary muscle paralyzing agents and with and without carriers. The subjects were emmetropic individuals aged 45 years or older with baseline near visual acuity of 20.100 and baseline distance visual acuity of 20.20. Topical administration of 1% w / v pilocarpine in saline improved near visual acuity to 20.40 (8a), but this improvement came at the expense of a decrease in distance visual acuity to 20.100 (8b). 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). However, in some cases, slight irregular astigmatism was induced (a slightly blemished area in the reading field of vision). Topical application of 1.55% w / v acecilidine in saline improved near visual acuity to 20.40 over a long period of 6 hours without affecting baseline distance visual acuity (10b) (10a). Figures 10c and 10d show the effect of administering aceline in a carrier 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 carrier enhances the effective effect of aceline, resulting in near visual acuity of 20.20 or higher. 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 aceline in the carrier. As seen in 10e, near visual acuity improves to 20.15 with rapid onset of maximum visual acuity. As seen in 10f, a similar improvement in distance visual acuity is observed. In summary, Figure 1 shows that aceline can temporarily correct near visual acuity in presbyopic subjects without affecting baseline distance visual acuity. Similar results were obtained when a ciliary muscle paralyzing agent such as tropicamide was added.

[0167] The present invention further relates to an ophthalmic composition comprising a tonicity modifier and a preservative.

[0168] The tension modifier may be, but is not limited to, a salt such as sodium chloride ("NaCl") or potassium chloride, mannitol or glycerin, or another pharmaceutically or ophthalmologically acceptable tension modifier. In a particular embodiment, the tension modifier is 0.037% w / v NaCl.

[0169] Preservatives that may be used in the present invention include, but are not limited to, benzalkonium chloride ("BAK"), sorbic acid, oxychloro complex, citric acid, chlorobutanol, thimerosal, phenylmercury acetate, disodium ethylenediaminetetraacetate, phenylmercury nitrate, perborate, or benzyl alcohol. In preferred embodiments, the preservative is BAK, sorbic acid, oxychloro complex, or a combination thereof. In a more preferred embodiment, the BAK is present at a concentration of about 0.001% to about 1.0% w / v, more preferably at a concentration of about 0.007%, 0.01%, or 0.02% w / v. In another preferred embodiment, the preservative is a perborate at a concentration of 0.01% to about 1.0% w / v, more preferably at a concentration of about 0.02% w / v.

[0170] The ophthalmic compositions of the present invention can be prepared using various buffers and means for adjusting the pH. Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, and borate buffers. It is understood that the pH of the composition can be adjusted as needed, preferably to a concentration of 1 to 10 mM, more preferably to about 3 mM or 5 mM, using an acid or base. 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.

[0171] The present invention further relates to ophthalmic compositions further comprising antioxidants. Antioxidants that can be used in conjunction with the present invention include, but are not limited to, disodium ethylenediaminetetraacetate in concentrations of about 0.005% w / v to about 0.50% w / v, citrate in concentrations of about 0.01% w / v to about 0.3% w / v, and dicalcium diethylenetriaminepentaacetate ("Ca2DTPA") in concentrations of about 0.001% w / v to about 0.2% w / v, preferably about 0.01% w / v Ca2DTPA, which can be formulated by adding 0.0084% w / v Ca(OH)2 and 0.0032% w / v pentetic acid to the formulation and slowly mixing. Further combinations of antioxidants may be used. Other antioxidants that can be used in conjunction with the present invention include those well known to experts in the art, such as ethylenediaminetetraacetic acid at concentrations of about 0.0001% w / v to about 0.015% w / v.

[0172] It is a surprising and unexpected discovery that one of the preferred embodiments of the topical formulation of the present invention, particularly one comprising 1.35% w / v to 1.55% w / v aceline; 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, provides significantly extended contact lens wear and comfort after a single daily topical instillation. The single daily use of the preferred embodiment has enabled subjects with dry eye to sleep with lenses in for up to a week, whereas previously they had to remove, clean, or replace film-coated contact lenses even overnight due to blurred vision (see Example 7).

[0173] In a preferred embodiment, the ophthalmic composition of the present invention comprises aceline, an antifreeze agent, optionally a ciliary muscle paralyzing agent, a nonionic surfactant in a concentration of about 1% to about 5% w / v, and a viscous agent in a concentration of about 0.75% to about 1.6% w / v, preferably about 1.25% to about 1.5% w / v.

[0174] The following representative embodiments are provided for illustrative purposes only and are not intended to limit the invention in any way.

[0175] <Typical Embodiments> In one embodiment, the ophthalmic composition comprises the following: Aceline at a concentration of approximately 1.75% w / v; and Mannitol at a concentration of approximately 2.5% w / v.

[0176] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Mannitol at a concentration of approximately 2.5% w / v; and Tropicamide at a concentration of approximately 0.02% w / v.

[0177] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 5.0% w / v; Carboxymethylcellulose at a concentration of approximately 1.4% w / v; BAK at a concentration of approximately 0.015% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM, Here, the pH is approximately 5.

[0178] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 0.5% w / v; NaCl with a concentration of approximately 0.10% to 0.50% w / v; Carbopol® 940 at a concentration of approximately 0.95% w / v; BAK at a concentration of approximately 0.01% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM, Here, the pH is approximately 5.

[0179] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 2.0% w / v; NaCl with a concentration of approximately 0.50% w / v Carbopol® 940 at a concentration of approximately 1.5% w / v; BAK at a concentration of approximately 0.015% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM, Here, the pH is approximately 5.25.

[0180] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 0.25% w / v; NaCl at a concentration of approximately 0.1% w / v; Boric acid at a concentration of approximately 0.12% w / v; Carbopol® 940 at a concentration of approximately 0.95% w / v; and BAK at a concentration of approximately 0.015% w / v; Here, the pH is approximately 5.

[0181] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 0.50% w / v; NaCl at a concentration of approximately 0.05% w / v; Boric acid at a concentration of approximately 0.2% w / v; Carbopol® 940 at a concentration of approximately 0.95% w / v; BAK at a concentration of approximately 0.01% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM, Here, the pH is approximately 5.

[0182] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 0.1% w / v; Boric acid at a concentration of approximately 0.2% w / v; Carbopol® 940 at a concentration of approximately 0.9% w / v; BAK at a concentration of approximately 0.05% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM, Here, the pH is approximately 5.

[0183] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 0.1% w / v; NaCl at a concentration of approximately 0.1% w / v; Boric acid at a concentration of approximately 0.12% w / v; Carbopol® 940 at a concentration of approximately 0.95% w / v; BAK at a concentration of approximately 0.01% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM, Here, the pH is approximately 5.

[0184] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Tropicamide at a concentration of approximately 0.01% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 5.0% w / v; CMC concentration of approximately 1.4% w / v; BAK at a concentration of approximately 0.015% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM, Here, the pH is approximately 5.

[0185] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Tropicamide at a concentration of approximately 0.02% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 0.25% w / v; NaCl at a concentration of approximately 0.1% w / v; Boric acid at a concentration of approximately 0.12% w / v; Carbopol® 940 at a concentration of approximately 0.95% w / v; and BAK at a concentration of approximately 0.01% w / v. Here, the pH is approximately 5.

[0186] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Tropicamide at a concentration of approximately 0.015% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 0.75% w / v; NaCl at a concentration of approximately 0.05% w / v; Boric acid at a concentration of approximately 0.2% w / v; Carbopol® 940 at a concentration of approximately 0.95% w / v; BAK at a concentration of approximately 0.01% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM. Here, the pH is approximately 5.

[0187] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Tropicamide at a concentration of approximately 0.025% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 0.1% w / v; Boric acid at a concentration of approximately 0.2% w / v; Carbopol® 940 at a concentration of approximately 0.9% w / v; BAK at a concentration of approximately 0.05% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM. Here, the pH is approximately 5.

[0188] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Tropicamide at a concentration of approximately 0.02% w / v; Mannitol at a concentration of approximately 2.5% w / v; Polysorbate 80 at a concentration of approximately 0.1% w / v; NaCl at a concentration of approximately 0.1% w / v; Boric acid at a concentration of approximately 0.12% w / v; Carbopol® 940 at a concentration of approximately 0.95% w / v; BAK at a concentration of approximately 0.01% w / v; and A phosphate buffer solution with a concentration of approximately 3 mM. Here, the pH is approximately 5.

[0189] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.75% w / v; Tropicamide at a concentration of approximately 0.040% w / v; Polyoxyl 40 stearate at a concentration of approximately 5.0% w / v; Mannitol at a concentration of approximately 2.5% w / v; Acetic acid or phosphate buffer at a concentration of approximately 3.0 mM; and BAK at a concentration of approximately 0.01% w / v, Here, the composition has a pH of approximately 4.75.

[0190] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.55% w / v; Tropicamide at a concentration of approximately 0.040% w / v; Polyoxyl 40 stearate at a concentration of approximately 5.0% w / v; Citric acid monohydrate at a concentration of approximately 0.1% w / v; Mannitol at a concentration of approximately 4.0% w / v; Carbopol® 940 at a concentration of 0.09% w / v; and Acetate or phosphate buffer solution at a concentration of approximately 3.0 mM; Here, the composition has a pH of about 5.0.

[0191] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.50% w / v; Tropicamide at a concentration of approximately 0.042% w / v; Polyoxyl 40 stearate at a concentration of approximately 5.5% w / v; Mannitol at a concentration of approximately 2.5% w / v; Phosphate buffer solution with a concentration of approximately 3.0 mM; Carbopol® 940 at a concentration of approximately 0.85% w / v; and BAK at a concentration of approximately 0.01% w / v, Here, the composition has a pH of approximately 4.75.

[0192] In another embodiment, The ophthalmic composition includes the following: Aceline at a concentration of approximately 1.45% w / v; Tropicamide at a concentration of approximately 0.042% w / v; Polyoxyl 40 stearate at a concentration of approximately 5.5% w / v; Citric acid monohydrate at a concentration of approximately 0.1% w / v; Acetate buffer solution at a concentration of approximately 3.0 mM; and Carbopol® 940 at a concentration of approximately 0.75% w / v, Here, the composition has a pH of approximately 4.75.

[0193] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of approximately 1.45% w / v; Tropicamide at a concentration of approximately 0.042% w / v; Polyoxyl 40 stearate at a concentration of approximately 5.5% w / v; Mannitol at a concentration of approximately 2.0% w / v; Citric acid monohydrate at a concentration of approximately 0.1% w / v; A phosphate buffer solution with a concentration of approximately 3.0 mM; and Carbopol® 940 at a concentration of approximately 1.0% w / v, Here, the composition has a pH of approximately 4.75.

[0194] In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; Approximately 2.5% w / v mannitol; Polysorbate 80 at approximately 2.75% w / v; and Approximately 1.25%; 1.0%~1.80% w / v hydroxypropyl methylcellulose (depending on molecular weight).

[0195] In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; Approximately 0.005% to 0.011% tropicamide; Approximately 2.5% w / v mannitol; Polysorbate 80 at approximately 2.75% w / v; and Approximately 1.25%; 1.0%~1.80% w / v hydroxypropyl methylcellulose (depending on molecular weight).

[0196] In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; Approximately 0.010% w / v tropicamide; Approximately 2.5% w / v mannitol; Approximately 5.0% w / v polysorbate 80; High viscosity carboxymethylcellulose with approximately 1.40% w / v; Approximately 3mM phosphate buffer; and Approximately 0.010% BAK = as a preservative, at a pH of approximately 5.0.

[0197] In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; Approximately 0.006% w / v tropicamide; Approximately 2.5% w / v mannitol; Approximately 2.5% w / v polysorbate 80; Approximately 1.25%; 1.0%~1.80% w / v hydroxypropyl methylcellulose (depending on molecular weight); Approximately 3mM phosphate buffer; and Approximately 0.020% BAK = as a preservative, at a pH of approximately 5.0.

[0198] In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; Approximately 0.006% w / v tropicamide; Approximately 2.5% w / v mannitol; Approximately 2.5% w / v polysorbate 80; Approximately 1.25%; 1.0%~1.80% w / v hydroxypropyl methylcellulose (depending on molecular weight); Approximately 3mM phosphate buffer; Approximately 0.50% w / v NaCl; and Approximately 0.020% BAK = as a preservative, at a pH of approximately 5.0.

[0199] In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; Approximately 2.5% w / v mannitol; Approximately 3.5% w / v polysorbate 80; Approximately 1.25%; 1.0%~1.80% w / v hydroxypropyl methylcellulose (depending on molecular weight); Approximately 3mM phosphate buffer; Approximately 0.50% w / v NaCl; and As a preservative, use approximately 0.020% BAK or 0.15% sorbic acid, at a pH of approximately 5.0.

[0200] In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; Approximately 2.5% w / v mannitol; Approximately 3.5% w / v polysorbate 80; and Approximately 1.25%; 1.0%~1.80% w / v hydroxypropyl methylcellulose (depending on molecular weight); In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; Approximately 2.5% w / v mannitol; Approximately 3.5% w / v polysorbate 80; Approximately 1.25%; 1.0%~1.80% w / v hydroxypropyl methylcellulose (depending on molecular weight); and One or more excipients selected from the group consisting of approximately 0.50% w / v sodium chloride, approximately 0.02% w / v benzalkonium chloride, approximately 0.10% w / v sorbate, approximately 0.01% w / v ethylenediaminetetraacetic acid (EDTA), and 0.10% w / v citric acid.

[0201] In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; Approximately 2.5% w / v mannitol; Approximately 0.01% w / v tropicamide; Approximately 0.1% w / v sodium citrate, anhydrous; Approximately 0.02% w / v benzalkonium chloride; Approximately 0.12% w / v sorbic acid; Approximately 0.1% w / v disodium edetate dihydrate; Polysorbate 80 at approximately 4.0% w / v; and Approximately 1.25% w / v hydroxypropyl methylcellulose, Here, the pH is approximately 5.0.

[0202] In another embodiment, the ophthalmic composition includes: Approximately 1.75% w / v aceline; About 2.5% w / v mannitol; About 0.01% w / v tropicamide; About 0.1% w / v sodium citrate, anhydrous; About 0.02% w / v benzalkonium chloride; About 0.1% w / v sorbic acid; About 0.1% w / v EDTA; About 3.5% w / v polysorbate 80; and About 1.25%; 1.0% - 2.25% w / v hydroxypropyl methylcellulose (depending on molecular weight), where the pH is about 5.0.

[0203] In another embodiment, the ophthalmic composition comprises: About 1.75% w / v acridine; About 2.5% w / v mannitol; About 0.01% w / v tropicamide; About 3 mM phosphate buffer; About 0.02% w / v benzalkonium chloride; About 0.1% w / v sorbic acid; About 0.1% w / v citrate; About 3.5% w / v polysorbate 80; and About 1.25%; 0.25% - 2.25% w / v hydroxypropyl methylcellulose (depending on molecular weight); where the pH is about 5.0.

[0204] In another embodiment, the ophthalmic composition comprises: Acridine at a concentration of 1.5% w / v, mannitol at a concentration of 2.5% w / v.

[0205] In another embodiment, the ophthalmic composition comprises: Acridine at a concentration of 1.55% w / v, mannitol at a concentration of 2.5% w / v.

[0206] In another embodiment, the ophthalmic composition comprises: Aceline at a concentration of 1.6% w / v, and mannitol at a concentration of 2.5% w / v.

[0207] In another embodiment, the ophthalmic composition includes: 1.65% w / v aceline and 2.5% w / v mannitol.

[0208] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of 1.7% w / v, and mannitol at a concentration of 2.5% w / v.

[0209] In another embodiment, the ophthalmic composition includes: Acelysine at a concentration of 1.75% w / v, and mannitol at a concentration of 2.5% w / v.

[0210] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of 1.80% w / v, mannitol at a concentration of 2.75% w / v, and Carbopol® 940 at a concentration of 0.09% w / v.

[0211] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of 1.48% w / v, mannitol at a concentration of 1.5% w / v, and Carbopol® 940 at a concentration of 0.50% w / v.

[0212] In another embodiment, the ophthalmic composition includes: Aceline at a concentration of 1.80% w / v, mannitol at a concentration of 2.5% w / v, and Carbopol® 940 at a concentration of 0.9% w / v.

[0213] The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way. [Examples]

[0214] [Example 1] Effect of Aceclidine on Vision in Subjects Aged 47 to 67 Table 1 demonstrates the effect on the near-focus ability of presbyopic subjects before and after ophthalmic administration of a composition containing aceclidine. Each composition contained aceclidine at the indicated concentration and 5.5% w / v HPβCD, 0.75% w / v CMC, 0.25% w / v NaCl, and 0.01% w / v BAK. Additionally, the compositions administered to Subjects 4 and 5 contained 0.125% w / v tropicamide. Since aceclidine is an enantiomer, clinical efficacy can vary at different ratios. For this study, an approximately exact 50:50 ratio of stereoisomers was measured and optimized by polarimetry.

[0215] [Table 1]

[0216] As seen in Table 1, all subjects had incomplete near vision (20 / 20) in both the left and right eyes (objects at 15 inches from the eye), and most subjects had incomplete distance vision prior to administration of the composition. After administration of the composition, all subjects experienced an improvement in their near vision that lasted from 7 to 12 hours. Surprisingly, the majority of subjects also experienced an improvement in their distance vision during the same time period. Even more surprisingly, the improvement in the near point was much closer than the 16 inches typically required for comfortable reading and, in some cases, was approximately 8.5 inches, which is more commonly seen in individuals under 30. The addition of tropicamide, a cycloplegic agent, had no additive or detrimental effect on vision correction.

[0217] [Example 2] Effect of Concentrations of Aceclidine and Tropicamide

[0218] [Table 2]

[0219] 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 size, OD indicates the right eye; OS indicates the left eye; OU indicates both eyes.

[0220] All percentages are in w / v. "pt" reflects the size of the printing material, with 4 being equivalent to 20 / 20 visual and 3 being equivalent to 20 / 15 visual.

[0221] "Time" refers to the duration of the effect.

[0222] As shown in Table 2, aceline at a concentration of at least 1.1% w / v was able to reduce pupil size to 1.63 mm one hour after topical instillation, resulting in near and distance visual acuity correction for at least 10 hours. Reducing the concentration of aceline to 0.75% w / v (Formula #3) reduced the miotic effect to 2.0–2.5 mm after one hour, and the visual correction lasted only 6.5 hours. The addition of 0.03% w / v brimonidine reduced ocular redness (without brimonidine, 4 out of 4, not shown) to 1.5 out of 4 within 30 minutes after topical instillation, and this was maintained throughout the period of visual correction. Switching the nonionic surfactant to HPβCD (Formulas #2–6) further reduced ocular redness. Reducing the aceline concentration to 0.75% w / v (prescription #3) further reduced ocular redness, but as described above, it also reduced the duration of visual correction with this prescription.

[0223] Pain and stabbing at the supraorbital margin of the eye were prominent in prescriptions #1–3, which had pain levels of 2 out of 4, accompanied by mild nausea, stomach upset, and fatigue. Surprisingly, the addition of the ciliary muscle paralyzer tropicamide reduced supraorbital pain and stabbing to 0.5 out of 4 and 0 out of 4, respectively, and the supraorbital pain subsided after 60 minutes (prescription #4). Furthermore, increasing the concentration of acecilidine to 1.1% w / v restored corrected vision for a longer duration, as seen in prescriptions #1–2, without increasing ocular conjunctivitis. However, significant supraorbital pain occurred with re-instillation of prescription #4 at the end of 10 hours. Topical instillation of prescriptions #5 (OD) and (OS), along with increasing tropicamide concentration following prescription #4, alleviated the supraorbital pain experienced with reintroduction of prescription #4. At the end of the effective period of prescription #5, a third topical instillation of prescription #5 again resulted in considerable supraorbital pain. Again, with prescription #6, increasing the concentration of tropicamide was able to overcome the supraorbital pain. As an addition and unexpectedly, tropicamide, despite being a ciliary muscle paralyzer, had no effect on pupillary constriction or vision correction. Surprisingly, the addition of tropicamide resulted in an extension of the duration of optimal pupillary size constriction.

[0224] To determine the effect of brimonidine on pupillary constriction, prescription #7 was administered. Administration of prescription #7 resulted in the same improvement in distance and near visual acuity as prescription #5, along with a very slight reduction in pupillary constriction to 1.70 mm. Conjunctival injections were observed in patients 2-3.

[0225] All baseline visual data were based on vision corrected with distance contact lenses. Near visual acuity was observed by subjects to protrude more than 8 inches horizontally 1.5 hours after introduction. All pupil size measurements were performed using a Marco Autorefractor with an infrared camera and a loaded pupil calibration scale. Once an image is selected, it remains displayed on the screen, allowing for accurate calibration.

[0226] [Example 3] Effects of concentrations of aceline, brimonidine, guanfacine, fadormidine, tropicamide, and additives

[0227] [Table 3]

[0228] All percentages are in w / v. Scores for nasal congestion, initial stinging, stinging, 3 minutes, initial congestion, 15 minutes, whitening, pain, and overall are on a scale of 4.

[0229] "pt" reflects the size of the printing material; 4 is equivalent to a 20 / 20 visual, and 3 is equivalent to a 20 / 15 visual.

[0230] Baseline visual acuity was 20.20 for distance vision in both eyes; 20.70 for near vision in the uncorrected right eye; and 20.80 for near vision in the left eye (up to 16 inches).

[0231] D / C indicates that treatment was discontinued after eye washing due to unbearable stinging pain.

[0232] Acecilidine at a concentration of 1.55% w / v could reduce pupil size to approximately 1.63 mm 30 minutes after topical instillation, resulting in corrected near and distance visual acuity of 20.20 or higher for at least 6 hours, with the significant effect lasting approximately 7.5 hours, as seen in Table 3. Reducing the concentration of acecilidine to 1.25% w / v (not shown) resulted in a useful improvement in near visual acuity to approximately 20.25–20.30, but in the higher dose range, alkaline pH was not as effective as it was in producing a faster onset, longer duration, and greater effect. The addition of 0.037% w / v brimonidine reduced ocular redness to baseline within 15 minutes after topical instillation (without brimonidine, 4 out of 4, not shown), and this was maintained for almost the entire duration of visual correction. The addition of 0.10% w / v glycerin significantly reduced stinging sensation. Adding poloxamer 188 0.05% w / v and polyoxyl 40 stearate 0.05% w / v instead further reduced initial stinging, but it was more viscous. The combination of poloxamer 188 0.1% w / v with glycerin 0.1% w / v at pH 6.5 significantly reduced onset, duration, comfort, and efficacy. AB11T, without glycerin, poloxamer 188, or polyoxyl 40 stearate, resulted in substantial stinging and interruption of the experiment, requiring eye flushing immediately after topical instillation. Substituting guanfacine 0.037% w / v for brimonidine in AB12T resulted in minimal initial redness along with prolonged reduction in conjunctivitis and some whitening, and appears to provide the best overall cosmetic effect, although a slightly higher aceline concentration is required for optimal effect.

[0233] All baseline visual data were based on vision corrected with distance contact lenses. Near visual acuity was observed to be 8 to 10 inches horizontally projected 30 minutes after the introduction of AB4T and AB6T lenses, depending on the subject.

[0234] AB4T and AB6T were repeated in both monocular and binocular eyes. Compared to monocular treatment, substantial improvements in depth perception, near point visual acuity to 3pt (0.15), and near point distance (8 inches, 20.20) were observed when both eyes were treated. Monocular treatment resulted in a deterioration of binocular vision compared to testing only the treated eye.

[0235] [Example 4] Effects of the concentrations of aceline, brimonidine, tropicamide, and additives

[0236] [Table 4]

[0237] As seen in Table 4, increasing brimonidine to 0.42% w / v in prescriptions #8-9 resulted in a reduction in congestion to 0.5%, while 0.75% w / v CMC resulted in a watery viscosity. Unexpectedly, in prescriptions #10-11, increasing CMC from 0.75% w / v to the range of 0.80% w / v-0.87% w / v, and increasing NaCl from 0.25% w / v to 0.75% w / v resulted in a thicker viscosity and an increase in residual time from 7 hours to 10-12 hours, reducing the amount of drug discharged into the nasolacrimal duct. This reduced drug delivery via nasal passage resulted in less nasal congestion.

[0238] In prescriptions #13–18, a decrease in the amount of aceline from 1.61% w / v to 1.53% w / v resulted in a pupil size range of 1.8–2.0 mm. Blurred vision resulting from pupillary restriction decreased linearly from 1.5 to 0.5 with decreasing aceline levels. Specifically, pupils of 1.8–2.0 mm produced 41% more light than pupils of 1.5–1.7 mm. Surprisingly, pupils of 1.8–2.0 mm had a near depth of field increase of 1.75 D, which is only a loss of 0.25 D from the beneficial 2.00 D seen in the 1.5–1.7 mm range. Therefore, the 1.80mm-2.0mm range generates 41% more light while also enabling the full benefit of increased near vision in individuals under 60 years of age; on the other hand, individuals 60 years of age and older also experienced the full benefit of improved near vision and some increased near vision.

[0239] An increase in tropicamide concentration from 0.042% w / v (prescriptions #8-#11) to 0.044% w / v (prescriptions #13-#18) resulted in a negligible reduction in pain. The degree of pain may also correlate with the individual's age. For individuals such as those under 45 years of age, an increase in tropicamide concentration to the range of 0.046% w / v to 0.060% w / v may be preferable.

[0240] Furthermore, Table 4 shows the unexpected results observed in prescriptions #13 and #17, where an increase in NaCl from 0.25% w / v to the range of 0.50% w / v to 0.75% w / v resulted in an acceptable hyperemia score of only 1.0, even without the addition of the hyperemia-reducing agent brimonidine.

[0241] Prescriptions #15, #16, and #17 each result in an overall maximum rating of 5 by combining the following benefits: (1) a decrease in aceline concentration to improve the amount of light produced without significantly affecting the near vision benefit seen in prescriptions #8-#12; (2) an increase in NaCl concentration resulting in a further reduction in conjunctivitis even in the absence of brimonidine; and (3) an increase in CMC concentration resulting in a longer retention time on the eye.

[0242] Prescription #19 is an excellent alternative for a small number of individuals who respond well to prescriptions #15-17 and obtain significant blurring with 1.53% w / v aceline. Prescription #20 is an excellent alternative for a small number of individuals who respond poorly to prescription #19. Finally, prescription #21 is an excellent alternative for a small number of individuals who respond poorly and obtain only an insufficient pupillary response with prescription #20.

[0243] [Example 5] Comparison of the effects of polyoxyl 40 stearate, HPβCD, and poloxamer 407

[0244] [Table 5]

[0245] Clinical protocol Twenty presbyopic patients with complete distance correction were each given one of the above prescriptions (#22-#23). All patients underwent distance and near visual acuity measurements, Zeiss Visante® (Visante is a registered trademark of Carl Zeiss Meditec AG) optical coherence tomography, axial length measurement, and contrast visual acuity testing (i.e., Colenbrander-Michelson 10% Lum target) before and after infusion, with the following results: All patients achieved pupil constriction of 1.5 mm to 2.20 mm; The patient did not experience ciliary pain, ciliary spasm, or induction of accommodation; All patients achieved visual acuity of 20 / 30+ or ​​higher at 14 inches, were very satisfied with their high-contrast near vision results, and had no significant complaints of burning or pain; The effects lasted for 6 to 8 hours in all cases. Binocular vision provided all patients with an additional 1–1.5 lines of near visual acuity compared to monocular testing. The last 10 patients were tested at 20 inches (i.e., computer distance, cell phone distance), and all achieved near visual acuity of 20 / 25 or higher; Uncorrected presbyopic individuals with moderate hyperopia (approximately +2.25 spheres) were very satisfied with improved distance visual acuity, reaching levels of 20 / 25 or higher in both distance and near vision within a 20 / 30 range; and Uncorrected distance visual acuity often improved in patients who chose not to routinely correct small refractive errors.

[0246] As seen in Table 5, the use of polyoxyl 40 stearate provides the most comfortable aceline formulation with minimal visual blurring and hyperemia. To achieve similar results to formulation #22, formulation #23 requires a higher concentration of nonionic surfactant than 10–15%, and formulation #24 requires a higher concentration of nonionic surfactant than 15–20%. HPβCD induced a color change over time, likely indicating oxidation. Similar findings were obtained when Captisol® (sulfobutyl ether β-cyclodextrin) was substituted.

[0247] [Example 6] Adjustment of aceline concentration in a preferred embodiment. Preferred embodiment: Aceline 1.35%~1.55% w / v; Polyoxyl 40 stearate 5.5% w / v; NaCl 0.037% w / v; A viscous agent, preferably CMC 0.80% w / v or an amount of Carbopol® 934 or 940 sufficient to achieve a viscosity of about 5 to about 35 cps when applied topically, for example, Carbopol® 940 at a concentration of about 0.09% to about 1.0% w / v; BAK 0.015%w / v; and A solution of approximately 3 to 10 mM phosphate, citrate, citrophosphate, or acetate buffer, where the pH is approximately 4.75 to 6.0.

[0248] Regarding 1.35% w / v aceline - Localized stinging sensation upon instillation: 0.25 / 4.0 (lasts approximately 2-5 seconds). Congestion induced in 10 minutes: 1.0-1.5 / 4.0; Congestion induced in 30 minutes: 0.0~0.25 / 4.0; Comfort: Very high. Moisture: Very high; the eye maintains an improved feeling of moisture for most of the 24-hour period following a single topical instillation. Depth of field of view: Excellent. Depth of focus (near view): Excellent.

[0249] When testing the above formulation in several subjects, we found a slight range in clinical efficacy depending on the concentration of acelinezine, where 1.35% to 1.55% w / v acelinezine is preferred, but concentrations of 1.35% w / v and 1.45% w / v provide the desired benefit to most subjects.

[0250] Furthermore, it was found that the clinical efficacy of 1.35% w / v acekidine can be improved when instilled as follows: 1) Baseline effect: 1 drop in each eye. 2) Enhancement of effect: Apply 2 drops to each eye. 3) Greater effect: Repeat step 1) above after step 2) above. 4) Maximum effect: Repeat step 2) above after step 2).

[0251] [Example 7] Use of a preferred embodiment for extending contact lens wear. Preferred embodiment: Aceline 1.45% w / v; Polyoxyl 40 stearate 5.5% w / v; NaCl 0.037% w / v; A viscous agent, preferably CMC 0.80% w / v or an amount of Carbopol® 934 or 940 sufficient to achieve a viscosity of about 5 to about 35 cps when applied topically, for example, Carbopol® 940 at a concentration of about 0.09% to about 1.0% w / v; BAK 0.02%w / v; and A buffer solution of approximately 3 to 10 mM phosphate, citrate, or acetate, with a pH of approximately 4.75 to 6.0.

[0252] As a baseline, subjects who normally wore daily disposable contact lenses (Air Optix®; Air Optix is ​​a registered trademark of Novartis AG) slept with these lenses in overnight. Each morning upon waking, subjects' vision was blurred, and the contact lenses required cleaning and removal of film and deposits that had formed overnight. Average distance vision upon waking: 20.60; average near vision on the Michelson contrast visual acuity chart: 20.80.

[0253] Next, the above prescription was instilled as a single dose daily between 7:00 AM and 10:00 AM for seven consecutive days. The subjects wore Air Optix® lenses all day and slept with the lenses in overnight. Each morning upon waking, the subjects' distance vision was 20.20+; their uncorrected near vision was 20.40 (this corresponds to the subjects' baseline presbyopia if they did not wear the lenses overnight and instead inserted them upon waking).

[0254] [Example 8] Comparison of the effects of polyoxyl 40 stearate and Captisol® (sulfobutyl ether β-cyclodextrin)

[0255] [Table 6]

[0256] As seen in Table 6, when using polyoxyl 40 stearate as a surfactant, the exclusion of EDTA results in reduced congestion and the highest overall rating among the polyoxyl 40 stearate compositions (formulations #25 and #26). The addition of cocamidopropyl betaine ("CAPB") further reduces congestion but causes significant pain (formulation #31). Replacing polyoxyl 40 stearate with Captisol® (sulfobutyl ether β-cyclodextrin) and adding mannitol achieves similar results in reducing congestion as with the addition of CAPB to polyoxyl 40 stearate, but without the associated pain and resulting in the highest overall rating among the aceline compositions (formulation #32). After several weeks, formulations using Captisol® (sulfobutyl ether β-cyclodextrin) exhibited an orange hue, likely indicating oxidation.

[0257] [Example 9] Preferred cold chain composition composition Aceline at concentrations of approximately 1.40% w / v to 1.80% w / v; and Approximately 0.42% w / v tropicamide; Approximately 5.5% w / v polyoxyl 40 stearate; Mannitol at a concentration of approximately 2.5% w / v to 4.5% w / v; Carbomer 940 at concentrations of approximately 0.09% w / v to approximately 2.0% w / v; Optionally, a preservative such as BAK at a concentration of approximately 0.2% w / v; Selectively, citrate at a concentration of approximately 0.1%; Optionally, 2 to 100 mM, more preferably 3 to 5 mM, acetate buffer or phosphate buffer. Here, the composition has a pH of about 4.5 to about 5.0; preferably about 4.75 to about 5.0; and Here, w / v represents the weight per unit volume.

[0258] The composition described above was administered to a 62-year-old subject. This resulted in pupils of 1.8–1.9 mm ou, reading visual acuity of 20.20+, and distance visual acuity of 20.20+; on the other hand, without carbomer 940, 2.5% mannitol resulted in decreased efficacy, and 4.0% mannitol resulted in no effect on near visual acuity. There was no ciliary spasm or loss of distance visual acuity. Onset occurred within approximately 15 minutes. Approximately 1 in 4 transient hyperemia was observed for approximately 20 minutes without alpha-agonist vasoconstriction. The presence or absence of BAK had no clinical effect and was used to provide an optional preservative.

[0259] [Example 10] Stable aceline formulation Compositions tested: Aceline at a concentration of approximately 1.50% w / v; Tropicamide at a concentration of approximately 0.042% w / v; Polyoxyl 40 stearate at a concentration of approximately 5.5% w / v; Mannitol at a concentration of approximately 2.5% w / v; Citrate at a concentration of approximately 3 mM; Here, the composition has a pH of approximately 4.75.

[0260] Twenty samples of the above composition were equally divided and stored at 25°C and 4°C. Before storage, the initial concentration of aceline was measured using high-performance liquid chromatography (HPLC). The amount of aceline in each solution was calculated by the area under the main peak compared to an aceline reference solution. The samples were then stored for three months. Aceline measurements were performed at one month, two months, and three months. The results of the stability tests are shown in Table 7.

[0261] [Table 7]

[0262] As shown in Table 7, "cold chain storage" or storage of aceline compositions at 2°C to 8°C resulted in a significant increase in aceline stability at all three time points.

[0263] [Example 11] Use of a composition containing little to no ciliary muscle paralyzing agent

[0264] Acelidine alone can cause severe ciliary muscle spasms (supraorbital pain) and myopic blurring, similar to migraines. These effects are inversely correlated with age, with the highest reported incidence in subjects aged 40 and the lowest in subjects aged 60 and older. Addition of ciliary muscle paralyzers alleviates ciliary spasms and associated supraorbital pain, migraines, pressure around the eyes, or other symptoms of ciliary spasms. Surprisingly, the addition of ciliary muscle paralyzers does not reduce the myopic effect of acelidine. However, the addition of 2.5% w / v mannitol reduces the myopic effect of acelidine. Increasing the concentration of acelidine overcomes this reduction in myopic effect observed with mannitol addition.

[0265] However, surprisingly, increased aceline does not correlate with increased ciliary muscle spasms. Even more surprisingly, the concentration of ciliary muscle paralyzers can be reduced or eliminated in the presence of mannitol without increasing ciliary muscle spasms. Therefore, high concentrations of aceline in the presence of mannitol, with little or no combination of ciliary muscle paralyzers, improve near vision without the same side effects as low concentrations of aceline and high concentrations of ciliary muscle paralyzers.

[0266] Furthermore, unexpectedly, the addition of nonionic surfactants increases both the quantitative measurement and duration of near vision improvement. This effect is concentration-sensitive. In preferred embodiments, the nonionic surfactant is at least 1%, preferably at least 2%, more preferably about 1% to about 5%, and most preferably about 5%. For example, polysorbate 80 or polyoxyl 40 stearate at a concentration of about 1% to about 5% w / v results in an improvement of about 1.5 to about 2.0 lines and a duration of about 4 to about 5 hours.

[0267] While I don't want to be confined to any particular theory, increasing surfactant concentration can cause congestion on the corneal surface, and at optimal concentrations, this congestion results in small, possibly nanometer-sized, diameters, and given the bipolarity of the surfactant, this enhances the corneal absorption of captured, highly polar aceline molecules, with nonionic properties being most preferable.

[0268] Adding a viscous agent to the formulation itself does not extend the duration. Surprisingly, adding a viscous agent to a formulation containing the optimal ratio of aceline, tropicamide, and a nonionic surfactant dramatically improves the duration. For example, the formulation of the present invention containing 1.75% aceline, 2.5% mannitol, 0.01% tropicamide, and 5% polysorbate 80 improves near visual acuity in presbyopic patients for approximately 4 to 5 hours with a maximum of 3-line vision. Adding 1.4% CMC further increases the improvement in near visual acuity to approximately 7 to 10 hours. While we do not wish to be bound by any particular theory, thresholds exceeding the critical micelle threshold significantly enhance penetration through the cornea by reducing micelle size from micrometers to nanometers. See Figure 2.

[0269] Table 8 below shows examples of compositions that contain little to no ciliary muscle paralyzing agents.

[0270] [Table 8-1]

[0271] [Table 8-2]

[0272] [Table 8-3]

[0273] [Table 8-4]

[0274] [Table 8-5]

[0275] [Table 8-6]

[0276] [Table 8-7]

[0277] [Table 8-8]

[0278] The effectiveness index is shown in Figure 3. Briefly, the score is calculated by multiplying the improvement line in near vision by the number of hours the improvement continues. For example, the scores are as follows: 5 corresponds to a +1 line improvement in near vision over 5 hours, 10 corresponds to a +1.5 line improvement over 6.7 hours, 15 corresponds to a 2 line improvement over 7.5 hours, 20 corresponds to a 2.5 line improvement over 8 hours, 25 corresponds to a 3+ line improvement over 8.3 hours, and 35 corresponds to a 3.75+ line improvement over 9 hours.

[0279] As demonstrated by comparing the baseline readings and efficacy indices at 40cm for prescriptions #L33 to #L37, prescriptions containing 1.40% or higher aceline are superior in correcting presbyopia than prescriptions containing 1.25% aceline. Conversely, lower concentrations of aceline improve overall user comfort. Adding 2.5% mannitol to a 1.45% aceline prescription improves overall comfort but reduces the presbyopia correction effect (compare #L37 and #L47). This decrease in near visual acuity improvement is exacerbated by the addition of 4.0% mannitol (compare #L47 and #L48). Increasing the aceline concentration to 1.65% or 1.75% overcomes the decrease in near visual acuity improvement seen with mannitol addition (compare #L47 with #L49 and #L50).

[0280] Furthermore, prescriptions containing 1.75% aceline and 2.5% mannitol increased efficacy and duration in treating presbyopia, correlating with an increase of up to 5.0% in polysorbate 80, and subsequently inversely correlating with a decrease in CMC from 1.45% to 1.40% (compare prescriptions #L66 and #L78). Optimal prescriptions were shown by #L77, #L78, and #L85–#L94, each exhibiting the best reading improvement at the 40cm visual acuity line of 3.5–3.75, the best efficacy index score of 25–34, and the longest duration of 7–9 hours, respectively. The increase in efficacy and duration of prescriptions #L66–#L78 also inversely correlated with the decrease in tropicamide from 0.0275% to 0.01%. This same trend is demonstrated by the increase in efficacy (i.e., readings relative to baseline 40cm) when comparing #L85 and #L94.

[0281] This data indicates that mannitol effectively reduces ciliary spasms caused by acelyn, thereby reducing the need for ciliary muscle paralyzers such as tropicamide. Furthermore, this data shows that the addition of nonionic surfactants and viscous agents can further enhance the efficacy and duration of compositions containing acelyn, mannitol, and low levels of tropicamide. This data also indicates that the use of ciliary muscle paralyzers in acelyn compositions containing polysorbate 80 and CMC is most beneficial for correcting presbyopia when the ciliary muscle paralyzer concentration is closer to 0.006% than 0.025%. Finally, this data indicates that compositions containing acelyn and mannitol are sufficient to correct tolerable painful presbyopia.

[0282] [Example 12] Use of further high-tropicamide formulations The following are examples of aceline formulations containing more than 0.03% tropicamide.

[0283] [Table 9] The ciliary spasm score corresponds to the following: 0 = No discomfort; 0.5 = minor puncture wound; 1 = Significant pressure / discomfort; 2 = Pain lasting less than 30 minutes; 3 = Pain lasting more than 1 hour; and 4 = Severe to unbearable pain.

[0284] As shown in the comparison with prescriptions #L39-#L41 and #L74-#L78 in Table 8, prescriptions containing approximately 1.40%-1.45% aceline, approximately 0.035%-0.04% tropicamide, approximately 5.5% polyoxyl stearate, and approximately 0.75% CMC are effective in treating presbyopia, although they are not as effective as prescriptions containing approximately 1.65%-1.75% aceline, approximately 2.5% mannitol, approximately 5% polysorbate 80, and approximately 1.40% CMC. This effectiveness decreases sharply when the tropicamide concentration is increased to approximately 0.05%-0.08%.

[0285] [Example 13] Use of compounds containing mannitol Prescription: Acetolysine 1.75% w / v Tropicamide 0.006% w / v Mannitol 2.5% w / v Polysorbate 802.75% w / v NaCl 0.5% w / v Hydroxypropyl methylcellulose 0.5%~1.80% w / v Phosphate buffer 3mM pH 5.0, and As a preservative, 0.020% BAK.

[0286] method: Each subject received two drops of the above formulation in their eye, and any excess was wiped off the lid and eyelashes.

[0287] result: Within 20 minutes, a slight dilation resulted in an improvement in near vision of approximately 3 lines. Throughout the day, near vision remained enhanced without loss of distance vision. Furthermore, in subjects with a history of mild refractive errors, distance vision improved. Between 5 and 8 hours, the pupils began to recover slightly, and after several hours, minimal dilation was no longer observed. Both the excellent near vision just before the onset of symptoms and the slight improvement in near vision likely continued, as the pupils began to increase slightly from their minimum size earlier that day.

[0288] [Example 14] Use of a preferred embodiment that optimizes tropicamide and hydroxypropyl methylcellulose composition Aceline 1.75% w / v Tropicamide 0.010% w / v Mannitol 2.50% w / v Polysorbate 803.50% w / v NaCl 0.50% w / v HPMC 1.25%w / v BAK 0.02%w / v Phosphate buffer 3mM pH 5.00

[0289] method The subjects received two drops of the above-mentioned prescription in each eye, followed by one drop in each eye, and then a second drop five minutes later.

[0290] result: Comfort, duration, and efficacy were evaluated. Stinging during instillation and the first hour was minimal, rated 0.25 out of 4. Redness during the first hour was also minimal, rated 0.5 out of 4 at 20 minutes. The onset of visual acuity improvement occurred within the first 20-25 minutes after instillation. Baseline near visual acuity (i.e., 40 centimeters) improved to a visual acuity of 3.5 lines. The improvement in near visual acuity lasted for 8.5 hours. Comparing this prescription to the prescription in Table 8, the efficacy index score was 29.75. Replacing 1.80% w / v HPMC with 1.65% w / v HPMC slightly reduced the improvement in near visual acuity to a visual acuity of 3.25 lines and slightly reduced the duration to just over 6 hours. Comparing this prescription to the prescription in Table 8, the efficacy index score was 19.5.

[0291] [Example 15] Use of mannitol-containing compounds including various nonionic surfactants. composition Table 10 shows the active ingredients, excipients, and their concentrations for compositions including both test and hypothetical examples of nonionic surfactants.

[0292] method The subjects received two drops of the above-mentioned formula into each eye, and any excess was wiped away from the lid and eyelashes.

[0293] result All nonionic surfactants tested showed substantial improvement in near vision. Of those tested, only Brij® 35 showed minimal significant corneal irritation, redness, and resulting reduction in duration. Polysorbate 80 and Poly 35 castor oil were the most preferred, with polyoxyl 40 stearate and poloxamer 407 also performing well. However, polyoxyl 40 stearate caused a precipitation reaction with cellulose viscous agents, adding other stability issues.

[0294] The comfort level and duration of each nonionic surfactant were also tested and are listed in Table 10. Stinging and redness were rated on a scale of 0 to 4, with 0 being none and 4 being the most severe. Except for Brij® 35, stinging and redness were mild or minimal. The duration of each nonionic surfactant tested was excellent.

[0295] [Table 10]

[0296] [Example 16] Use of a compound including the addition and optimization of concentrations of nonionic surfactants and antioxidants. composition Aceline 1.75% w / v Tropicamide 0.010% w / v Mannitol 2.50% w / v Polysorbate 804.00% w / v NaCl 0.00% w / v HPMC 1.25% w / v (high MW, equivalent to a viscosity of approximately 400 cps units) BAK 0.02%w / v Sorbic acid 0.12% w / v BAK 0.02%w / v EDTA 0.01% Citrate buffer 3mM pH 5.00

[0297] method In the two cases, two drops of the above-mentioned prescription were instilled into each eye at approximately 5-minute intervals. result: Comfort, duration, and efficacy were evaluated. Inhalation and stinging during the first hour were minimal in each subject, lasting approximately 15 seconds and rated 0.50 out of 4. Conjunctival congestion during the first hour was also minimal in each subject, rated 0.25 out of 4 at 20 minutes. The onset of visual acuity improvement occurred within the first 20–25 minutes after instillation. In Subject 1, baseline near visual acuity (40 cm) improved by 4.0–4.25 lines, lasting 11.5 hours. In Subject 2, baseline near visual acuity improved by 3.5 lines, lasting 9.5 hours. Efficacy index scores were 47.38 and 33.25, the highest scores for each formulation.

[0298] [Example 17] Aceline composition for cold chain storage (hypothetical example)

[0299] [Table 11-1]

[0300] [Table 11-2]

[0301] [Table 11-3]

[0302] method Acelyzine cold chain storage compositions CS#1-5 and 11-20 were each filled into vials under a nitrogen overlay, followed by nitrogen purging of the remaining headspace. CS#6-10 were each filled into vials under ambient air and headspace. One vial of each composition was stored at 25 degrees Celsius, and the other at 5 degrees Celsius.

[0303] result

[0304] [Table 12-1]

[0305] [Table 12-2]

[0306] As shown in Figure 4, CS#3-5 containing 0.10% sodium ascorbate, 0.10% sodium bicarbonate, or 0.10% sodium metabisulfite remained stable for approximately 2 months at 25 degrees Celsius and for approximately 26 months at 5 degrees Celsius.

[0307] As shown in Table 12, filling vials under a nitrogen overlay and purging the headspace with nitrogen improved refrigeration stability by 4–5 months. Adding HPMC further extended stability by 3 months; sodium citrate, sodium bisulfate, or sodium metabisulfite further extended it by 3 months. Adding sorbic acid and BAK for an additional 2 months further extended the stability. CS#20 improved stability up to 22 months.

[0308] [Example 18] Stability of a pouch lined with Mylar® The aceline formulation of the present invention was placed in a container and then in a pouch lined with biaxially oriented polyethylene terephthalate at -20, 5, and 25°C for up to 3 months. The total amount of aceline-related substances was recorded at 1, 2, 3, and 6 months. The results of this test can be seen in Table 13 below.

[0309] Mylar® was used as the source of biaxially oriented polyethylene terephthalate. Mylar is a registered trademark of DuPont Teijin Films US Limited and is available from DuPont Teijin Films US Limited.

[0310] [Table 13]

[0311] As shown in Table 13, the use of pouches lined with Mylar® helped maintain the efficacy of aceline by reducing the rate of degradation. Specifically, we compared the total rate of change of 4.46% without a pouch at room temperature (25°C) with the total rate of change of -0.05% and 0.041% with pouches at room temperature (25°C).

Claims

1. An aqueous ophthalmic composition for treating presbyopia in subjects requiring treatment for presbyopia, The aqueous ophthalmic composition comprises (i) aceline lysine at a concentration of about 0.50% to about 1.90% w / v, and (ii) mannitol at a concentration of about 2.00% to about 4.00% w / v, where w / v represents the weight by total volume of the aqueous ophthalmic composition. The aqueous ophthalmic composition lacks tropicamide, The aqueous ophthalmic composition has a pH of approximately 5.0 to approximately 7.

0. The aqueous ophthalmic composition is stored for at least seven months in a container having a headspace at a temperature of approximately 2 to 8 degrees Celsius, and the headspace contains an inert gas. The aqueous ophthalmic composition contains at least 90% of the aceline contained in the aqueous ophthalmic composition at the start of storage. Acekidine is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 The aqueous ophthalmic composition.

2. The aqueous ophthalmic composition according to claim 1, wherein the aceline is present at an aceline concentration of approximately 1.4% to approximately 1.75% w / v, where w / v represents the weight relative to the total volume of the composition.

3. The aqueous ophthalmic composition according to claim 1, wherein the aqueous ophthalmic composition further comprises (i) hydroxypropyl methylcellulose (HPMC) and (ii) sodium citrate, citrate buffer, sodium bisulfite, or sodium metabisulfite.

4. The aqueous ophthalmic composition according to claim 1, further comprising HPMC at a concentration of 0.75% to 1.25% w / v and sodium citrate at a concentration of 0.10% to 0.25% w / v.

5. The aqueous ophthalmic composition according to claim 1, wherein the aqueous ophthalmic composition has been stored for at least 12 months.

6. The aqueous ophthalmic composition according to claim 5, wherein the aqueous ophthalmic composition has been stored for at least 18 months.

7. The aqueous ophthalmic composition according to claim 6, wherein the composition has been stored for at least 22 months.

8. The aqueous ophthalmic composition according to claim 1, wherein the aqueous ophthalmic composition has a viscosity of about 1 centipoise (cp) to about 25 cps at a high shear rate of blinking, and a viscosity of about 50 cps to about 200 cps at a low shear rate between blinks.

9. The aqueous ophthalmic composition according to claim 1, further comprising a surfactant.

10. The aqueous ophthalmic composition according to claim 1, further comprising a thickening agent.

11. The aqueous ophthalmic composition according to claim 10, wherein, compared to a composition without a thickening agent, aceline remains in the composition for at least seven months further, and the thickening agent is HPMC.

12. It is a system, The aforementioned system, a) (i) a closure, and (ii) a container including a vessel; and b) an aqueous ophthalmic composition comprising (i) aceline lysine disposed in the container, wherein the concentration of aceline lysine is about 0.50% to about 1.90% w / v, and (ii) mannitol is about 2.00% to about 4.00% w / v. Includes, Here, w / v represents the weight by total volume of the aqueous ophthalmic composition. The aqueous ophthalmic composition lacks tropicamide, The aqueous ophthalmic composition has a pH of approximately 5.0 to approximately 7.

0. The container includes a headspace between the aqueous ophthalmic composition and the closure, and the closure is configured to prevent the aqueous ophthalmic composition from coming out of the container. Acekidine is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 The aqueous ophthalmic composition, when stored for at least seven months in a container having headspace at a temperature of about 2 to about 8 degrees Celsius, comprises, after storage, at least 90% of the aceline contained in the ophthalmic composition at the start of storage.

13. The system according to claim 12, wherein the aqueous ophthalmic composition further comprises (i) hydroxypropyl methylcellulose (HPMC) and (ii) sodium citrate, citrate buffer, sodium bisulfite, or sodium metabisulfite.

14. The system according to claim 12, wherein the aqueous ophthalmic composition further comprises HPMC at a concentration of 0.75% to 1.25% w / v and sodium citrate at a concentration of 0.10% to 0.25% w / v.

15. The system according to claim 12, wherein the aqueous ophthalmic composition is stored for at least 12 months.

16. The system according to claim 12, wherein the aqueous ophthalmic composition is stored for at least 18 months.

17. The system according to claim 12, wherein the aqueous ophthalmic composition is stored for at least 22 months.

18. The system according to claim 12, wherein the aqueous ophthalmic composition has a viscosity of about 1 centipoise (cp) to about 25 cps at a high shear rate of blinking and a viscosity of about 50 cps to about 200 cps at a low shear rate between blinks.

19. The system according to claim 12, wherein the aceline is present at an aceline concentration of approximately 1.4% to approximately 1.75% w / v, where w / v represents the weight relative to the total volume of the composition.

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