Compositions and methods for treating presbyopia

Abstract

The present invention provides compositions and methods for treating presbyopia. The method preferably includes storing the composition in a container having a headspace at a temperature of from about 2 degrees Celsius to about 8 degrees Celsius. The method further includes filling the container under a cover layer of inert gas and / or sealing the container in an anti-immersion material or placing the container in a second container comprising an anti-immersion material.

Description

[0001] This application is a divisional application of the Chinese Patent Application No. 201980067359.1 with the filing date of October 8, 2019, entitled “Compositions and Methods for Treating Presbyopia” (which corresponds to the PCT Application No. PCT / US2019 / 055116 with the filing date of October 8, 2019) for the invention of the same name. BACKGROUND

[0002] Assuming that distance vision is corrected or is excellent, the minimum distance from the eye to the object at which focus occurs increases as a person ages. For example, a 10-year-old child can focus on an object or “point of focus” that is only 3 inches (0.072 meters) from the eye while still maintaining excellent distance vision; a 40-year-old person can focus on an object or “point of focus” that is 6 inches (0.15 meters) from the eye; and a 60-year-old person, inconveniently, can focus on an object or “point of focus” that is 39 inches (1.0 meter) from the eye. This increase in the minimum distance of focus for an individual with excellent uncorrected distance vision is called presbyopia, also roughly translated as “old person’s eye.”

[0003] Excellent uncorrected distance vision is also referred to as emmetropia. Inability to focus on a far point of focus is called myopia, and inability to focus on a near point of focus is called hyperopia. Specifically, “distance” vision is considered to be any point of focus that is 1 meter or more from the eye, and near vision is any point of focus that is less than 1 meter from the eye. The minimum distance of focus at which an object begins to come into focus is called the “near point.” The change in focus from the far point to the near point and any point of focus in between is called accommodation, which decreases approximately 13 diopters from age 10 to age 60 (1 ÷ 0.072 meters = 13.89 diopters; 1 ÷ 1 meter = 1 diopter).

[0004] The highest incidence of first complaint of presbyopia occurs in the 42-44 year old population. Presbyopia occurs because the accommodative ability of the eye, which utilizes the near reflex-pupil constriction, convergence of the eyes, and particularly the contraction of the ciliary muscle, decreases as a person ages. This decrease in accommodative ability results in an inadequate change in the normal thickening and an increase in curvature of the anterior surface of the lens necessary to shift the point of focus from distant objects to near objects. Important near point of focus work affected by presbyopia includes looking at computer screens (21 inches) and reading printed material (16 inches).

[0005] Presbyopia is a normal and inevitable consequence of aging and is the first noticeable sign of aging for many people in their 40s. A study found that there were over 1 billion presbyopes worldwide in 2005. The study also projected that this number will almost double by 2050. If every person over 45 is considered a presbyope, then it is estimated that there were 122 million presbyopes in the United States alone in 2010. This number will only increase as the baby boomer generation reaches critical age.

[0006] Presbyopia carries a stigma due to the limitations in the ability to quickly perform many tasks that require focusing on both far and near points, which is almost immediately apparent once presbyopia occurs. In presbyopes, these tasks can only be performed with the use of glasses, contact lenses, or after undergoing an invasive surgery. Monovision procedures, an optical modification method, can be performed with the use of glasses, contact lenses, or even surgery. Monovision procedures correct one eye for near focus and the other eye for far focus. However, monovision correction is often accompanied by loss of depth perception and distance vision, especially in dim light (e.g., night). Other surgical methods that have been developed to alleviate presbyopia include: (1) implantation of an artificial lens (Presbia® Technolas Perfect Vision GMBH, PresbiBio LLC, AcuFocus, Inc., and Vue+, AcuFocus, AcuFocus,

[0007] Similar effects can be obtained using a general miotic agent such as pilocarpine (a non-selective muscarinic acetylcholine receptor agonist), carbachol (a non-selective muscarinic acetylcholine receptor agonist), and echothiophate iodide (an acetylcholinesterase inhibitor). These general miotic agents are capable of inducing a pinhole pupil to a pupil of 2.0 mm or less in sufficient concentration, and potentially very much like an inlay, expanding the depth of focus, but when the concentration is sufficient to cause a pinhole pupil diameter of 2.0 mm or less, these drugs trigger an increase in ciliary muscle contraction and induce any remaining reserve accommodation to improve near vision at the expense of distance vision in individuals who still retain some accommodative function. Ciliary spasm causes side effects of migraine such as supraorbital neuralgia and blurred vision from uncorrectable near vision with pinhole pupils, thus necessitating the use of lower concentrations, shorter acting, less impactful miotic agents such as pilocarpine. In this case, even a slight hyperopia can offset the induced myopia, and even a very small myopic increment can exacerbate myopia. In extreme cases, this ciliary spasm can be associated with a shallower anterior chamber and traction on the retinal ora serrata, leading to retinal tears and / or retinal detachment.

[0008] Miotic agents have been described in various patents and patent applications for the treatment of presbyopia. U.S. Patent Nos. US 6,291,466 and US 6,410,544 describe the use of pilocarpine to modulate contraction of the ciliary muscle to return the eye to its resting state and potentially restore its accommodative ability.

[0009] U.S. Patent No. US 8,524,758 describes the use of pilocarpine with the non-steroidal anti-inflammatory drug diclofenac to reduce supraorbital neuralgia from ciliary spasm and increase the time of accommodation ciliary muscle contraction. International PCT Application Publication WO / 2013 / 041967 describes the use of pilocarpine with oxymetazoline or meloxicam to temporarily overcome ocular conditions such as presbyopia.

[0010] U.S. Patent No. US 8,299,079 (HEK Development LLC) describes the use of directly acting general miotic agents such as pilocarpine, carbachol, and echothiophate iodide with the alpha 2 selective vasoconstrictor brimonidine at concentrations of 0.05% to 3.0% w / v. However, the use of brimonidine at concentrations of about 0.20% (or any 0.05% or above) w / v causes ciliary spasm, often accompanied by supraorbital neuralgia and / or headache of migraine intensity, and often results in increased rebound hyperemia. For example, 25% of patients using 0.20% w / v brimonidine (ALPHAGAN®) ALPHAGAN® (Allergan, Inc.) experience rebound redness.

[0011] U.S. Patent Application Publication No. US2014 / 0113946 describes the use of pilocarpine with the a1 and mild a2 agonist vasoconstrictor oxymetazoline, demonstrating limitations in distance acuity and duration, thus requiring most mild hyperopes to negate the induced myopia (Table 1). Of the 16 eyes treated, only 3 were -0.25 to -0.50 diopters, while 8 were mild hyperopes. Of the -0.50 diopter eyes, two were reduced to 20.40 distance. Furthermore, the duration was limited as the full effect waned in approximately four hours. The pupil size ranged from 2.0 mm to 2.7 mm, with enhanced near effect and distance acuity ranging from minimal to nonexistent from the depth of focus.

[0012] These attempts at miotic treatment of presbyopia all induce a temporary myopia of several diopters, resulting in a reduction of distance vision to approximately legal blindness or worse, in exchange for improved near vision for the duration of their effect, typically for several hours. This myopic effect is magnified by a reduction in distance acuity index, in terms of uncorrected, naked eye vision. For example, a person with mild myopia (e.g., -0.25 D, -0.50 D sphere equivalent) typically associated with distance vision without glasses, will lose multiple lines of distance vision (e.g., -0.75 D sphere equivalent) after instillation of 1% pilocarpine.

[0013] Pilocarpine, in addition to apraclonidine, has been used in the past for the treatment of glaucoma and has been associated with ciliary spasm, brow and / or headache, and myopic blur. In addition, apraclonidine is unstable in solution. Typically, apraclonidine is stored in a dual vial system. One vial contains lyophilized apraclonidine, while the second vial contains the diluent required to reconstitute the lyophilized apraclonidine prior to topical instillation. The primary problem with its use as a miotic for presbyopia is the accompanying pain, and in some cases, the potential for distance blur.

[0014] U.S. Patent No. US 9,089,562 describes a composition of aceclidine and a cycloplegic agent used in combination, in a preferred embodiment, 1.45% of aceclidine is combined with 0.042% of tropicamide. The addition of the cycloplegic agent at very low concentrations (less than 0.10%) surprisingly still results in pupil constriction and allows useful distance and improved near vision without inducing cyclospasm, which is induced by the use of aceclidine alone, typically supraorbital neuralgia, which can be very painful and disabling. Furthermore, aceclidine and the cycloplegic agent require a particularly narrow defined ratio and concentration range relative to each other, such that complications arise during manufacturing and adjustment, particularly the need for lyophilization of aceclidine for stable storage, and the concomitant effect of the cryoprotective agent / lyoprotective agent (hereinafter referred to as "cryoprotective agent") required. The present invention found that the addition of a cryoprotective agent, such as a polyol, in a preferred embodiment, mannitol, results in a decrease in the efficacy of the defined range and concentration ratio of US 9,089,562. Due to these medical and practical inefficiencies, it was found that aceclidine compositions require the same or slightly higher concentrations of aceclidine, and much lower concentrations than US 9,089,562, or in some cases no cycloplegic agent, while preferably allowing formulation adjustments to be made to lyophilized aceclidine for a commercially stable formulation for the treatment of presbyopia. However, to date, no aceclidine composition with lower amounts than those defined in US 9,089,562 has been effectively used for the treatment of presbyopia. Thus, as mentioned above, the use of aceclidine alone, particularly in young and middle-aged presbyopes (45 to 58 years old), induces severe cyclospasm in certain subjects and can cause accommodation-induced distance blur.

[0015] Thus, there is a need in the art for a non-invasive and convenient method of treatment of presbyopia with minimal side effects. In particular, there is a need for an ophthalmic composition that will allow a person suffering from presbyopia to focus on near objects without significant side effects, such as a decrease in distance vision, blurring of vision, pain, redness, impaired night driving or loss of vision in dim light, induced rhinorrhoea, or risk of retinal detachment. Furthermore, there is a need in the art to reduce or eliminate the cycloplegic agent used with aceclidine, which can enhance the duration and efficacy, and a means for storing the aceclidine composition, which is preferably simultaneously enhanced in the far and near focal depth, with pupil constriction to the range of 1.50 to 2.0 mm without clinically significant side effects. SUMMARY

[0016] In certain embodiments, the present invention relates to compositions and methods for the treatment of presbyopia.

[0017] In certain embodiments, the present application relates to compositions and methods for treating presbyopia comprising a muscarinic agonist, wherein the muscarinic agonist preferentially activates Ml and M3 muscarinic acetylcholine receptors. In more preferred embodiments, the muscarinic agonist is more selective for Ml than M3. In certain embodiments, the present application relates to compositions and methods for treating presbyopia comprising a muscarinic agonist that preferentially activates Ml and M3 muscarinic acetylcholine receptors.

[0018] In certain embodiments, the present application relates to compositions and methods for treating presbyopia comprising a muscarinic agonist selected from the group consisting of aceclidine, tasimelidine, sabcomeline, cevimeline, WAY- 132983, AFB267B (NGX267), AC-42, AC-260584, 77-LH-28-1, and LY593039, or any pharmaceutically acceptable salt, ester, analog, prodrug, or derivative thereof.

[0019] In certain embodiments, the present application relates to compositions and methods for treating presbyopia comprising a muscarinic agonist that preferentially activates Ml and M3 muscarinic acetylcholine receptors.

[0020] In certain other embodiments, the present application relates to ophthalmic compositions for treating presbyopia comprising aceclidine.

[0021] In certain preferred embodiments, the present application relates to ophthalmic compositions for treating presbyopia comprising aceclidine and a cycloplegic agent, preferably at a concentration of about 0.25% to about 2.0% w / v aceclidine and preferably at a concentration of about 0.004% to 0.015% w / v of a cycloplegic agent, preferably tropicamide.

[0022] In certain preferred embodiments, the present application relates to ophthalmic compositions for treating presbyopia comprising aceclidine and a cryoprotective agent, preferably at a concentration of about 0.25% to about 2.0% w / v aceclidine and preferably at a concentration of about 1.0% to about 10.0% w / v of a cryoprotective agent, preferably mannitol, more preferably 2.5% w / v mannitol. In certain preferred embodiments, the present application relates to ophthalmic compositions for treating presbyopia comprising:

[0023] about 1.75% w / v aceclidine;

[0024] about 2.5% w / v mannitol; and

[0025] optionally, about 0.004% to 0.015% w / v tropicamide.

[0026] In certain preferred embodiments, the present application relates to ophthalmic compositions for treating presbyopia comprising:

[0027] acetazolamide about 1.75% w / v;

[0028] mannitol about 2.5% w / v;

[0029] non-ionic surfactant about 1.0% to about 6.0% w / v;

[0030] hydroxypropyl methylcellulose about 0.1% to about 2.25% w / v; and

[0031] optionally, povidone about 0.004% to 0.015% w / v.

[0032] In certain preferred embodiments, the present application relates to ophthalmic compositions for the treatment of presbyopia, comprising:

[0033] acetazolamide about 1.75% w / v;

[0034] mannitol about 2.5% w / v;

[0035] non-ionic surfactant about 1.0% to about 6.0% w / v, preferably selected from the group consisting of polysorbate, tyloxapol, poloxamer, cyclodextrin, vitamin E TPGS and polyethylene glycol, more preferably polysorbate 80, even more preferably polysorbate 80 about 1.0% to about 5.0% w / v, most preferably polysorbate 80 about 2.0% to about 4.0% w / v;

[0036] hydroxypropyl methylcellulose about 0.1% to about 2.25% w / v, more preferably hydroxypropyl methylcellulose about 0.75% to about 1.5% w / v, most preferably hydroxypropyl methylcellulose about 1.0% to about 1.25% w / v;

[0037] sorbic acid about 0.10% to about 0.12% w / v;

[0038] benzalkonium chloride about 0.005% to about 0.02% w / v; and

[0039] optionally, povidone about 0.004% to 0.015% w / v.

[0040] In certain preferred embodiments, the present application relates to ophthalmic compositions for the treatment of presbyopia, comprising:

[0041] acetazolamide about 1.75% w / v;

[0042] mannitol about 2.5% w / v;

[0043] about 1.0% to about 6.0% w / v of a non-ionic surfactant, preferably selected from the group consisting of polysorbate, tyloxapol, poloxamer, cyclodextrin, vitamin E TPGS, and polyethylene glycol, 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;

[0044] about 0.1% to about 2.25% w / v of hydroxypropyl methylcellulose, more preferably about 0.75% to about 1.5% w / v of hydroxypropyl methylcellulose, most preferably about 1.0% to about 1.25% w / v of hydroxypropyl methylcellulose;

[0045] about 0.10% to about 0.12% w / v of sorbic acid;

[0046] about 0.005% to about 0.02% w / v of benzalkonium chloride;

[0047] 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, sodium citrate, or citrate buffer; and

[0048] optionally, about 0.004% to 0.015% w / v of tropicamide.

[0049] In certain preferred embodiments, the present application is directed to an ophthalmic composition for treating presbyopia, comprising:

[0050] about 1.75% w / v of aceclidine;

[0051] optionally, about 0.004% to 0.015% w / v of tropicamide;

[0052] about 1.0% to about 6.0% w / v of a non-ionic surfactant;

[0053] about 0.1% to about 2.25% w / v of hydroxypropyl methylcellulose;

[0054] about 0.10% to about 0.12% w / v of sorbic acid; and

[0055] about 0.005% to about 0.02% w / v benzalkonium chloride,

[0056] wherein the composition is maintained at a temperature of about 2 to about 8 degrees Celsius.

[0057] In certain preferred embodiments, the present application is directed to an ophthalmic composition for treating presbyopia, comprising:

[0058] about 1.75% w / v of aceclidine;

[0059] about 2.5% w / v of mannitol;

[0060] about 4.0% w / v of polysorbate 80;

[0061] about 1.25% w / v of hydroxypropyl methylcellulose;

[0062] about 0.12% w / v of sorbic acid;

[0063] about 0.1% w / v of ethylenediaminetetraacetic acid dihydrate;

[0064] about 0.02% w / v of benzalkonium chloride; and

[0065] about 0.1% w / v of sodium citrate or citrate buffer.

[0066] In certain preferred embodiments, the present application relates to ophthalmic compositions for treating presbyopia, comprising:

[0067] about 1.75% w / v of aceclidine;

[0068] about 2.5% w / v of mannitol;

[0069] about 4.0% w / v of polysorbate 80;

[0070] about 1.25% w / v of hydroxypropyl methylcellulose;

[0071] about 0.12% w / v of sorbic acid;

[0072] about 0.1% w / v of ethylenediaminetetraacetic acid dihydrate;

[0073] about 0.02% w / v of benzalkonium chloride;

[0074] about 0.1% w / v of sodium citrate or citrate buffer; and

[0075] about 0.01% w / v of tropicamide.

[0076] In a preferred embodiment, the concentration of hydroxypropyl methylcellulose is from about 0.1% to about 2.25% w / v, more preferably from about 0.75% to about 1.5% w / v, and most preferably from about 1.0% to about 1.25% w / v. Preferably, the concentration of hydroxypropyl methylcellulose is such that the viscosity prior to instillation is from about 1 to about 10,000 cps, more preferably from about 200 to about 500 cps, and most preferably about 400 cps.

[0077] In another preferred embodiment, the ophthalmic composition of the present application includes one or more antioxidants selected from the group consisting of ethylenediaminetetraacetic acid ("EDTA"), ethylenediaminetetraacetic acid dihydrate, sodium citrate, and citrate buffers, preferably 0.1% w / v ethylenediaminetetraacetic acid dihydrate; and 0.1% w / v sodium citrate or sodium citrate buffer.

[0078] In another preferred embodiment, the non-ionic surfactant is selected from the group consisting of polysorbate, tyloxapol, poloxamer, cyclodextrin, vitamin E TPGS, and polyethylene glycol, preferably polysorbate 80, more preferably 4.0% w / v polysorbate 80.

[0079] In another preferred embodiment, the pH of the ophthalmic composition of the present application without tropicamide is from about 4.0 to about 8.0, and the pH of the composition with tropicamide is from about 4.0 to about 6.0, more preferably 5.0, not accounting for the amount of tropicamide.

[0080] In certain preferred embodiments, the present application is directed to an ophthalmic composition for the treatment of presbyopia comprising aceclidine, a cryoprotective agent, and a non-ionic surfactant, preferably the concentration of aceclidine is from about 0.25% to about 2.0% w / v; the cryoprotective agent is preferably a polyol, preferably the concentration of mannitol is from about 1.0% to about 10.0% w / v, more preferably 2.5% w / v mannitol; and the non-ionic surfactant is preferably selected from the group consisting of polysorbate, polyoxyl castor oil, polyoxyl stearate, poloxamer, polyethylene glycol, polyoxyethylene alkyl ether, tyloxapol, and 2-[[10, 13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-lH-cyclopenta[a]phenanthryl-3-yl]oxy]ethanol), more preferably polysorbate 80 or polyoxyl 35 castor oil, more preferably the concentration is from about 0.5% to about 10.0% w / v, more preferably from about 1.0% to about 7.0% w / v, even more preferably about 2.5% or 3.5% w / v.

[0081] In certain preferred embodiments, the present application is directed to an ophthalmic composition for the treatment of presbyopia comprising aceclidine, a cryoprotective agent, tropicamide, a non-ionic surfactant, and a viscosity agent. Preferably, aceclidine is present in a concentration of about 0.25% to about 2.0% w / v, more preferably 1.75% w / v; the cryoprotective agent is preferably a polyol, preferably mannitol in a concentration of about 1.0% to about 10.0% w / v, more preferably 2.5% w / v; tropicamide is preferably present in a concentration of about 0.004% to about 0.025% w / v, more preferably about 0.005% to about 0.007%; the non-ionic surfactant is preferably polysorbate 80, more preferably in a concentration of about 0.5% to about 10.0% w / v, more preferably about 2.0% to about 6.0% w / v, even more preferably about 2.5% to about 4.0% w / v; and the viscosity agent is preferably selected from the group consisting of cellulose extract, hyaluronate, carbomer, and gum, more preferably high molecular weight carboxymethylcellulose or carbomer 940, preferably in a concentration of about 1.0% to about 2.0% w / v, more preferably about 1.35% to 1.45% w / v, even more preferably about 1.42% w / v, or other viscosity agents such as hydroxypropylmethylcellulose, preferably in 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 prior to instillation into the eye can be about 25 to about 10,000 centipoise, more preferably about 100 to about 5,000 centipoise, and the composition can be non-Newtonian, and / or induce tear secretion, thereby minimizing blurring, or have minimal blurring between high shear (blinking) and low shear (between blinks) after instillation.

[0082] In certain preferred embodiments, the present application is directed to an ophthalmic composition for the treatment of presbyopia comprising aceclidine, a cryoprotective agent, tropicamide, a non-ionic surfactant, a viscosity agent, and a preservative. Preferably, aceclidine is present in a concentration of about 0.25% to about 2.0% w / v, more preferably 1.75% w / v; the cryoprotective agent is preferably a polyol, more preferably mannitol in a concentration of about 1.0% to about 10.0% w / v, more preferably 2.5% w / v; tropicamide is preferably present in a concentration of about 0.004% to about 0.025% w / v, more preferably about 0.005% to about 0.007%; the non-ionic surfactant is preferably polysorbate 80, more preferably in a concentration of about 0.5% to about 10.0% w / v, more preferably about 2.0% to about 6.0% w / v, even more preferably about 2.5% to about 4.0% w / v; the viscosity agent is preferably selected from the group consisting of cellulose extract, hyaluronate, carbomer, and gum, more preferably high molecular weight carboxymethylcellulose or carbomer 940, preferably the viscosity agent is present in a concentration of about 1.0% to about 2.0% w / v, more preferably about 1.35% to 1.45% w / v, even more preferably about 1.42% w / v, or other viscosity agents such as hydroxypropylmethylcellulose, preferably in a concentration of about 0.5% to about 1.75%, more preferably about 0.75% to 1.5%, more preferably about 1% to 1.5%, and most preferably about 1.05% to 1.25%, wherein the initial viscosity of the composition prior to instillation into the eye can be about 25 to about 10,000 centipoise, more preferably about 100 to about 5,000 centipoise, and the composition can be non-Newtonian and have minimal blurring between high shear (blinking) and low shear (between blinks) after instillation; and the preservative is preferably selected from the group consisting of benzalkonium chloride ("BAK"), sorbic acid, and oxychloro complex.

[0083] In certain other embodiments, a method of stabilizing a composition comprising aceclidine, the method comprising storing the composition in a container having a headspace at a temperature of about 2 degrees Celsius to about 8 degrees Celsius, preferably about 5 degrees Celsius.

[0084] In certain other embodiments, the composition of the present application is filled into a container having a headspace under an inert gas, preferably nitrogen, and preferably the headspace is purged with the inert gas, preferably nitrogen.

[0085] In certain other embodiments, the present application is directed to a method of stabilizing a composition comprising aceclidine, a viscosity agent, and a non-ionic surfactant, the method 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 nitrogen gas overlay and purged with nitrogen gas headspace, and wherein the composition provides a low shear (1 / sec) viscosity of about 50 to about 1000 centipoise and a high shear (1:1000 / sec) viscosity of about 0.5 or less centipoise.

[0086] In certain other embodiments, the container of the present application comprises a closure and a vessel, wherein a portion of the closure and a portion of the vessel are sealed with a water-resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil, preferably biaxially oriented polyethylene terephthalate.

[0087] In certain other embodiments, the container of the present application is placed within a second container formed of or lined with a water-resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil.

[0088] In certain other embodiments, the present application is directed to a method of stabilizing a composition comprising aceclidine, the method comprising storing the composition in a container having a headspace at a temperature of about 22 degrees Celsius to about 25 degrees Celsius, wherein the container comprises a closure and a vessel, wherein a portion of the closure and a portion of the vessel are sealed with a water-resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil, and / or, the container is placed within a second container formed of or lined with biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil.

[0089] In certain other embodiments, the second container comprises a second closure, wherein the second closure provides a hermetic seal.

[0090] In certain other embodiments, the hermetic seal is resealable.

[0091] In certain other embodiments, the aceclidine is at a concentration of about 0.25% to about 4.0% w / v aceclidine.

[0092] In certain other embodiments, the method of the present application stabilizes at least 90% of the aceclidine 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.

[0093] In certain other embodiments, the compositions described herein further comprise a viscosity agent, a polysorbate, a cryoprotectant, and a preservative.

[0094] In certain other embodiments, the viscosity agent provides a viscosity of at least 50 centipoise, a viscosity of at least 100 centipoise, or a viscosity of at least 200 centipoise.

[0095] In certain other embodiments, the cryoprotectant is selected from the group consisting of a polyol, a sugar, an ethanol, a lower alkanol, a lipophilic solvent, a hydrophilic solvent, a bulking agent, a solubilizing agent, a surfactant, an antioxidant, a cyclodextrin, a maltodextrin, a colloidal silicon dioxide, a polyvinyl alcohol, 2-methyl-2,4-pentanediol, cellobiose, gelatin, polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), formamide, antifreeze protein 752, or a combination thereof.

[0096] In certain other embodiments, the preservative is selected from the group consisting of benzalkonium chloride, a sorbate, an antioxidant, and a combination thereof.

[0097] In certain other embodiments, the antioxidant is selected from the group consisting of sodium ascorbate, sodium bisulfite, sodium metabisulfite, n-acetyl cysteine, or a combination thereof.

[0098] In certain other embodiments, the present application is directed to a method of stabilizing a composition comprising aceclidine, hydroxypropyl methylcellulose, polysorbate 80, mannitol, a sorbate, and an antioxidant selected from the group consisting of sodium ascorbate, sodium bisulfite, sodium metabisulfite, n-acetyl cysteine, or a combination thereof, the method 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 a blanket of an inert gas, preferably nitrogen, and the headspace is purged with an inert gas, preferably nitrogen.

[0099] In certain other embodiments, the concentration of aceclidine is about 0.25% to about 4.00% w / v, the concentration of hydroxypropyl methylcellulose is about 0.75% to about 1.25% w / v, the concentration of polysorbate 80 is about 2% to about 4% w / v, the concentration of mannitol is about 2% to about 4% w / v, the concentration of a sorbate is about 0.10% to about 0.12% w / v, and the concentration of an antioxidant is about 0.10% to about 0.25% w / v.

[0100] In certain other embodiments, the present application is directed to a container comprising aceclidine, the process of making the container comprising the steps of:

[0101] a) providing a container;

[0102] b) filling the composition comprising acetylcysteine into the container under inert gas, preferably nitrogen;

[0103] c) purging the headspace formed during the filling step b) with inert gas, preferably nitrogen;

[0104] d) capping the container, and

[0105] e) optionally, storing the container at a temperature of about 2 degrees Celsius to about 8 degrees Celsius.

[0106] In certain other embodiments, the present application relates to a composition comprising about 0.25% to about 4.0% w / v acetylcysteine and one or more methods of stabilizing the composition selected from the group consisting of filling the composition into a container under inert gas cover and purging the headspace formed upon filling with inert gas, preferably nitrogen, the total viscosity of the composition is at least 50 centipoise or higher, adding a preservative to the composition and the preservative is selected from the group consisting of sorbate, benzalkonium chloride, sodium ascorbate, sodium bisulfate, sodium metabisulfite, n-acetyl cysteine, and combinations thereof,

[0107] wherein the composition is stored at a temperature of about 2 to about 8 degrees Celsius, and wherein w / v means weight per total volume of the composition.

[0108] In certain other embodiments, the present application relates to a method of treating presbyopia, the method comprising administering to a subject in need thereof a composition of the present application.

[0109] In certain other embodiments, the present application is directed to a method of treating presbyopia, the method comprising administering to a subject in need thereof the ophthalmic composition of the present application, wherein the near visual acuity of the subject is improved by about 4 lines of resolution or more for at least 8 hours, wherein the non-ionic surfactant is added at 0.50% to 10%, more preferably 1.0% to 6.0%, and still more preferably 3.0% to 5.0%; and optionally one or more of: increasing the viscosity by using 1.25% of hydroxypropyl methylcellulose, for example, in preferred embodiments, by about 400 cps; and the preservative combination of BAK and sorbate; and the antioxidant combination of one or more of EDTA and citrate, wherein the near visual acuity of the subject is improved by about 4 lines or more of resolution for at least 8 hours; thereby further improving one or more of: i) reducing redness; ii) improving near distance line improvement without distance blur; iii) excellent comfort; and iv) extending duration. In certain other embodiments, the present application is directed to a method of treating refractive error of an eye of a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically acceptable amount of the composition of the present application, wherein the refractive error of the eye is selected from the group consisting of presbyopia, myopia, hyperopia, astigmatism, or a combination thereof.

[0110] In certain other embodiments, the present application is directed to a method of treating refractive error of an eye of a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically acceptable amount of the composition of the present application, wherein the pupil size is reduced to about 1.5 to about 2.5 mm, preferably about 1.7 to about 2.2 mm, and the refractive error is selected from the group consisting of: for mild to moderate hyperopia, distance corrected visual acuity in the range of 3.0 D or less; mild to moderate myopia of -5.0 D or less; regular astigmatism of 3.0 D or less; uncorrected distance visual acuity of +0.50 to -0.50 sphere (spheq) with regular astigmatism of 0.75 D or less in emmetropia; corneal irregular astigmatism, expansion-induced corneal irregular, transparency-induced corneal irregular, high-order aberrations, and refractive surgery-induced high-order aberrations. The present application is also directed to a method of increasing the visual depth of field (i.e., depth of focus) next to pupil constriction, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the ophthalmic composition of the present application. The present application is also directed to a method of reducing the side effects of ocularized cyclogyl administration by modulating the effect of the agonist on the ciliary body of the eye to significantly reduce or eliminate ciliary spasm, ciliary muscle-induced supraorbital neuralgia, and / or ciliary muscle-induced headache.

[0111] The present application is also directed to a method of allowing physiological, local presbyopia correction of both eyes.

[0112] The present invention is also directed to a method of eliminating the need for monocular restriction due to distance blur, or reducing the treatment of hyperopia to counteract the induced near blur typically associated with pilocarpine, or a combination of pilocarpine and alpha agonists.

[0113] The present invention is also directed to a method of improving near vision by increasing accommodation without reducing distance visual acuity. This is accomplished by simultaneously increasing the accommodative reserve while maintaining the ability to induce velocity and total accommodative amplitude, such that the associated near blur does not break through while simultaneously causing a pinhole effect of pupil constriction, thereby filtering refractive error and maintaining distance clarity.

[0114] The present invention is also directed to a method of improving depth perception of vision while improving uncorrected near vision, said method comprising administering to the eyes of a subject in need thereof (binocular vision) a pharmaceutically effective amount of the ophthalmic composition of the present invention, wherein such binocular vision further improves over the near vision of either eye alone.

[0115] The present invention is also directed to a method of improving vision in a subject having refractive error (abnormal vision), said method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition of the present invention.

[0116] The present invention is also directed to a method of improving vision in a subject having refractive error, said method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition of the present invention, wherein the refractive error is selected from the group consisting of myopia, hyperopia, regular astigmatism, irregular astigmatism, and high regular astigmatism.

[0117] The present invention is also directed to a method of eliminating optical aberrations including the area adjacent or peripheral to the central 1.5 mm optical zone caused by corneal irregularities, haze, or high regular astigmatism, thereby causing an improvement in visual acuity and quality of vision by filtering out aberrant optics in patients with irregular astigmatism or high more regular astigmatism, such as occurs in, for example, keratoconus, light refractive keratotomy induced corneal haze, diffuse lamellar keratitis ("DLK") (post-operative DLK), irregularities caused by other iatrogenic corneal disease such as cataract incisions, glaucoma filtration blebs, implanted glaucoma flaps, corneal inlays with or without removal, post-operative expansion of the cornea (laser), and secondary infection.

[0118] The present invention also relates to improving acuity relative to existing uncorrected refractive errors. With this improvement in acuity, patients who would otherwise need to wear toric contact lenses that are less comfortable and have reduced optical effect with each blink can now in many cases need only non-toric soft contact lenses or no contact lenses at all. In addition, those who need gas permeable contact lenses can no longer need them or can need only more comfortable soft contact lenses. Patients with high astigmatism can now need no correction or reduced correction for astigmatism. Patients with mild to moderate myopia can need less correction or no correction. Patients with mild to moderate hyperopia (farsightedness) can need no correction or reduced correction.

[0119] The present invention relates to methods and ophthalmic compositions for improving vision. In a preferred embodiment, the present invention relates to methods and ophthalmic compositions for treating presbyopia. In a more preferred embodiment, the present invention relates to ophthalmic compositions comprising aceclidine.

[0120] The present invention relates to a method of treating irregular astigmatism, keratoconus, low myopia or hyperopia with or without astigmatism, comprising administering to a subject in need thereof an ophthalmic composition of the present invention. The present invention also relates to a method of stabilizing aceclidine, comprising providing a first composition comprising about 1.75% w / v aceclidine and about 2.5% w / v mannitol in a first chamber, and providing a second composition comprising about 0.01% 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 in a second chamber, wherein the efficacy of aceclidine is maintained for at least one month after mixing the first composition and the second composition. The present invention also relates to a method of stabilizing aceclidine, comprising storing the composition described herein at a temperature of 0 to 8 degrees Celsius.

[0121] The present invention also relates to a method of inhibiting the growth of microorganisms and fungi, comprising the steps of:

[0122] Provided is an ophthalmic composition comprising about 1.75% w / v aceclidine, about 2.5% w / v mannitol, about 0.01% w / v tropicamide, about 4.0% w / v polysorbate 80, and about 1.25% w / v hydroxypropyl methylcellulose;

[0123] about 0.10% to 0.12% w / v sorbic acid is added; and

[0124] One or more of about 0.1% w / v ethylenediaminetetraacetic acid dihydrate and about 0.1% w / v sodium citrate or citrate buffer are added. BRIEF DESCRIPTION OF DRAWINGS

[0125] Figure 1 is a graph of the effect of pilocarpine and echothiophate on near and distance vision in patients over 45 years of age with or without tolteridine and with or without a carrier.

[0126] Figure 2 is a graph of the effect of the addition of a non-ionic surfactant and a viscosity agent on near acuity and duration of effect. Row-hours indicates the duration of effect of the improvement in rows.

[0127] Figure 3 is a graph of the efficacy index of formulations #L33 - #L94. The color of the box indicates the level of comfort, white is good, cross-hatched is fair, and black is poor.

[0128] Figure 4 is a graph of the percent stability of a composition containing echothiophate refrigerated at 5 degrees Celsius and 25 degrees Celsius for over 30 months. DETAILED DESCRIPTION

[0129] The present invention relates to compositions and methods for treating presbyopia, irregular astigmatism and / or refractive errors comprising administering to a patient in need thereof a pharmaceutical composition comprising a muscarinic agonist that preferentially activates Ml and M3 muscarinic acetylcholine receptors, preferably Ml greater than M3, most preferably echothiophate or a derivative thereof. Using the compositions of the present invention, it has been surprisingly and unexpectedly discovered that echothiophate can provide enhanced reversal of presbyopia during the day or night (when viewing includes one or more direct or reflected light sources) with negligible side effects.

[0130] Traditionally, aceclidine is used to treat 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 a diluent required to reconstitute the lyophilized aceclidine prior to topical instillation. Romano J.H., Double-blind cross-over comparison of aceclidine and pilocarpine in open-angle glaucoma, Brit J Ophthal, August 1970, 54(8), 510-521. Another aspect of the present invention is to provide a stable aqueous aceclidine composition in conjunction with cold chain storage. Yet another aspect of the present invention is to provide a method of stabilizing an aqueous aceclidine solution by combining effective excipients, effective pH range, and effective temperature range.

[0131] The compositions and methods of the present invention treat presbyopia by increasing the depth of focus in a presbyopic patient, by administering an ophthalmic composition that reduces pupil dilation in dark or dim light, produces a certain degree and duration of pupil constriction without accommodation, provides cosmetic whitening and / or prevents induced redness. The compositions and methods of the present invention also do not cause significant pupil rebound, rapid tolerance, ciliary spasm, induce myopia, or decrease distance vision. In addition, the compositions and methods of the present invention allow further improvement in visual acuity and binocular (two-eyed) depth perception treatment. The ophthalmic compositions of the present invention surprisingly produce a pupil of about 1.5 to about 2.4 mm at the anterior iris plane, and a pupil of about 2.0 mm at the corneal surface. Without wishing to be bound by a particular theory, the clinical effect appears to involve both a modulation increase in accommodative tone and an enhancement of pinhole near focal depth to improve near vision, estimated to be about -1.25 D or less, but limited in the ability to remain within the pinhole corrective distance range, found to be about -1.00 D or less, resulting in a sum increase that in some cases can make near vision increase +2.00 D or more without distance blur; and a reduction or elimination of redness, which otherwise is a hallmark feature of using a miotic. The miotic of the present invention with this modulation and limitation of accommodative tone peak is superior to and Flexivue The pinhole effect of the corneal inlay allows binocular treatment without dimming the peak. The pupil constrictor of the present invention with accommodative modulating is also superior to the inlay because the actual constriction of the pupil does not cause the concomitant severe night vision interference caused by the light scattering boundaries of the anterior corneal pinhole created by the inlay. Further, the pupil constrictor provides greater field of view and more transmission of focused light and the optimal pupil range for use of the present invention formulation is found to be about 1.5 mm to 2.1 mm, and without counting the dimming which is mild and very tolerable, improves contrast and distance vision, reduces night glare and improves near vision.

[0132] The use of aceclidine has minimal effect on the longitudinal ciliary muscle when compared to the use of general muscarinic agonists such as pilocarpine and carbachol, thereby reducing the risk of retinal detachment. Further, the inclusion of a ciliary muscle paralytic results in only a 0.04 mm shallowing of the anterior chamber. Aceclidine, especially enhanced according to the present invention, also has greater control of strength, duration and minimum pupil diameter than traditional pilocarpine with or without alpha agonists, and less anterior chamber inflammation with long term use. The present invention composition achieves these advantages by simultaneously allowing pinhole near vision depth perception benefits and accommodative increase below the threshold of near distance blur induced by pupil constriction, and therefore, without wishing to be bound by a particular theory, it is believed in the preferred embodiment that the rate of pupil constriction and the rate of accommodative increase are maintained in a synchronized balance thereby allowing pinhole correction in applications for presbyopia correction, which otherwise induces accommodative blur that occurs in prior art applications. Thus, this combination is found to avoid distance blur, and the reaction typical of patients using pilocarpine and / or carbachol is the induction of pupil constriction, which is not found with the present invention formulation, as well as accommodative hyperopia and ciliary muscle spasm manifesting as supraorbital neuralgia or migraine-like headaches.

[0133] To achieve any reasonable duration of utility, such conventional preparations of pilocarpine are still limited to less than or equal to about 4 hours in most cases, because the high proportion of pupil constriction accommodation requires a minimum concentration of pilocarpine of about 1.0% that does not eliminate distance induced near vision blur and ciliary spasm. In addition, pilocarpine must be instilled monocularly to minimize the intolerable distance blur to still annoying 2-3 line distance blur. Even monocularly instilled, pilocarpine can cause annoying accompanying distance blur, as well as having to be limited to about 1.0%. In most subjects, after instillation of 1.0% pilocarpine, the pupil size is about 2.3 mm or greater, limiting any significant pinhole depth perception benefit as well as any induced myopic ray pinhole filtering. Attempts to prevent the very strong accommodation of 5D to 11D that is well known to occur with higher pilocarpine concentrations are limited to about 1.0% for conventional preparations of pilocarpine, with a short duration of time, and still annoying but reduced distance blur in emmetropia or myopia (slightly neutralized in mild hyperopia).

[0134] In preferred embodiments, by using a miotic agent in combination with a cycloplegic agent and restricting both to narrow and specific ratios, any effect on accommodation can be further reduced or completely eliminated, where such ratios are found in US Patent 9,089,562, for example the ratio of about 35: 1 in one preferred embodiment. For the present invention, the ratio is increased by about 300-700% in the presence of a cryoprotective agent. Eucilidine is capable of producing increased depth of focus by pupil constriction below 2.3 mm and modest accommodation as described in the present invention. The use of the present invention composition results in a particularly enhanced pupil constriction. This enhanced pupil constriction makes it possible to use a-2 agonists at very low concentrations if a reduction in mild ocular redness is desired. Without such agonists, the combination of other inactive ingredients reduces or effectively eliminates induced redness. In addition, because of the apparent and surprising selectivity of eucilidine, and the discovery of commercially stable eucilidine formulations in the present invention, the administration of the present invention composition to the eye results in a net strong enhancement of near visual acuity from the pupil constriction pinhole effect and the cycloplegic accommodation. These benefits are accompanied by a filtering pupil effect, where the filtering pupil effect eliminates any distance blur from accommodation, which in many cases can correct residual refractive error and optical aberrations, thereby improving distance vision. Thus, the administration of eucilidine results in pupil constriction without excessive accommodation and accompanying distance blur. However, the use of eucilidine alone can induce hyperemia and supraorbital neuralgia. Without the present invention formulation enhancement, for example the need for a cycloplegic agent, a cryoprotective agent or both, eucilidine at low concentrations can produce less than optimal pupil constriction, or at higher concentrations can produce pupil constriction beyond the desired peak to achieve a satisfactory duration of greater than 3-4 hours. However, it has been found that the use of a cycloplegic agent is highly sensitive to other inactive ingredients in the formulation, which are generally unrelated to the action of the active agent, particularly for a cryoprotective agent, in one preferred embodiment because of the commercially preferred eucilidine reduction or elimination of the need for such a cycloplegic agent, reducing its concentration to an extremely low concentration, 0.042% has been high enough to result in a significant reduction in efficacy when a cryoprotective agent is present, for example a polyol such as mannitol. In addition, without the present invention formulation enhancement of eucilidine, in dim or absent lighting results in a darkening of vision, and cycloplegic pain beyond a threshold of reasonable tolerance, which can last for an hour or more, and is similar to a severe migraine headache.

[0135] Certain embodiments of the present invention enhance the degree of mydriasis found, preferably, in preferred embodiments, by the use of non-ionic surfactants and viscosity agents, a stable mydriasis effect range of about 1.50-2.20 mm is provided for most patients. Similar benefits can be obtained using other penetration enhancers, especially hydroxypropyl methylcellulose, high viscosity carboxymethylcellulose, The exact concentration of a particular viscosity agent will be well known to those skilled in the art to depend on the molecular weight and concentration of the agent selected, such that for increased molecular weight, a reduced concentration can have the same viscosity. Due to the rheological properties of the preferred embodiments, the present invention additionally prevents nasal congestion when high levels of eucatropine reach the nasal mucosa.

[0136] The combination of eucatropine and a low concentration of a selective a-2 adrenergic receptor agonist (a-2 agonist or a-2 adrenergic agonist), such as famotidine, brimonidine or guanfacine, can achieve the desired effect of mydriasis with reduced or no redness. The use of a low concentration of a selective a-2 agonist can result in a substantial reduction of hyperemia, greatly reducing the risk of rebound hyperemia found at concentrations of about 0.06% w / v or higher. Furthermore, the use of a low concentration of a selective a-2 agonist does not adversely alter the pupillary constriction caused by eucatropine. In contrast, when brimonidine 0.20% w / v is used topically for night vision pupillary accommodation, almost 100% of subjects develop a rapid immunity to pupillary accommodation due to upregulation of a-2 receptors in the subjects over four weeks.

[0137] Surprisingly, the addition of a cycloplegic agent, by further reducing the degree of cyclospasm when topically instilled without compromising pupillary response, reduces any supraorbital neuralgia or associated discomfort. More surprisingly and surprisingly, in one preferred embodiment of U.S. Patent No. 9,089,562, a ratio of 1.40% eucatropine to about 0.040% tropicamide (35:1) in the presence of mannitol becomes about 1.75% eucatropine to about 0.004% to 0.010% tropicamide (350:1, 175:1, respectively), where 2.5% of the effect is superior to 4.0%.

[0138] The lack of miosis response is an unexpected and surprising finding because specific cycloplegics, such as tropicamide, have a known pupillary dilation effect at concentrations as low as 0.01% w / v (Griinberger J. et al., The pupillary response test as a method to differentiate various types of dementia, Neuropsychiatr, 2009, 23(1), p. 57). More specifically, cycloplegics cause pupillary mydriasis (i.e., dilation of the iris’ radiating muscles). In addition, the addition of a cycloplegic to a miotic unexpectedly increases the time that the pupil remains within the desired size range without becoming overly restricted. The peak miosis effect at 30-60 minutes can be titrated inversely by the concentration of the cycloplegic. It was discovered in the present invention that concentrations of tropicamide significantly caused the ciliary muscles to relax more than the iris radial musculature. In fact, it was discovered that iris pupil dilation could be inhibited by adding tropicamide to the composition used in the present invention containing a concentration of aceclidine, while the level of pupil constriction was more uniform during the miotic effect. In addition, surprisingly, and unexpectedly, the addition of tropicamide can reduce the peak degree of pupil constriction, without inducing pupil dilation, resulting in a constant and ideal pupil size throughout the drug-induced miosis process. This more uniform pupil size enables beneficial near and far vision without the diffraction limitations caused by a greatly reduced pupil size at the peak of pupil constriction (e.g., 1.25 mm), which in turn results in an adverse darkening or loss of resolution.

[0139] Previously, in U.S. Patent No. 9,089,562, it was surprisingly discovered that, in a preferred embodiment, the addition of at least 0.04% w / v of a cycloplegic reduced the ciliary side effects caused by aceclidine (1.40%) administered to the eye. However, the composition of the formulation was not stable enough for commercial use and generally had a duration of about 5 to 6 hours at most.

[0140] Additional findings of the present invention are commercially stable aceclidine formulations with enhanced efficacy and duration:

[0141] Surprisingly, and in contrast to the synergistic effect of adding 0.040% of a cycloplegic agent to 1.40% of aceclidine, the present invention found that a combination of aceclidine with a cryoprotective agent can achieve similar pupil range with reduced or no cycloplegic side effects, aceclidine at 1.50% - 2.0%, preferably about 1.75%, and a cryoprotective agent, preferably a polyol, more preferably in one preferred embodiment mannitol, particularly 0.5% to 4.0%, and most preferably about 2.5% mannitol. In contrast to the teaching of the cycloplegic agent concentration range claimed in US 9,089,562, when a cryoprotective agent is combined with aceclidine, lyophilization can be performed without degrading aceclidine, while further reducing or eliminating the need for a cryoprotective agent in the present invention. Optionally, as found in the preferred embodiments of the present invention, the added cryoprotective agent can also thus be used to greatly reduce (i.e. no more than 0.025% w / v of a cycloplegic agent, preferably no more than 0.004% to 0.015%, most preferably 0.005% to 0.010%) the cycloplegic agent concentration, necessitating further elimination of the mild but potentially troublesome cycloplegic side effects, particularly in younger hyperopes, and further modulating the pupil constriction, reducing and in most cases eliminating any bothersome darkening peak concentration, by using aceclidine and a cryoprotective agent alone or in combination. In preferred embodiments, it was found that about 1.50% - 2.0%, more preferably 1.75% aceclidine and about 0.5% - 4.0%, more preferably 2.5% mannitol provided the optimal concentration combination of the present invention, which was necessary but not sufficient for the about 3 lines of near improvement and 5 hours or more duration desired for an effective topical presbyopia combination, wherein additional formulations were found to further enhance the desired clinical near improvement amplitude and duration.

[0142] Surprisingly, it was found that adding a viscosity agent to the above a. composition only modestly improved the amplitude and duration, however, when a non-ionic surfactant, such as polyethylene glycol stearate or polysorbate 80 was first added, an optimal concentration was found which provided a greatly improved amplitude and duration for the present invention, which could provide a substantially significant duration than when added alone. It was found that a concentration of 1.0% to 10.0%, preferably about 2.5% to 5.0% w / v of polysorbate 80 or polyethylene glycol 40 stearate was beneficial.

[0143] When the above a. improved formulation and b. improved formulation are combined, a preferred embodiment results, such as aceclidine 1.75%, mannitol 2.5% and polysorbate 80 2.75%. Surprisingly, viscosity agents such as high viscosity carboxymethylcellulose ("CMC") modestly enhance the amplitude and greatly extend the duration, unlike the above a. formulation alone. High molecular weight CMC concentrations of 0.75% to 1.75%, most preferably about 1.40%, or hydroxypropylmethylcellulose ("HPMC") of about 0.25% to 2.0%, more preferably about 0.50% or 1.50%, most preferably about 1.0% to 1.25%, when combined with the a. improved formulation and b. improved formulation can sustain a myopic vision improvement of about +3 lines or more for about 5-10 hours, on average about 7 hours or more, as compared to less than 4 hours of duration for 1.0% pilocarpine.

[0144] Without wishing to be bound by a particular theory, when citrate is combined with EDTA as a preferred embodiment, the buffer appears to: 1) reduce redness; 2) improve shelf life of sorbate preservative, and when combined with 0.005% to 0.02% (preferably 0.02%) BAK, also improves myopic vision lines to about 4 lines and duration to about 8 to 12 hours.

[0145] In a preferred embodiment, 0.5% or 1.5% sodium chloride is additionally added. Optionally, the sodium chloride can be replaced by boric acid or potassium borate, preferably 0.35% boric acid; preferably 0.47% potassium borate.

[0146] Without wishing to be bound by a particular theory, it appears that the addition of non-ionic surfactants at an optimal concentration of about 2.5% to 5.0% enhances the penetration of aceclidine into the eye, which can be related to optimal micelle size, particularly once the micelle or nanomicelle range is reached. This increase in penetration is consistent with an increase in the desired magnitude and duration of the increase in ciliary muscle sensation with a slight increase in lightening and dimming in the absence of tropicamide but in the presence of mannitol. Thus, the use of a cycloplegic in the combination formulation is no longer required in the presence of the combination of the improved formulations of a.-d. above. The addition of non-ionic surfactants at the preferred concentrations can further improve the use of lower concentrations of cycloplegics than US 9.089,562, such as about 0.042% tropicamide and 1.40% aceclidine. In a preferred embodiment of the present application, about 1.75% aceclidine, 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% tropicamide, more preferably about 0.005% to 0.007% tropicamide, most preferably about 0.005% to 0.006% tropicamide are included. Micelle formers above the critical micelle concentration allow the micelles to spread over the tear film surface and at low concentrations to cover the surface, while at higher concentrations, the micelles gradually shrink and "squeeze" along the surface. Without wishing to be bound by a particular theory, it is believed that at the optimal concentration, a minimum micelle diameter is reached before significant multiple lamellae (layering) occurs. It is believed that at the optimal concentration of about 100-250 nm, the nanomicelles formed along the surface surround the highly charged and hydrophilic aceclidine, thereby facilitating its penetration through the lipophilic epithelial cells.

[0147] Without being bound by a specific theory, a composition containing 0.02% BAK to about 0.10% sorbate, about 0.10% EDTA, preferably 1.75% acetylcholine, 2.5% mannitol, 0.01% tropicamide, and citrate buffer (1 to 100 mM, preferably 3 to 5 mM) has a micelle concentration higher than the critical micelle concentration of BAK. BAK and BAK micelles, as cationic surfactants, form an ionic micelle gradient with a +charge NH4+ tetravalent nitrogen, causing the polar heads to aggregate on the periphery and the hydrophobic tails of the lipophilic alkyl chains to aggregate on the inside. This can result in remarkably similar acecridin arrangements due to their dipole orientation of the quaternary NH3 nucleophilic or NH4 protonated nitrogen along the outer polar heads and the more hydrophobic carbonyl C=O along the hydrophobic BAK micelle tails. These prevent, greatly reduce, or moderately reduce collisions between any nonionic acecridin molecules—nucleophiles—that, if oriented in solution such that they randomly collide with the carbonyl group of another acecridin, will cause the acecridin to undergo a chemical transformation by nucleophilic attack on the target carbonyl group. This reproducible orientation can be repeated in such nucleophiles and other acecridins. Without BAK orientation, the presence of 0.005% micelles, preferably 0.01% to 0.02% micelles, most preferably micelles, will result in instability. In a preferred embodiment, at a preferred pH, the concentration of such nonionic nucleophiles is relatively low, but these nonionic nucleophiles have a high ability to repeatedly destabilize adjacent acetylcholine without self-degradation. Once the double-chamber bottle is opened and the lyophilized acetylcholine / mannitol is mixed with the remaining formulation in a diluent, the potency can be improved for more than one month, and / or the stability of the solution can be improved to make it commercially viable, either at room temperature or via a cold chain.

[0148] It has been found that BAK alone cannot provide sufficient antiseptic efficacy against bacteria and fungi, but BAK and sorbate or sorbate alone can satisfactorily preserve the diluents and / or mixtures of the present invention.

[0149] Not wishing to be bound by a specific theory, a preferred embodiment of the present invention, for example containing 1.25% hydroxypropyl methylcellulose, can have a viscosity of about 400 cps before instillation, but this is different from conventional high-viscosity artificial tear formulations (e.g., those with a viscosity of about 400 cps). Or about 100 Unlike other viscosities, the viscosity is approximately 400 cps. It may cause blurred vision for 10-20 minutes, approximately 100 cps. Will cause similar but slightly reduced blurring, only about 60 seconds of blurring but rapidly dissipates as the tear secretion rushes in; in this case, both the high shear non-Newtonian viscosity reduction (e.g., about 1 / 1000 of a second during a blink) and the parasympathetic trigger of tear secretion as a sialate precursor of aceclidine can play a role.

[0150] General mydriatic agents, such as pilocarpine, carbachol and phospholine diesterase, can cause pupil constriction, which improves near vision in presbyopic patients. However, these general mydriatic agents are associated with a concomitant decrease in distance vision, which is not optimal in terms of efficacy and accommodation. Aceclidine does not have this problem. Surprisingly, co-administration of a cycloplegic agent with aceclidine can attenuate the decrease in distance vision.

[0151] The preferred embodiments of the ophthalmic compositions of the present application have comfort, safety and efficacy due to the presence of non-ionic surfactants, viscosity enhancers, tonicity agents, preservatives and a pH of about 5.0 to about 8.0. Among them, the non-ionic surfactants are, for example, alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin, preferably 2-hydroxypropyl beta-cyclodextrin ("HR beta CD") and sulfobutyl ether of beta-cyclodextrin polyethylene glycol alkyl (such as polyethylene glycol 40 stearate and polyethylene glycol 35 castor oil), or poloxamer (such as poloxamer 108 and poloxamer 407), polysorbate (such as polysorbate 80 or 35) (Brij is a registered trademark of Uniqema Americas LLC); viscosity agents such as carboxymethylcellulose ("CMC"); tonicity agents such as sodium chloride; preservatives such as benzalkonium chloride. In addition, an increase in the concentration of non-ionic surfactants can result in a decrease in redness. Specifically, an increase in polysorbate from 0.10% to 0.50-1.0% can result in a decrease in redness. In addition, an increase in CMC or 940 from 0.50% w / v to 1.5% w / v (preferably 1.40-1.43% w / v) can improve near vision, both quantitatively and in duration.

[0152] The viscosity of the compositions of the present application, including viscosity agents, can be about 1 to about 10,000 cps before topical instillation into the eye. Due to the shear forces experienced as the composition exits the administration device, the viscosity decreases to about 1 to about 25 cps under the high shear forces of a blink, and to 50 to 200 cps under the low shear forces between blinks, thereby allowing greater drop retention, less spillage, less nasolacrimal drainage and systemic absorption upon topical instillation.

[0153] Definitions

[0154] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0155] As used herein, the term "stabilize" refers to any process that promotes and / or maintains an active agent in solution. The term "stabilize" as used herein also refers to any method or process that inhibits and / or reduces the tendency of a toxobin agonist, including acetylcholine, to degrade.

[0156] As used herein, "about" is defined as plus or minus 10% of the indicated numerical value, weight, etc. For example, "about 5% w / v" is understood to mean "4.5% to 5.5% w / v". Thus, numerical values within 10% of the stated amounts are included within the scope of the present claims.

[0157] As used herein, "% w / v" refers to the weight percent of the total composition.

[0158] As used herein, the term "subject" refers broadly and without limitation to a human or other animal.

[0159] As used herein, the term "container" refers to a pharmaceutically acceptable container, which includes a chamber suitable for holding a liquid pharmaceutical product. Containers include, for example, vials, syringes, capsules, and ampoules.

[0160] As used herein, "headspace" refers to the area between the composition in the chamber of the container and the cap when the cap is oriented away from the direction of gravitational pull.

[0161] As used herein, the term "cap" or "closure" refers to any article capable of preventing the composition from exiting the container.

[0162] The term muscarinic receptor agonist ("muscarinic agonist") includes agonists that activate muscarinic-type acetylcholine receptors ("muscarinic receptors"). Muscarinic receptors are divided into five subtypes, which are referred to as Ml -M5. Muscarinic agonists of the present invention include those that preferentially activate Ml and M3 receptors over M2, M4, and M5 receptors ("Ml / M3 agonists").

[0163] M1 / M3 agonists include, but are not limited to, aceclidine, xanomeline, talsaclidine, sabcomeline, cevimeline, arvanil, myristylbenzyl quaternary ammonium salt, milameline, SDZ-210-086, YM-796, RS-86, CDD-0102A (5-[3-ethyl-l,2,4-oxadiazol-5-yl]-l,4,5,6-tetrahydropyrimidine hydrochloride), N-arylurea substituted 3-morpholino myristylbenzyl quaternary ammonium salt, VUO255-035 (N-[3-oxo-3-[4-(4-pyridinyl)-l-piperazinyl]propyl]-2,l,3-benzothiadiazole-4-sulfonamide), benzyl quinolone carboxylic acid (BQCA), WAY- 132983, AFB267B (NGX267), AC-42, AC-260584, chloro-pyrazines including, but not limited to, L-687,306, L-689-660, 77-LH-28-1, LY593039, and any quiniclidine having one or more carbon substitutions, including, but not limited to, esters, thiols, or 5 or 6 carbon ring structures having one or more substituted nitrogens and / or oxygens, or any pharmaceutically acceptable salt, ester, analog, prodrug, or derivative thereof. A preferred M1 / M3 agonist is aceclidine. In a preferred embodiment, the muscarinic agonists of the present application include those that preferentially activate M1 and M3, but not M2, M4, and M5, and more preferably activate M1, but not M3. In a more preferred embodiment, the muscarinic agonists of the present application include those that activate M1 only.

[0164] The term "aceclidine" includes salts, esters, analogs, prodrugs, and derivatives thereof, including, but not limited to, aceclidine as a racemic mixture, aceclidine (+) enantiomer, aceclidine (-) enantiomer, aceclidine analogs, and aceclidine prodrugs. Aceclidine analogs include, but are not limited to, 1,2,5-thiadiazole substituted analogs having high M1 selectivity, such as those disclosed in Ward, J. S., et al., 1,2,5-Thiadiazole analogues of aceclidine as potent m1 muscarinic agonists, J Med Chem, 1998, Jan. 29, 41(3), 379-392, as potent Ml muscarinic agonists. Aceclidine prodrugs include, but are not limited to, carbamates.

[0165] The term "selective a-2 adrenergic receptor agonist" or "a-2 agonist" includes all a-2 adrenergic receptor agonists with an affinity for the a-2 adrenergic receptor that is more than 900-fold or greater than the affinity for the a-1 adrenergic receptor, or an affinity for the a-2a or a-2b adrenergic receptor that is more than 300-fold or greater than the affinity for the a-1 adrenergic receptor. The term also includes pharmaceutically acceptable salts, esters, prodrugs, and other derivatives of the selective a-2 adrenergic receptor agonists.

[0166] 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.

[0167] The term "low concentration" or "low dose" of an a-2 adrenergic receptor agonist refers to a concentration of between about 0.0001% to about 0.065% w / v. More preferably, about 0.001% to about 0.035% w / v; and more preferably, about 0.01% to about 0.035% w / v; and even more preferably, about 0.03% to about 0.035% w / v.

[0168] The term "brimonidine" includes, but is not limited to, brimonidine salts and other derivatives, and specifically includes, but is not limited to, brimonidine tartrate, 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, and

[0169] The terms "treating" and "treatment" refer to the reversal, alleviation, inhibition, or slowing of the progression of the disease, disorder, or condition to which such terms apply, or one or more symptoms of such disease, disorder, or condition.

[0170] The term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable, i.e., the material does not cause an unacceptably adverse effect on the biological activity or interaction of the material.

[0171] The term "pharmaceutically effective amount" as used herein refers to an amount sufficient to effect a desired biological result, such as a beneficial result, including, but not limited to, preventing, alleviating, ameliorating, or eliminating a sign or symptom of a disease or disorder. Thus, the total amount of each active ingredient of the pharmaceutical composition or method is sufficient to show a meaningful benefit to the subject. The "pharmaceutically effective amount" will thus depend on the context in which the medicament is being used. A pharmaceutically effective amount can be administered in one or more administrations of prophylaxis or treatment.

[0172] The term "prodrug" refers to compounds, including but not limited to monomers and dimers of the compounds of the present invention, which have cleavable groups and become by physiological action in vivo the compounds which are active in the human body.

[0173] As used herein, "salt" refers to those salts which retain the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable at the dosage administered. The salts of the compounds of the present application can be made from inorganic or organic acids or bases.

[0174] The term "higher order aberrations" refers to image deviations selected from starburst, halos (spherical aberrations), double vision, multiple images, blurred vision, dizziness, and trilobes.

[0175] The term "cold chain" refers to storage at a temperature of about 2 to about 8 °C from manufacture to immediate administration before use.

[0176] The compounds of the present application can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids or bases. The phrase "pharmaceutically-acceptable salt" means salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically-acceptable salts in detail in J. Pharm. Sci., 1977, 66: 1 et seq. Pharmaceutical Sciences, Pharmaceutically-acceptable salts are described in more detail in Berge S. M. et al. J. Pharm. Sci. 1977, 66: 1 et seq.

[0177] These salts can be prepared in situ during the final isolation and purification of the compounds of the application, or by separately reacting the free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, trimethylacetate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. Additionally, salts of the base moiety with pharmaceutically acceptable amino acids can be formed, such as with arginine, lysine, and the like. Salts of the compounds of the application can be converted into other salts as a pharmaceutical preparation. Furthermore, the compounds of the application can be administered in a form suitable for rectal administration. Such administration forms include, for example, suppositories for rectal administration comprising the active ingredient with a pharmaceutically acceptable non-irritating excipient. Examples of such excipients are cocoa butter and other glycerides. The compounds of the application can also be administered in a form suitable for vaginal administration. Such administration forms include, for example, pessaries, ovules, or

[0178] Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the application, by reacting a carboxylate-containing moiety with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia, or with an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, those based on alkali or alkaline earth metal cations such as sodium, potassium, calcium, magnesium, and aluminum, and nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium, and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0179] The term "ester" as used herein is represented by— OC(O)A 1 or— C(O)OA 1 wherein A1may be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, or other suitable substituent.

[0180] Compositions of the application

[0181] In one embodiment, the present application is directed to ophthalmic compositions comprising aceclidine. In a preferred embodiment, the concentration of aceclidine is from about 0.25% to about 2.0% w / v, more preferably from about 0.50% to about 1.90% w / v, and more preferably from about 1.65% to about 1.85% w / v, most preferably about 1.75% w / v. Since aceclidine is a tertiary amine with asymmetry, there are + and - optical isomers (in some studies the (+) is more effective while in others it is felt that the (-) can be more effective). For the above concentrations, polarimetry has demonstrated that the ratio of the (+) and (-) isomers is exactly equal for these concentrations. Therefore, changing the ratio can change the concentration range that is proportional to the change in ratio.

[0182] The present application is also directed to an ophthalmic composition comprising a muscarinic agonist, preferably a non-ionic surfactant above the critical micelle concentration of the composition, and a viscosity enhancing agent or in situ gelling agent. In a preferred embodiment, the initial viscosity of the composition upon topical administration is greater than 20 cps, preferably 50 cps, more preferably greater than 70 cps at low shear (1 / s) viscosity.

[0183] A cryoprotectant is a compound that prevents freezing or prevents damage to a compound during freezing. As used herein, the term "cryoprotectant" or "cryoprotectants" includes lyoprotectants. Cryoprotectants suitable for use in the present application include, but are not limited to, polyols, sugars, ethanol, lower alkanols, lipophilic solvents, hydrophilic solvents, bulking agents, solubilizing agents, 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.

[0184] As used herein, the term "polyol" refers to a compound having multiple hydroxyl functional groups available for organic reactions, such as monomeric polyols, such as glycerol, pentaerythritol, ethylene glycol, and sucrose. In addition, polyol can refer to polymeric polyols including glycerol, pentaerythritol, ethylene glycol, and sucrose reacted with propylene oxide or ethylene oxide. In a preferred embodiment, the polyol is selected from the group consisting of mannitol, glycerol, erythritol, lactitol, xylitol, sorbitol, isosorbide, ethylene glycol, propylene glycol, maltitol, threitol, arabitol, and ribitol. In a more preferred embodiment, the polyol is mannitol.

[0185] Sugars suitable for use in the present application as cryoprotectants include, but are not limited to, glucose, sucrose, trehalose, lactose, maltose, fructose, and dextran.

[0186] In another preferred embodiment, the alcohol includes, but is not limited to, methanol.

[0187] In one embodiment, the present application excludes each of the cryoprotective agents from the definition of cryoprotective agent, individually.

[0188] The cryoprotective agent can be present in the composition of the present application at a concentration of about 0.1% to about 99% w / v, preferably about 1% to about 50% w / v, more preferably about 1% to about 10% w / v.

[0189] As used herein, "lower alkanol" includes C1-C6 alkanols. Lower alkanols suitable for use in the present application include, but are not limited to, pentanol, butanol, sec-butanol, t-butanol, n-butanol, ethanol, isobutanol, methanol, isopropanol, and propanol.

[0190] Filling agents suitable for use in the present application include, but are not limited to, sugars, polyvinylpyrrolidone, cyclodextrin, and trehalose.

[0191] Solubilizing agents suitable for use in the present application include, but are not limited to, cyclamates, gentisic acid, and cyclodextrin.

[0192] In a preferred embodiment, surfactants suitable for use in the present application include, but are not limited to, non-ionic surfactants, more preferably surfactants having a hydrophilic-lipophilic balance ("HLB") value of 1 to 18.

[0193] In a preferred embodiment, antioxidants suitable for use in the present application include, but are not limited to, bisulfites, ascorbic acid, disodium or tetrasodium ethylenediaminetetraacetate, citrate, butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), sulfites, propyl gallate, amino acids containing sulfhydryl groups, and thiols.

[0194] Non-ionic surfactants suitable for use in the present application include cyclodextrin, polyethylene glycol alkyl, poloxamer, or combinations thereof, and can additionally include combinations with other non-ionic surfactants such as polysorbates. Preferred embodiments include polyethylene glycol 40 stearate and optionally poloxamer 108, poloxamer 188, poloxamer 407, polysorbate 20, polysorbate 80, beta-cyclodextrin with or without an ionic charge of butyrate 2-Hydroxypropyl-β-cyclodextrin (“HPβCD”), α-cyclodextrin, γ-cyclodextrin, polyethylene glycol 35 castor oil, and polyethylene glycol 40 hydrogenated castor oil, or combinations thereof. Furthermore, other nonionic surfactants compatible with ophthalmic applications offer similar alternative formulation advantages and may include, but are not limited to, one or more nonionic surfactants, such as any poloxamer analogues or derivatives (e.g., poloxamer, poloxamer 103, poloxamer 123, poloxamer 124, poloxamer 407, poloxamer 188, and poloxamer 338), any polysorbate analogues or derivatives (e.g., polysorbate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), and any cyclodextrin analogues or derivatives (cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, etc.). -γ-cyclodextrin, randomly methylated β-cyclodextrin, β-cyclodextrin sulfonyl ether, γ-cyclodextrin sulfonyl ether or glucosyl-β-cyclodextrin), polyoxyethylene, polyoxypropylene glycerol ether, polysorbate analogues or derivatives, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (200), polyoxypropylene glycerol ether (70), polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, polyethylene glycol stearate, nonylphenol ether, octylphenol polyoxyethylene ether, nonylphenol polyoxyethylene ether, propylene glycol monocaprylate (capryols), propylene glycol monolaurate, polyethylene glycol (“PEG”) 35, 78, 98, 700 (polyoxyethylene glycol alkyl ether), glyceryl laurate, lauryl glucoside, decyl glucoside or cetyl alcohol; or a zwitterionic surfactant such as palmitoyl carnitine, cocamide DEA, cocamide DEA derivatives, cocamidopropyl betaine or trimethyl glycine, N-2(2-acetylamino)-2-aminoethanesulfonic acid (ACES), N-2-acetylaminoiminodiacetic acid (ADA), N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 2-[Bis-(2-hydroxyethyl)-amino]-2-hydroxymethyl-propane-1,3-diol (Bis-Tris), 3-cyclohexylamino-1-propane sulfonic acid (CAPS), 2-cyclohexylamino-1-ethane sulfonic acid (CHES), N,N-bis(2-hydroxyethyl)-3-amino-2-hydroxypropane sulfonic acid (DIPSO), 4-(2-hydroxyethyl)-1-piperazine propane sulfonic acid (EPPS), N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid (HEPES), 2-(N-morpholino)-ethane sulfonic acid (MES), 4-(N-morpholino)-butane sulfonic acid (MOBS), 2-(N-morpholino)-propane sulfonic acid (MOPS), 3-morpholino-2-hydroxypropane sulfonic acid (MOPSO), 1,4-piperazine-bis(ethane sulfonic acid) (PIPES), piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) (POPSO), N-tris(hydroxymethyl)methyl-2-aminopropane sulfonic acid (TAPS), N-[tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropane sulfonic acid (TAPSO), N-tris(hydroxymethyl)methyl-2-aminoethane sulfonic acid (TES), 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris), tylorox, Soulan TM 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]phenanthryl-3-yl]oxy]ethanol) and 20-80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate and sorbitan monooleate). In certain embodiments, it can be preferred to add an anionic surfactant such as sodium dodecyl sulfate and / or sodium dodecyl sulfate. In other embodiments, it is preferred to add polysorbate 80. In addition to the non-ionic surfactants described above, any non-ionic surfactant is suitable for use in the present application as long as its concentration is above the critical micelle concentration of the non-ionic surfactant. Preferably, the non-ionic surfactants used in the present application reach micelles of sub-micron diameter, more preferably less than 200 nanometers, more preferably less than 150 nanometers.

[0195] Ophthalmic in situ gels that can replace or supplement one or more non-ionic surfactants include, but are not limited to, gelatin, carbomers of various molecular weights (including carbomer 934P and 974P), xanthan gum, alginic acid (alginate), guar gum, locust bean gum, chitosan, pectin, and other gelling agents known to those skilled in the art.

[0196] In preferred embodiments, the non-ionic surfactant is polyoxyl 40 stearate at a concentration of about 1 to about 15% w / v, more preferably 5.5% w / v.

[0197] In such preferred embodiments, polyoxyl 40 stearate is found to preferentially enhance the redness-reducing effects of alpha-2 agonists over aqueous solutions and other non-ionic surfactants such as poloxamer 407.

[0198] In other preferred embodiments, the non-ionic surfactant is polysorbate 80 at a concentration of about 0.5% to about 10% w / v, more preferably about 1% to about 7% w / v, more preferably about 2% to about 5% w / v, more preferably about 2.5% to about 4% w / v, most preferably about 2.5% or 2.75% or 3% or 4% or 5% w / v.

[0199] Viscosity agents suitable for use in the present application include, but are not limited to, gums such as guar gum, hydroxypropyl guar (“hp-guar”), and xanthan gum, alginates, chitosan, vegetable gels, hyaluronic acid, dextran, (polyacrylic acid or carbomer), cellulose derivatives, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, gellan gum, carrageenan, alignic acid, carboxyvinyl polymer, or combinations thereof, wherein, including 900 series, 900 series including 940 (carbomer 940), 910 (carbomer 910), and 934 (carbomer 934), cellulose derivatives such as carboxymethylcellulose (“CMC”), methylcellulose, methylcellulose 4000, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose 2906, carboxypropylmethylcellulose, hydroxypropylethylcellulose, and hydroxyethylcellulose.

[0200] In preferred embodiments, the viscosity agent has an equilibrium viscosity of less than 100 cps, preferably about 15 to about 35 cps, most preferably about 30 cps. In one preferred embodiment, the viscosity agent is 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 certain combinations, it has been surprisingly found that non-ionic surfactant / viscosity agent combinations can result in phase separation and formation of a precipitate over time. In this case, particularly for polyethylene glycol, in one preferred embodiment polyethylene glycol 40 stearate and a cellulose derivative, particularly hydroxypropyl methylcellulose. The use of non-polysaccharide derivatives to enhance viscosity, such as polyacrylic acid derivatives (in preferred embodiments carbomers, carbomer 934 or 940) can prevent this separation; or non-polyoxy non-ionic surfactants can be used instead, such as polysorbate 80 with a cellulose derivative or non-cellulose derivative viscosity agent.

[0201] In another preferred embodiment, the viscosity agent is carboxymethylcellulose at a concentration of about 1% to about 2% w / v, more preferably 1.35% to about 1.45% w / v, most preferably 1.42% w / v or 1.40% w / v.

[0202] In another preferred embodiment, the viscosity agent is hydroxypropyl methylcellulose at a concentration of about 0.5% to about 1.75%, more preferably about 0.75% or 1.5%, still more preferably about 1.0% to about 1.5%, most preferably about 1.25%.

[0203] Without wishing to be bound by a particular theory, the quinuclidine nucleus on aceclidine appears to be electron rich, and thus readily attacks surrounding compounds and itself.

[0204] It has been discovered that several modifications can be used, alone or in combination, to enhance cold chain stable storage, including, in addition to the preferred embodiments, one or more of aceclidine 1.40% to 1.75%, tropicamide 0.025% to 0.10%, and optionally a non-ionic surfactant (such as polyethylene glycol 40 stearate) 0.5%-10%, preferably 5.5% (see Table 1):

[0205] An acidic pH, preferably less than 5.5, preferably less than 5.0, most preferably at about 4.75;

[0206] A viscosity agent, preferably having a viscosity of about 15-50 cps at 25°C, more preferably 20-45 cps, with a preferred embodiment being carbomer 940 at 0.09%-1.5%;

[0207] In a preferred embodiment the cryoprotectant added is a polyol, preferably 2.5-4.0% mannitol;

[0208] Add a buffer, preferably an acetate or phosphate buffer, in the range of 2-100 millimoles, preferably 3-5 millimoles; and

[0209] Add a preservative, wherein preferably BAK 0.015%.

[0210] The selective alpha-2 agonist can be included in the compositions of the present invention or, if additional means of reducing nasal congestion or redness in sensitive subjects is desired, preferably topically applied shortly before or not preferably topically applied shortly after. Suitable selective alpha-2 agonists for use in the present invention have minimal alpha-1 agonist activity at low concentrations. For example, brimonidine or fadolmidine for purposes of the present invention, 1% to 2% w / v is considered a very high amount, 0.5% to 1.0% w / v still highly induces alpha-1 receptors and is toxic. Further, 0.10% to 0.5% w / v is still too high, even 0.070% to 0.10% w / v is associated with a higher incidence of rebound congestion than desired (however, for dexmedetomidine, its greater lipophilicity and intraocular penetration can reduce the rebound risk in this range). Only 0.065% w / v or less is potentially acceptable, 0.050% w / v or more preferably 0.035% w / v or less is desired for most alpha-2 agonists, depending on the degree of selectivity. Some degree of useful activity can occur at concentrations further reduced by one or more orders of magnitude. In preferred embodiments of the present invention, brimonidine, fadolmidine and guanfacine preferentially stimulate alpha-2 adrenergic receptors, even more preferably alpha-2b adrenergic receptors, such that stimulation of alpha-1 adrenergic receptors is insufficient to cause excessive large vasoconstriction and vasoconstrictive ischemia. Further, it has been found that prevention or reduction of the redness phenomenon of drugs that otherwise directly cause skin redness (e.g. acetylcholine agonists, epi-nephrine) enhances compliance in sensitive subjects who can experience skin redness or nasal congestion even if the present formulation does not contain an alpha-2 agonist. However, since alpha-2 agonists shift to their ionic equilibrium, acidic agonists counteract the effects of such agonists at neutral or basic pH to some extent. Thus, each alpha-2 agonist has a preferred pH range when added to the present composition with epi-nephrine, depending on its lipophilicity and pKa. For the present invention, while a pH range of 5.0 to 8.0 is acceptable, a preferred embodiment is a pH of 5.5 to 7.5, more preferably 6.5 to 7.0. Further, it has been found that cyclodextrin and / or polyoxyl 40 stearate as a non-ionic surfactant component or as the only non-ionic surfactant in the composition results in a greater whitening effect when the alpha-2 agonist is included rather than poloxamer 407. The alpha-2 agonist can optionally be administered alone or in certain preferred embodiments the alpha-2 agonist is administered with a present formulation that does not contain an alpha-2 agonist, for example those formulations with 5.5% w / v polyoxyl 40 stearate as a non-ionic surfactant. Although alpha-2 agonists are not necessary except for occasional sensitive subjects.Fadomidine represents the alpha-2 agonist with the highest hydrophilicity and thus the highest surface retention of the present invention. Guanfacine also has high selectivity and hydrophilicity. Brimonidine has high selectivity and moderate lipophilicity. Finally, dexmedetomidine has high selectivity and high lipophilicity, which for the purposes of the present invention can be used to reduce redness less effectively (although it can cause fatigue as a side effect in some patients). In a preferred embodiment, the use of polyoxyl 40 stearate 5.5% w / v, CMC 0.80% w / v, NaCl 0.037% w / v, ethylenediaminetetraacetic acid ("EDTA") 0.015% w / v, borate buffer 5 mM, and BAK 0.007% w / v results in a redness of about 1 to 1.5 of 4, which is transient lasting about 10 minutes, with a return to baseline after 30 minutes.

[0211] In one embodiment, the selective alpha-2 adrenergic receptor agonist is a compound having a binding affinity of about 900-fold or greater, more preferably about 1000-fold or greater, and most preferably about 1500-fold or greater.

[0212] The concentration of the selective alpha-2 adrenergic receptor agonist is about 0.0001% to about 0.065% w / v; preferably, it is about 0.001% to about 0.035% w / v; and more preferably, it is about 0.020% to about 0.035% w / v.

[0213] In one embodiment, the selective alpha-2 adrenergic receptor is selected from the group consisting of brimonidine, guanfacine, fadomidine, dexmedetomidine, (+)-(S)-4-[l-(2,3-dimethyl-phenyl)-ethyl]-l,3-dihydro-imidazole-2-thione, l-[(imidazolidin-2-yl)imino]indazole, and mixtures thereof. Analogs of these compounds having high selective alpha-2 agonist functionality can also be used in the compositions and methods of the present invention.

[0214] In a more preferred embodiment, the selective alpha-2 agonist is selected from the group consisting of fadomidine, guanfacine, and brimonidine. In another more preferred embodiment, the selective alpha-2 agonist is brimonidine in salt form 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 salt.

[0215] In another more preferred embodiment, the selective alpha-2 agonist is fadomidine in hydrochloride ("HC1") form at a concentration of about 0.005% to about 0.05% w / v, more preferably 0.02% to about 0.035% w / v.

[0216] In another more preferred embodiment, the selective alpha-2 agonist is guanfacine in the form of its HC1 salt at a concentration of from about 0.005% to about 0.05% w / v, more preferably from 0.02% to about 0.035% w / v.

[0217] In another more preferred embodiment, the selective alpha-2 agonist is dexmedetomidine in the form of its HC1 salt at a concentration of from about 0.005% to about 0.05% w / v, more preferably from 0.04% to about 0.05% w / v.

[0218] In another preferred embodiment, it was found that pH values below physiological pH enhance the whitening effect of brimonidine, preferably at a pH of 4.5 to 6.5, more preferably at a pH of 5.5 to 6.0. However, all pHs achieve a reduction in redness, and the enhancement of absorption of aceclidine occurs at alkaline pHs, resulting in a better effect at a given concentration, and thus the effective pH range of the present application is from 4.5 to 8.0, preferably from 6.5 to 7.5, most preferably from 7.0 to 7.5.

[0219] The present application also relates to ophthalmic compositions further comprising a cycloplegic agent. It was surprisingly and completely unexpectedly found that certain cycloplegic agents of the present application can be used in combination with miotic agents, particularly aceclidine for the present application, without reducing the onset, amplitude or duration of the miotic agent; and further blunting the peak of the pupillary constriction effect typically associated with the peak absorption time of an aqueous formulation, providing a constant pupillary constriction effect (compared to the time of onset) from 15 minutes to 30 minutes to 6 hours to 10 hours after onset, depending on the desired formulation. The addition of a cycloplegic agent also reduces any residual associated discomfort that can occur shortly after topical instillation, which can be the result of ciliary spasm or excessive pupillary constriction.

[0220] Cycloplegic agents suitable for use in the present application include, but are not limited to, atropine, cyclopentolate hydrochloride), scopolamine, pirenzepine, tropicamide, atropine, 4-diphenylacetyloxy-N-methylpiperidinemethyl bromide (4-DAMP), AF-DX 384, mesoxalol, tripitramine, darifenacin, solifenacin (Vesicare), tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium, and otenzapine (a.k.a. AF-DX 116 or 11-{[2-(diethylamino)methyl]-1-piperidinyl}acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepin-6-one). In a preferred embodiment, the cycloplegic agent is tropicamide at a concentration of about 0.004% to about 0.025% w / v, preferably about 0.005% to about 0.015% w / v, more preferably about 0.005% to about 0.011%, about 0.005% to about 0.007%, about 0.005% to about 0.06%. In another preferred embodiment, the cycloplegic agent is a mixture of tropicamide at a concentration of about 0.04% to about 0.07% w / v or pirenzepine or otenzapine at a concentration of about 0.002% to about 0.05% w / v.

[0221] In a preferred embodiment, it was discovered that 0.01% w / v of tropicamide can slightly reduce supraorbital neuralgia without reducing the average reduction in diameter of the pupil over the duration of effect, 0.030% w / v of tropicamide can further reduce supraorbital neuralgia, and 0.04% to about 0.07% w / v of tropicamide can completely eliminate supraorbital neuralgia. In preferred embodiments, tropicamide has shown a completely unexpected sensitivity effect, with about 0.04% w / v of tropicamide unexpectedly and very effectively reducing or eliminating supraorbital neuralgia and ciliary spasm pain, 0.042% w / v of tropicamide very noticeably further reducing supraorbital neuralgia and ciliary spasm pain, and 0.044% of tropicamide eliminating supraorbital neuralgia and ciliary spasm pain in preferred embodiments without cycloplegia (surprising given its common use as a mydriatic). However, tropicamide does not reduce the average degree of pupil constriction, the onset time of pupil constriction, or the subsequent visual benefits. Rather, tropicamide blunts the peak of miosis that occurs in aqueous formulations, resulting in a smooth and consistent constriction effect over time. It allows for modulation of the peak of pupil constriction to achieve a more even effect over time without the dilation that has occurred with previous uses. Specifically, in some embodiments, tropicamide can be used to prevent the short-lived constriction below 1.50 mm at 30 to 60 minutes post-acetylcholine and to reduce the excessive short-lived constriction and undesirable dimming of vision that can occur at the onset of the peak at about 30 minutes. As an example, an ophthalmic composition includes 1.53% w / v of acetylcholine, 5% w / v of HPpCD, 0.75% w / v of CMC, 0.25% w / v of NaCl, 0.01% w / v of BAK, and a phosphate buffer at pH 7.0; or 1.45% w / v of acetylcholine, 5.5% w / v of polyethylene glycol 40 stearate, 0.80% w / v of CMC, 0.037% w / v of sodium chloride, 0.015% w / v of EDTA, 0.007% w / v BAK, and a phosphate buffer at pH 7.0, ranging from 0.040% w / v tropicamide (noting a moderate dimming) to 0.044% w / v tropicamide (dimming becomes nearly undetectable except in very dark light conditions). This additional pupil size modulation with a cycloplegic allows for acetylcholine concentrations sufficient to prolong the effect while mitigating the accompanying undesirable peak over-constriction and any uncomfortable supraorbital neuralgia. Surprisingly, due to its short-acting nature, tropicamide achieves this blunting without causing pupil mydriasis.Further, in preferred embodiments, it was found that 0.014% w / v of tropicamide reduced supraorbital neuralgia, 0.021% w / v further reduced supraorbital neuralgia, 0.028% to 0.060% w / v, in some embodiments up to 0.09% w / v, completely eliminated supraorbital neuralgia without cycloplegia (i.e. paralysis of the eye's ciliary muscle).

[0222] It has been found that for racemic 50:50 of the (+) and (-) optical isomers of aceclidine, in some studies the (+) is stronger, in others the (-) can be stronger, the effect of tropicamide can depend on the ratio of aceclidine to tropicamide. For example, in an ophthalmic composition of the present invention, said ophthalmic composition comprising 1.55% w / v aceclidine, 5.5% w / v HPpCD, 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 and 0.035% w / v of tropicamide can be distinguished, the former showing normal room night vision, the latter with a slight dimming, which becomes more pronounced at lower concentrations. At higher concentrations, for example about 0.075% to about 0.090% w / v of tropicamide, the optimal range of pupil constriction 1.50 mm to 1.80 mm loss begins, and at higher concentrations, a noticeable pupil dilation begins to occur. Since the ratio of isomers can change the effective concentration, it must be taken into account for the clinical efficacy expected using aceclidine. For preferred embodiments of the present invention, the use of an optical rotator to determine the use of an exact 50:50 ratio of isomers (personal communication Toronto Research Chemicals) was used.

[0223] Figure 1The effects of pilocarpine with or without a cycloplegic agent and with or without a carrier are shown. The subjects are emmetropic eyes over 45 years of age with a baseline near vision of 20.100 and a baseline distance vision of 20.20. Topical administration to the eye of a 1% w / v pilocarpine salt solution can result in an improvement in near vision to 20.40 (8a), but at the expense of reducing distance vision to 20.100 (8b). The addition of 0.015% w / v of tropicamide can improve near vision to 20.25 (9a) and reduce distance vision to 20.55 (9b), although in some cases irregular astigmatism can occur (mild specking in the reading field). Topical administration of a pilocarpine salt solution containing 1.55% w / v of aceclidine can improve near vision to 20.40 (10a) over an extended period of 6 hours, without any effect on baseline distance vision (10b). 10c and 10d show the effect of aceclidine in a carrier consisting of 5.5% w / v of 2-hydroxypropyl β-cyclodextrin, 0.75% w / v of CMC (1% = 2,500 centipoise), 0.25% w / v of NaCl and 0.01% w of BAK. As shown in 10c, the carrier improves the beneficial effect of aceclidine, with near vision superior to 20.20. As shown in 10d, a similar improvement in distance vision occurs. 10e and 10f show the effect of adding 0.042% w / v of tropicamide to aceclidine in a carrier. As shown in 10e, near vision is improved to 20.15 and the onset of maximum visual acuity is faster. As shown in 10f, a similar improvement in distance vision occurs. In summary, Figure 1 Aceclidine is shown to temporarily correct near vision in presbyopic subjects without affecting baseline distance vision. Similar results can be achieved with different miotics, pilocarpine, plus a cycloplegic agent such as tropicamide. An appropriate pharmaceutical carrier can also have a beneficial effect.

[0224] The present invention also relates to an ophthalmic composition further comprising a tonicity adjusting agent and a preservative.

[0225] The tonicity adjusting agent can be, but is not limited to, a salt such as sodium chloride ("NaCl"), potassium chloride, mannitol or glycerol, or other pharmaceutically or ophthalmically acceptable tonicity adjusting agent. In certain embodiments, the tonicity adjusting agent is 0.037% w / v NaCl.

[0226] Preservatives that can be used in the present application include, but are not limited to, benzalkonium chloride ("BAK"), sorbic acid, oxychloro complex, citric acid, chlorobutanol, thimerosal, phenylmercuric acetate, disodium edetate, phenylmercuric nitrate, perborate, or benzyl alcohol. In a preferred embodiment, the preservative is BAK, sorbic acid, oxychloro complex, or a combination thereof. In another more preferred embodiment, the concentration of BAK is from about 0.001% to about 1.0% w / v, more preferably about 0.007% w / v, 0.01% w / v, or 0.02% w / v. In another preferred embodiment, the preservative is perborate, and the concentration of perborate is from 0.01% to about 1.0% w / v, more preferably about 0.02% w / v.

[0227] Various buffers and methods of adjusting pH can be used to prepare the ophthalmic compositions of the present application. Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, and borate buffers. It will be appreciated that an acid or base can be used to adjust the pH of the composition as needed, preferably to a concentration of 1 to 10 mM, more preferably about 3 mM or 5 mM. In a preferred embodiment, the pH is from about 4.0 to about 8.0, and in a more preferred embodiment, the pH is from about 5.0 to about 7.0.

[0228] The present application also relates to ophthalmic compositions that further comprise an antioxidant. Antioxidants that can be used in the present application include, but are not limited to, disodium edetate at a concentration of about 0.005% to about 0.50% w / v, citrate at a concentration of about 0.01% to about 0.3% w / w, calcium diethylene triamine pentaacetate ("Ca2DTPA") at a concentration of about 0.001% to 0.2% w / v, preferably about 0.01% w / v Ca2DTPA, which can be formulated by adding 0.0084% w / v Ca(OH)2and 0.0032% w / v triamine pentaacetate to the formulation and mixing slowly. Combinations of antioxidants can further be used. Other antioxidants that can be used with the present application include those known to those skilled in the art, such as ethylenediaminetetraacetic acid at a concentration of about 0.0001% to about 0.015% w / v.

[0229] Surprisingly and unexpectedly, it has been discovered that the topical formulation of the present application, and in particular the topical formulation of one of the preferred embodiments, comprising 1.35% to 1.55% w / v of vecuronium, 5.5% w / v of polyethylene glycol 40 stearate, 0.80% w / v of CMC, 0.037% w / v of sodium chloride, 0.015% w / v of EDTA, 0.007% w / v of BAK, 5 mM phosphate buffer, pH 7.0, greatly extends the wearing time and comfort of contact lenses after a single topical instillation per day. Daily use of the preferred embodiment enables dry eye patients to sleep in contact lenses for a week during which time they would have experienced blurring after even a single night of wear, requiring removal, cleaning or replacement of the film-coated contact lenses (see Example 7).

[0230] In a preferred embodiment, the ophthalmic composition of the present application comprises vecuronium, a cryoprotectant, an optional cycloplegic agent, a non-ionic surfactant at a concentration of about 1% to about 5% w / v and a viscosity agent at a concentration of about 0.75% to about 1.6% w / v, preferably about 1.25% to about 1.5% w / v.

[0231] The present application provides, without limitation, the following embodiments:

[0232] 1. A method of stabilizing a composition comprising vecuronium, the method comprising storing the composition in a container having a headspace at a temperature of about 2 degrees Celsius to about 8 degrees Celsius.

[0233] 2. The method of embodiment 1, wherein the composition is filled into the container under an inert gas blanket.

[0234] 3. The method of embodiment 2, wherein the headspace is purged with an inert gas.

[0235] 4. The method of embodiment 1, wherein the container comprises a closure and a vessel, wherein part of the closure and part of the vessel are sealed with an immersion resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene and aluminum foil.

[0236] 5. The method of embodiment 1, wherein the container is placed inside a second container formed from or lined with an immersion resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene and aluminum foil.

[0237] 6. The method of embodiment 1, wherein the concentration of vecuronium is about 0.25% to about 4.0% w / v, wherein w / v means weight per total volume of the composition.

[0238] 7. The method of embodiment 1, wherein the method provides at least 90% stability of aceclidine for at least 7 months.

[0239] 8. The method of embodiment 5, wherein the method provides at least 90% stability of aceclidine for at least 12 months.

[0240] 9. The method of embodiment 1, wherein the composition further comprises a viscosity agent, a polysorbate, a cryoprotectant, and a preservative.

[0241] 10. The method of embodiment 9, wherein the method provides at least 90% stability of aceclidine for at least 18 months.

[0242] 11. The method of embodiment 9, wherein the viscosity agent provides a viscosity of at least 50 centipoise.

[0243] 12. The method of embodiment 9, wherein the cryoprotectant is selected from the group consisting of a polyol, a sugar, an ethanol, a lower alkyl alcohol, a lipophilic solvent, a hydrophilic solvent, a bulking agent, a solubilizing agent, a surfactant, an antioxidant, a cyclodextrin, a maltodextrin, a colloidal silicon dioxide, a polyvinyl alcohol, 2-methyl-2,4-pentanediol, cellobiose, gelatin, polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), formamide, antifreeze protein 752, or a combination thereof.

[0244] 13. The method of embodiment 9, wherein the preservative is selected from the group consisting of benzalkonium chloride, sorbate, an antioxidant, and a combination thereof.

[0245] 14. The method of embodiment 11, wherein the antioxidant is selected from the group consisting of sodium ascorbate, sodium bisulfite, sodium metabisulfite, n-acetyl cysteine, and a combination thereof.

[0246] 15. A method of stabilizing a composition comprising aceclidine, a viscosity agent, and a non-ionic surfactant, the method 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 nitrogen overlay and the headspace is purged with nitrogen, wherein the composition provides a low shear (1 / sec) viscosity of about 50 to about 1000 centipoise and a high shear (1:1000 / sec) viscosity of about 0.5 or less centipoise.

[0247] 16. A method of stabilizing a composition comprising aceclidine, hydroxypropyl methylcellulose, polysorbate 80, mannitol, sorbate, and an antioxidant selected from the group consisting of sodium ascorbate, sodium bisulfate, sodium metabisulfite, n-acetyl cysteine, or combinations thereof, the method 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 a nitrogen blanket and the headspace is purged with nitrogen.

[0248] 17. The method of embodiment 16, wherein the concentration of aceclidine is about 0.25% to about 4.00% w / v, the concentration of hydroxypropyl methylcellulose is about 0.75% to about 1.25% w / v, the concentration of polysorbate 80 is about 2% to about 4% w / v, the concentration of mannitol is about 2% to about 4% w / v, the concentration of sorbate is about 0.10% to about 0.12% w / v, and the concentration of the antioxidant is about 0.10% to about 0.25% w / v, wherein w / v means weight per total volume of the composition.

[0249] 18. The method of embodiment 17, wherein the method provides stability of at least 90% aceclidine for at least 20 months.

[0250] 19. The method of embodiment 18, wherein the method provides stability of at least 90% aceclidine for at least 22 months.

[0251] 20. A container comprising aceclidine, prepared by a process comprising the steps of:

[0252] a) providing a container;

[0253] b) filling a composition comprising aceclidine into the container under an inert gas blanket;

[0254] c) purging a headspace formed during the filling step b) with an inert gas;

[0255] d) capping the container.

[0256] 21. The container of embodiment 20, wherein the process further comprises the step of storing the container at a temperature of about 2 degrees Celsius to about 8 degrees Celsius.

[0257] 22. The container of embodiment 20, wherein the composition further comprises a preservative selected from the group consisting of sorbate, benzalkonium chloride, sodium ascorbate, sodium bisulfate, sodium metabisulfite, n-acetyl cysteine, and combinations thereof.

[0258] 23. The container of embodiment 20, wherein the composition has a viscosity of at least 50 centipoise.

[0259] 24. A composition comprising about 0.25% to about 4.0% w / v aceclidine and one or more methods of stabilizing the composition selected from the group consisting of filling the composition into a container under an inert gas overlay and purging the headspace created upon filling with an inert gas, the total viscosity of the composition is at least 50 centipoise or greater, adding a preservative to the composition and the preservative is selected from the group consisting of sorbate, benzalkonium chloride, sodium ascorbate, sodium bisulfite, sodium metabisulfite, n-acetyl cysteine, and combinations thereof,

[0260] wherein the composition is stored at a temperature of about 2 to about 8 degrees Celsius, and wherein w / v means weight per total volume of the composition.

[0261] 25. A method of stabilizing a composition comprising aceclidine, the method comprising storing the composition in a container having a headspace at a temperature of about 22 degrees Celsius to about 25 degrees Celsius, wherein the container comprises a closure and a vessel, wherein part of the closure and part of the vessel are sealed with a water barrier material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil, and / or, placing the container within a second container formed from or lined with biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil.

[0262] 26. The method of embodiment 25, wherein the second container comprises a second closure, wherein the second closure provides a hermetic seal.

[0263] 27. The method of embodiment 26, wherein the hermetic seal is resealable.

[0264] The following representative embodiments are provided for illustrative purposes only and are not meant to limit the present invention in any way.

[0265] Representative Examples

[0266] In one embodiment, the ophthalmic composition comprises:

[0267] aceclidine at a concentration of about 1.75% w / v; and

[0268] mannitol at a concentration of about 2.5% w / v.

[0269] In another embodiment, the ophthalmic composition comprises:

[0270] acetazolamide at a concentration of about 1.75% w / v;

[0271] mannitol at a concentration of about 2.5% w / v; and

[0272] pH of about 5.0.

[0273] In another embodiment, the ophthalmic composition comprises:

[0274] acetazolamide at a concentration of about 1.75% w / v;

[0275] mannitol at a concentration of about 2.5% w / v; and

[0276] polysorbate 80 at a concentration of about 5.0% w / v;

[0277] carboxymethylcellulose at a concentration of about 1.4% w / v;

[0278] BAK at a concentration of about 0.015% w / v; and

[0279] phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.

[0280] In another embodiment, the ophthalmic composition comprises:

[0281] acetazolamide at a concentration of about 1.75% w / v;

[0282] mannitol at a concentration of about 2.5% w / v; and

[0283] polysorbate 80 at a concentration of about 0.5% w / v;

[0284] NaCl at a concentration of about 0.10% to 0.50% w / v;

[0285] pH of about 5.0. 940;

[0286] BAK at a concentration of about 0.01% w / v; and

[0287] phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.

[0288] In another embodiment, the ophthalmic composition comprises:

[0289] acetazolamide at a concentration of about 1.75% w / v;

[0290] mannitol at a concentration of about 2.5% w / v; and

[0291] polysorbate 80 at a concentration of about 2.0% w / v;

[0292] NaCl at a concentration of about 0.50% w / v

[0293] NaCl at a concentration of about 1.5% w / v 940;

[0294] BAK at a concentration of about 0.015% w / v; and

[0295] phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.25.

[0296] In another embodiment, the ophthalmic composition comprises:

[0297] acetaminosalol at a concentration of about 1.75% w / v;

[0298] mannitol at a concentration of about 2.5% w / v;

[0299] polysorbate 80 at a concentration of about 0.25% w / v;

[0300] NaCl at a concentration of about 0.1% w / v;

[0301] boric acid at a concentration of about 0.12% w / v;

[0302] NaCl at a concentration of about 0.95% w / v 940; and BAK at a concentration of about 0.015% w / v;

[0303] wherein the pH is about 5.

[0304] In another embodiment, the ophthalmic composition comprises:

[0305] acetaminosalol at a concentration of about 1.75% w / v;

[0306] mannitol at a concentration of about 2.5% w / v;

[0307] polysorbate 80 at a concentration of about 0.50% w / v;

[0308] NaCl at a concentration of about 0.05% w / v;

[0309] boric acid at a concentration of about 0.2% w / v;

[0310] NaCl at a concentration of about 0.95% w / v 940;

[0311] BAK at a concentration of about 0.01% w / v; and

[0312] phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.

[0313] In another embodiment, the ophthalmic composition comprises:

[0314] acetaminosalol at a concentration of about 1.75% w / v;

[0315] mannitol at a concentration of about 2.5% w / v;

[0316] polysorbate 80 at a concentration of about 0.1% w / v;

[0317] boric acid at a concentration of about 0.2% w / v;

[0318] sodium chloride at a concentration of about 0.9% w / v 940;

[0319] BAK at a concentration of about 0.05% w / v; and

[0320] a phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.

[0321] In another embodiment, the ophthalmic composition comprises:

[0322] acetaminosalol at a concentration of about 1.75% w / v;

[0323] mannitol at a concentration of about 2.5% w / v;

[0324] polysorbate 80 at a concentration of about 0.1% w / v;

[0325] NaCl at a concentration of about 0.1% w / v;

[0326] boric acid at a concentration of about 0.12% w / v;

[0327] sodium chloride at a concentration of about 0.95% w / v 940;

[0328] BAK at a concentration of about 0.01% w / v; and

[0329] a phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.

[0330] In another embodiment, the ophthalmic composition comprises:

[0331] acetaminosalol at a concentration of about 1.75% w / v;

[0332] tolypromide at a concentration of about 0.01% w / v;

[0333] mannitol at a concentration of about 2.5% w / v;

[0334] polysorbate 80 at a concentration of about 5.0% w / v;

[0335] CMC at a concentration of about 1.4% w / v;

[0336] BAK at a concentration of about 0.015% w / v; and

[0337] phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.

[0338] In another embodiment, the ophthalmic composition comprises:

[0339] acetaminophen at a concentration of about 1.75% w / v;

[0340] tolypromide at a concentration of about 0.02% w / v;

[0341] mannitol at a concentration of about 2.5% w / v;

[0342] polysorbate 80 at a concentration of about 0.25% w / v;

[0343] NaCl at a concentration of about 0.1% w / v;

[0344] boric acid at a concentration of about 0.12% w / v;

[0345] povidone at a concentration of about 0.95% w / v 940; and BAK at a concentration of about 0.01% w / v,

[0346] wherein the pH is about 5.

[0347] In another embodiment, the ophthalmic composition comprises:

[0348] acetaminophen at a concentration of about 1.75% w / v;

[0349] tolypromide at a concentration of about 0.015% w / v;

[0350] mannitol at a concentration of about 2.5% w / v;

[0351] polysorbate 80 at a concentration of about 0.75% w / v;

[0352] NaCl at a concentration of about 0.05% w / v;

[0353] boric acid at a concentration of about 0.2% w / v;

[0354] povidone at a concentration of about 0.95% w / v 940;

[0355] BAK at a concentration of about 0.01% w / v; and

[0356] phosphate buffer at a concentration of about 3 mM.

[0357] wherein the pH is about 5.

[0358] In another embodiment, the ophthalmic composition comprises:

[0359] acetaminosalol at a concentration of about 1.75% w / v;

[0360] tolypromide at a concentration of about 0.025% w / v;

[0361] mannitol at a concentration of about 2.5% w / v;

[0362] polysorbate 80 at a concentration of about 0.1% w / v;

[0363] boric acid at a concentration of about 0.2% w / v;

[0364] 940 at a concentration of about 0.9% w / v;

[0365] BAK at a concentration of about 0.05% w / v; and

[0366] phosphate buffer at a concentration of about 3 mM.

[0367] wherein the pH is about 5.

[0368] In another embodiment, the ophthalmic composition comprises:

[0369] acetaminosalol at a concentration of about 1.75% w / v;

[0370] tolypromide at a concentration of about 0.02% w / v;

[0371] mannitol at a concentration of about 2.5% w / v;

[0372] polysorbate 80 at a concentration of about 0.1% w / v;

[0373] NaCl at a concentration of about 0.1% w / v;

[0374] boric acid at a concentration of about 0.12% w / v;

[0375] 940 at a concentration of about 0.95% w / v;

[0376] BAK at a concentration of about 0.01% w / v; and

[0377] phosphate buffer at a concentration of about 3 mM.

[0378] wherein the pH is about 5.

[0379] In another embodiment, the ophthalmic composition comprises:

[0380] ​​acetaminophen at a concentration of about 1.75% w / v;

[0381] tolpipramine at a concentration of about 0.040% w / v;

[0382] polyethylene glycol 40 stearate at a concentration of about 5.0% w / v.

[0383] mannitol at a concentration of about 2.5% w / v;

[0384] acetate or phosphate buffer at a concentration of about 3.0 mM; and BAK at a concentration of about 0.01% w / v,

[0385] wherein the pH of the composition is about 4.75.

[0386] In another embodiment, the ophthalmic composition comprises:

[0387] acetaminophen at a concentration of about 1.75% w / v;

[0388] tolpipramine at a concentration of about 0.040% w / v;

[0389] polyethylene glycol 40 stearate at a concentration of about 5.0% w / v.

[0390] citric acid monohydrate at a concentration of about 0.1% w / v;

[0391] mannitol at a concentration of about 4.0% w / v;

[0392] at a concentration of 0.09% w / v 940; and

[0393] acetate or phosphate buffer at a concentration of about 3.0 mM; wherein the pH of the composition is about 5.0.

[0394] In another embodiment, the ophthalmic composition comprises:

[0395] acetaminophen at a concentration of about 1.75% w / v;

[0396] tolpipramine at a concentration of about 0.040% w / v;

[0397] polyethylene glycol 40 stearate at a concentration of about 5.0% w / v.

[0398] mannitol at a concentration of about 2.5% w / v;

[0399] phosphate buffer at a concentration of about 3.0 mM;

[0400] at a concentration of about 0.85% w / v 940; and BAK at a concentration of about 0.01% w / v,

[0401] wherein the pH of the composition is about 4.75.

[0402] In another embodiment, the ophthalmic composition comprises:

[0403] acetaminophen in a concentration of about 1.45% w / v;

[0404] tolcapone in a concentration of about 0.042% w / v;

[0405] polyethylene glycol 40 stearate in a concentration of about 5.5% w / v;

[0406] citric acid monohydrate in a concentration of about 0.1% w / v;

[0407] acetate buffer in a concentration of about 3.0 mM; and

[0408] acetaminophen in a concentration of about 1.0% w / v; 940, wherein the pH of the composition is about 4.75.

[0409] In another embodiment, the ophthalmic composition comprises:

[0410] acetaminophen in a concentration of about 1.45% w / v;

[0411] tolcapone in a concentration of about 0.042% w / v;

[0412] polyethylene glycol 40 stearate in a concentration of about 5.5% w / v.

[0413] mannitol in a concentration of about 2.0% w / v;

[0414] citric acid monohydrate in a concentration of about 0.1% w / v;

[0415] phosphate buffer in a concentration of about 3.0 mM; and

[0416] acetaminophen in a concentration of about 1.0% w / v; wherein the pH of the composition is about 4.75.

[0417] In another embodiment, the ophthalmic composition comprises:

[0418] acetaminophen in a concentration of about 1.45% w / v;

[0419] mannitol in a concentration of about 2.5% w / v;

[0420] polysorbate 80 in a concentration of about 2.75% w / v; and

[0421] about 1.25%; 1.0% - 1.80% w / v hydroxypropyl methylcellulose (depending on its molecular weight). In another embodiment, the ophthalmic composition includes:

[0422] about 1.75% w / v aceclidine;

[0423] about 0.005% to about 0.011% of tropicamide;

[0424] about 2.5% w / v mannitol;

[0425] about 2.75% w / v polysorbate 80; and

[0426] about 1.25%; 1.0% - 1.80% w / v hydroxypropyl methylcellulose (depending on its molecular weight). In another embodiment, the ophthalmic composition includes:

[0427] about 1.75% w / v aceclidine;

[0428] about 0.010% w / v of tropicamide;

[0429] about 2.5% w / v mannitol;

[0430] about 5.0% w / v polysorbate 80;

[0431] about 1.40% w / v high viscosity carboxymethylcellulose;

[0432] about 3 mM phosphate buffer; and

[0433] about 0.010% BAK = preservative,

[0434] pH is about 5.0.

[0435] In another embodiment, the ophthalmic composition includes:

[0436] about 1.75% w / v aceclidine;

[0437] about 0.006% w / v of tropicamide;

[0438] about 2.5% w / v mannitol;

[0439] about 2.5% w / v polysorbate 80;

[0440] about 1.25%; 1.0% - 1.80% w / v hydroxypropyl methylcellulose (depending on its molecular weight); about 3 mM phosphate buffer; and

[0441] about 0.020% BAK = preservative,

[0442] pH is about 5.0.

[0443] In another embodiment, the ophthalmic composition comprises:

[0444] about 1.75% w / v of aceclidine;

[0445] about 0.006% w / v of tropicamide;

[0446] about 2.5% w / v of mannitol;

[0447] about 2.5% w / v of polysorbate 80;

[0448] about 1.25%; 1.0% - 1.80% w / v of hydroxypropyl methylcellulose (depending on its molecular weight); about 3 mM of phosphate buffer;

[0449] about 0.50% w / v of NaCl; and

[0450] about 0.020% of BAK = preservative,

[0451] pH is about 5.0.

[0452] In another embodiment, the ophthalmic composition comprises:

[0453] about 1.75% w / v of aceclidine;

[0454] about 2.5% w / v of mannitol;

[0455] about 3.5% w / v of polysorbate 80;

[0456] about 1.25%; 1.0% - 1.80% w / v of hydroxypropyl methylcellulose (depending on its molecular weight); about 3 mM of phosphate buffer;

[0457] about 0.50% w / v of NaCl; and

[0458] about 0.020% of BAK or 0.15% of sorbic acid as preservative,

[0459] pH is about 5.0.

[0460] In another embodiment, the ophthalmic composition comprises:

[0461] about 1.75% w / v of aceclidine;

[0462] about 2.5% w / v of mannitol;

[0463] about 3.5% w / v of polysorbate 80; and

[0464] about 1.25%; 1.0% - 1.80% w / v of hydroxypropyl methylcellulose (depending on its molecular weight);

[0465] In another embodiment, the ophthalmic composition comprises:

[0466] about 1.75% w / v of aceclidine;

[0467] about 2.5% w / v of mannitol;

[0468] about 3.5% w / v of polysorbate 80;

[0469] about 1.25%; 1.0% - 1.80% w / v of hydroxypropyl methylcellulose (depending on its molecular weight); and

[0470] one or more excipients selected from about 0.50% w / v of sodium chloride, about 0.02% w / v of benzalkonium chloride, about 0.10% w / v of sorbate, about 0.01% w / v of ethylenediaminetetraacetic acid (EDTA), and 0.10% w / v of citric acid.

[0471] In another embodiment, the ophthalmic composition comprises:

[0472] about 1.75% w / v of aceclidine;

[0473] about 2.5% w / v of mannitol;

[0474] about 0.01% w / v of tropicamide;

[0475] about 0.1% w / v of anhydrous sodium citrate;

[0476] about 0.02% w / v of benzalkonium chloride;

[0477] about 0.12% w / v of sorbic acid;

[0478] about 0.1% w / v of disodium ethylenediaminetetraacetate;

[0479] about 4.0% w / v of polysorbate 80; and

[0480] about 1.25% w / v of hydroxypropyl methylcellulose,

[0481] wherein the pH is about 5.0.

[0482] In another embodiment, the ophthalmic composition comprises:

[0483] about 1.75% w / v of aceclidine;

[0484] about 2.5% w / v of mannitol;

[0485] about 0.01% w / v of tropicamide;

[0486] about 0.1% w / v of anhydrous sodium citrate;

[0487] about 0.02% w / v of benzalkonium chloride;

[0488] about 0.1% w / v of sorbic acid;

[0489] about 0.1% w / v of EDTA;

[0490] about 3.5% w / v of polysorbate 80; and

[0491] about 1.25%; 1.0% - 2.25% w / v of hydroxypropyl methylcellulose (depending on its molecular weight) wherein the pH is about 5.0.

[0492] In another embodiment, the ophthalmic composition comprises:

[0493] about 1.75% w / v of aceclidine;

[0494] about 2.5% w / v of mannitol;

[0495] about 0.01% w / v of tropicamide;

[0496] about 3 mM of phosphate buffer;

[0497] about 0.02% w / v of benzalkonium chloride;

[0498] about 0.1% w / v of sorbic acid;

[0499] about 0.1% w / v of citrate;

[0500] about 3.5% w / v of polysorbate 80; and

[0501] about 1.25%; 0.25% - 2.25% w / v of hydroxypropyl methylcellulose (depending on its molecular weight) wherein the pH is about 5.0.

[0502] In another embodiment, the ophthalmic composition comprises:

[0503] aceclidine at a concentration of 1.5% w / v, mannitol at a concentration of 2.5% w / v.

[0504] In another embodiment, the ophthalmic composition comprises:

[0505] aceclidine at a concentration of 1.55% w / v, mannitol at a concentration of 2.5% w / v.

[0506] In another embodiment, the ophthalmic composition comprises:

[0507] Acetylcholine esterase inhibitor at a concentration of 1.6% w / v, mannitol at a concentration of 2.5% w / v.

[0508] In another embodiment, the ophthalmic composition comprises:

[0509] Acetylcholine esterase inhibitor at a concentration of 1.65% w / v, mannitol at a concentration of 2.5% w / v.

[0510] In another embodiment, the ophthalmic composition comprises:

[0511] Acetylcholine esterase inhibitor at a concentration of 1.7% w / v, mannitol at a concentration of 2.5% w / v.

[0512] In another embodiment, the ophthalmic composition comprises:

[0513] Acetylcholine esterase inhibitor at a concentration of 1.75% w / v, mannitol at a concentration of 2.5% w / v.

[0514] In another embodiment, the ophthalmic composition comprises:

[0515] Acetylcholine esterase inhibitor at a concentration of 1.80% w / v, mannitol at a concentration of 2.75% w / v, and 940.

[0516] In another embodiment, the ophthalmic composition comprises:

[0517] Acetylcholine esterase inhibitor at a concentration of 1.48% w / v, mannitol at a concentration of 1.5% w / v, and

[0518] Acetylcholine esterase inhibitor at a concentration of 0.50% w / v 940.

[0519] In another embodiment, the ophthalmic composition comprises:

[0520] Acetylcholine esterase inhibitor at a concentration of 1.80% w / v, mannitol at a concentration of 2.5% w / v, and 940.

[0521] The following examples are provided for illustrative purposes only and are not meant to limit the application in any way.

[0522] Example

[0523] Example 1: Effect of acetylcholine esterase inhibitor on vision in subjects aged 47 to 67 years

[0524] Table 1 demonstrates the effect on near focus ability in presbyopic subjects before and after administration of ophthalmic compositions containing aceclidine. Each composition included aceclidine at the concentration shown and 5.5% w / v HPpCD, 0.75% w / v CMC, 0.25% w / v NaCl, and 0.01% w / v BAK. In addition, compositions administered to subjects 4 and 5 included 0.125% w / v tropicamide. Since aceclidine is an enantiomer, the clinical effect can vary with different ratios. For this study, an almost exact 50:50 stereoisomer ratio was best determined by polarimetry.

[0525] Table 1. Effect of aceclidine on vision in presbyopic patients.

[0526]

[0527] As shown in Table 1, all subjects had imperfect near vision (20.20) in both their left and right eyes (objects at 15 inches from the eye) and most subjects also had imperfect distance vision prior to administration. After administration of the compositions, all subjects had improved near vision that lasted for 7 to 12 hours. Surprisingly, most subjects also improved their distance vision during the same time period. More surprisingly, the improvement in near point was much closer than the 16 inches typically required for comfortable reading, in some cases, approaching 8.5 inches or less for 30 or 30-year-olds. The addition of tropicamide, a cycloplegic, had no adverse or deleterious effect on vision correction.

[0528] Example 2: Effect of concentration of aceclidine and concentration of tropicamide

[0529] Table 2: Effect of concentration of aceclidine and tropicamide.

[0530] #1 #2 #3 #4 #5 (OD) #5 (OS) #6 #7 Brimonidine 0.03％ 0.03％ 0.03％ 0.03％ 0.03％ 0.03％ 0.03％ Poloxamer 407 5.5％ HPBCD 5.5％ 5.5％ 5.5％ 5.5％ 5.5％ 5.5％ 5.5％ Clonidine 1.5％ 1.5％ 0.75％ 1.1％ 1.1％ 1.1％ 1.1％ 1.1％ Tropicamide 0.014％ 0.021％ 0.028％ 0.042％ 0.062％ NaCl 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ CMC 0.75％ 0.75％ 0.75％ 0.75％ 0.75％ 0.75％ 0.75％ 0.75％ BAK 0.1％ 0.1％ 0.1％ 0.1％ 0.1％ 0.1％ 0.1％ 0.1％ Redness (15m) 3+ 1 0.5 0.5 0 0 0 0 Redness (30m) 1.5 0.5 0.25 0.25 0 0 0 0 Supraorbital neuralgia (60m) 2+ 2+ 2 0.5 0.5 0.0 0.0 0.0 Pricking (10m) 2 2 0.5 0 0 0 0 0 BD-OD 20.20 20.20 20.20 20.20 20.20 20.20 20.20 20.20 BD-OS 20.25 20.25 20.25 20.25 20.25 20.25 20.25 20.25 BN-OD 8pt 8pt 8pt 8pt 8pt 8pt 8pt 8pt BN-OS 7pt 7pt 7pt 7pt 7pt 7pt 7pt 7pt BP - Bright vision 3mm 3mm 3mm 3mm 3mm 3mm 3mm 3mm BP - Intermediate vision 5mm 5mm 5mm 5mm 5mm 5mm 5mm 5mm Pupil constriction onset (m) 15 15 15 15 15 15 15 15 Pupil constriction (OU) (1 hr) 1.63mm 1.63mm 2.0-2.5mm 1.63mm 1.63mm 1.63mm 1.63mm 1.70mm Distance vision (OU) (20m) 20.20 20.20 20.20 20.20 20.20 20.20 20.20 20.20 Distance vision (OD) (1 hr) 20.15+2 20.15+2 20.20 20.15+2 20.15+2 20.15+2 20.15+2 20.15+2 Distance vision (OS) (1 hr) 20.15+2 20.15+2 20.20 20.15+2 20.15+2 20.15+2 20.15+2 20.15+2 Distance vision (OU) (1 hr) 20.10-3 20.10-3 20.15 20.10-3 20.10-3 20.10-3 20.10-3 20.10-3 Near vision (OU) (20m) 4pt 4pt 4pt 4pt 4pt 4pt 4pt 4pt Time (hr) 12.5 12.5 6.5 11 10 10

[0531] Abbreviations: (C) denotes corrected vision, (m) denotes minutes, (hr) denotes hours, mm denotes millimeters, BD denotes baseline distance vision; BN denotes baseline near vision, BP denotes baseline pupil size, OD denotes right eye; OS denotes left eye, OU denotes both eyes.

[0532] All percentages are w / v. "pt" stands for print size, 4 equals 20 / 20 vision, 3 equals 20 / 15 vision.

[0533] "Time" refers to the duration of the effect.

[0534] As shown in Table 2, at 1 hour after topical instillation, eucilidine at a concentration of at least 1.1% w / v was able to reduce the size of the pupil to 1.63 mm, resulting in a correction of myopia and hyperopia for at least 10 hours. Reducing the concentration of eucilidine to 0.75% w / v (Formula #3) reduced the effect of pupil constriction to 2.0-2.5 mm after 1 hour, and the correction of vision lasted for 6.5 hours. The addition of 0.03% w / v brimonidine within 30 minutes after topical instillation reduced the degree of redness of the eye (4 / 4 without brimonidine, not shown) to 1.5 / 4, and the vision was corrected throughout. Switching the non-ionic surfactant to HR beta CD (Formula #2-6) further reduced the degree of redness of the eye. Reducing the concentration of eucilidine to 0.75% w / v (Formula #3) further reduced the redness of the eye, but as shown above, this formula reduced the duration of the correction of vision.

[0535] Supraorbital pain and stinging was evident in Formulas #1-3, with a pain level of 2 / 4, and was accompanied by mild nausea, stomach discomfort, and a feeling of fatigue. Surprisingly, the addition of the cycloplegic agent tropicamide reduced the supraorbital pain and stinging to 0.5 / 4 and 0 / 4, respectively, and the supraorbital pain disappeared after 60 minutes (Formula #4), in addition, increasing the concentration of eucilidine to 1.1% w / v restored the longer duration of corrected vision seen in Formulas #1-2 without increasing the redness of the eye. However, upon re-topical instillation of Formula #4 at the end of 10 hours, supraorbital pain was evident. Subsequent instillation of Formula #4 after topical instillation of Formulas #5 (OD) and (OS), which increased the concentration of tropicamide, alleviated the supraorbital pain that occurred upon re-use of Formula #4. Upon a third topical instillation, re-topical instillation of Formula #5 at the end of the effective duration of Formula #5 again resulted in supraorbital pain. Again, in Formula #6, increasing the concentration of tropicamide was able to overcome the supraorbital pain. In addition, surprisingly, despite tropicamide being a cycloplegic agent, there was no effect on pupil constriction or correction of vision. Surprisingly, the addition of tropicamide extended the time of optimal pupil constriction.

[0536] To determine the effect of brimonidine on pupil constriction, Formula #7 was used. Administration of Formula #7 resulted in only a slight reduction in pupil constriction to 1.70 mm, and the improvement in hyperopia and myopia was the same as Formula #5. 2-3+ conjunctival injections were noted.

[0537] All baseline vision data was based on vision corrected with distance contact lenses. At 1.5 hours after instillation, the subject's near vision was noted to be outstanding from 8 inches to the horizon.

[0538] All pupil size measurements were taken using a Marco Autorefractor with an infrared camera and superimposed pupil calibration scale. After the image was selected, it was retained on the screen for precise calibration.

[0539] Example 3: Effect of Concentration of Acetylcholine, Brimonidine, Guanfacine, Fadolmidine, Tolipidine, and Additives

[0540] Table 3: Effect of Concentration of Acetylcholine, Brimonidine, Guanfacine, Fadolmidine, Tolipidine, and Additives

[0541] AB2T AB4T AB6T AB11T AB12T PROPH13 Clonidine 1.55 1.55 1.55 1.55 1.85 1.55 Brimonidine 0.037 0.037 0.037 0.037 Fadolmidine 0.037 Guanfacine 0.037 HPBCD 5.5 5.5 5.5 5.5 5.5 5 Tropicamide 0.043 0.043 0.043 0.043 0.042 0.043 CMC 0.075 0.075 0.075 0.075 0.075 0.075 NaCl 0.025 0.025 0.025 0.025 0.025 0.025 BAK 0.01 0.01 0.01 0.01 0.01 0.01 Glycerol 0.1 0.1 0.1 Poloxamer 188 0.1 0.05 Macrogol 40 stearate 0.05 pH 6.5 7.5 7.5 7.5 7.0 7.5 Congestion 0 0 0 0 0 0 Pricking initial 0.75 0 1.5 3.5 0 1.5 Pricking 3 min 0.5 0 0 Elimination 0 0 Redness initial 0 0 1 D / C 1 1 Redness 15 min 0 0 0 D / C 0 0 Whitening 0 0 0 D / C 1.5 1.5 Pain 0 0 0 D / C 0 0 Near vision 20.30 20.15 20.15 D / C 20.15 20.15 Distance vision 20.20 20.20 20.20 D / C 20.20 20.20 Onset time (min) 20 12 16 D / C 12 16 Duration (hrs) 5.5 7.5 7.5 D / C 7.5 7.5 Color Clear Yellow Yellow Yellow Yellow Yellow Overall 2.5 3.9 3.8 0 4 3.9

[0542] *1% = 2,500 cps

[0543] All percentages are w / v. Scores for nasal congestion, initial stinging, stinging at 3 minutes, initial redness, redness at 15 minutes, whiteness, pain, and overall were on a scale of 1 to 4.

[0544] "pt" stands for print size, 4 equals 20 / 20 vision, and 3 equals 20 / 15 vision.

[0545] Baseline vision was 20.20 in both eyes; the right eye had a 20.70 uncorrected near vision; and the left eye had a 20.80 uncorrected near vision (best at 16 inches).

[0546] D / C stands for drug discontinued after washing eyes due to intolerable stinging.

[0547] At 30 minutes post topical instillation, epi-nephrine at a concentration of 1.55% w / v reduced the pupil size to approximately 1.63 mm, resulting in near and distance vision that was at least 20.20 or better corrected for at least 6 hours and for approximately 7.5 hours, as shown in Table 3. Reducing the concentration of epi-nephrine to 1.25% w / v (not shown) resulted in useful near vision improvement to approximately 20.25-20.30, but was not as effective as at the higher dose range, and the basic pH resulted in faster onset, longer duration, and greater effect. The addition of 0.037% w / v brimonidine reduced the redness of the eye (4 / 4 without brimonidine, not shown) to baseline within 15 minutes post topical instillation, and this was maintained for approximately the entire time range with vision corrected. The addition of 0.10% w / v glycerin significantly reduced the stinging sensation. Instead, the addition of 0.05% w / v poloxamer 188 and 0.05% w / v polyoxyl 40 stearate further reduced the initial stinging sensation, but was more viscous. The combination of 0.1% w / v glycerin and 0.1% w / v poloxamer 188 at a pH of 6.5 significantly reduced the onset time, duration, comfort, and effectiveness. AB 11T, which does not contain glycerin, poloxamer 188, or polyoxyl 40 stearate, resulted in severe stinging immediately post topical instillation, and the experiment was discontinued with immediate flushing of the eye. Replacing brimonidine with 0.037% w / v guanoxabenz in AB 12T resulted in very slight initial redness, and a prolonged reduction in redness and some whitening, and it appears to provide the best cosmetic effect, although it provides a higher concentration of epi-nephrine for optimal effect.

[0548] All baseline vision data was based on vision corrected with distance contact lenses. For AB 4T and AB 6T, the subjects' near vision was noted to perform outstandingly from 8 to 10 inches to the horizon after 30 minutes of instillation.

[0549] AB 4T and AB 6T were repeated monocularly and binocularly. Binocular treatment improved depth perception, near point acuity to 3pt (20.15), and near point distance (8", 20.20) were significantly improved compared to monocular treatment. Monocular treatment resulted in vision deterioration when both eyes were open compared to the treated eye only.

[0550] Example 4: Effect of Concentration of Epi-nephrine, Brimonidine, Tropicamide, and Additives

[0551] Table 4: Effect of Concentration of Epi-nephrine, Brimonidine, Tropicamide, and Additives.

[0552]

[0553] As shown in Formulation #8-9 of Table 4, increasing Brimonidine to 0.42% w / v resulted in a decrease in redness to 0.5, while CMC at 0.75% w / v resulted in a watery thin consistency. Surprisingly, increasing CMC from 0.75% w / v to 0.80% w / v to 0.87% w / v and NaCl from 0.25% w / v to 0.75% w / v in Formulation #10-11 resulted in a higher consistency, an increase in dwell time from 7 hours to 10-12 hours, and a decrease in the amount of drug that drained into the nasolacrimal duct. This decreased delivery of drug to the nasal passage resulted in a decrease in nasal congestion.

[0554] In Formulation #13-18, the amount of aceclidine was decreased from 1.61% to 1.53% w / v, resulting in a range of 1.8-2.0 mm in pupil size. Due to the limitation of the pupil, the dimming results linearly decreased from 1.5 to 0.5 with the decrease of aceclidine. Specifically, a 1.8 to 2.0 mm pupil produces 41% more light than a 1.5 to 1.7 mm pupil. Surprisingly, the near depth increased by 1.75D from 1.8 to 2.0 mm. This is only a loss of 0.25D compared to the beneficial 2.00D seen from 1.5-1.7 mm range. Thus, a range of 1.80 to 2.0 mm can produce 41% more light while still providing the full benefit of near vision enhancement for individuals under 60 years of age; and individuals 60 years of age and older can still benefit from the overall, and in total, near the number of people who benefit also increases. Increasing the tropicamide concentration from 0.042% w / v (Formulation #8-#11) to 0.044% w / v (Formulation #13-#18) resulted in a decrease in pain to a negligible amount. The degree of pain can also be related to the age of the individual. For those under 45 years of age, it can be preferable to increase the concentration of tropicamide to a range of 0.046% to 0.060% w / v.

[0555] Additionally, Table 4 shows a surprising result seen in Formulation #13 and #17, where increasing NaCl from 0.25% w / v to a range of 0.50 to 0.75% w / v resulted in a redness score of only 1.0, which is acceptable, even without the addition of Brimonidine.

[0556] Formulation #15, #16, and #17 each resulted in an overall highest score of 5 by combining the following advantages: (1) decreasing the aceclidine concentration to improve the amount of light produced without significantly affecting the myopic effect of Formulation #8 in #8-#12; (2) increasing the NaCl concentration resulted in a further decrease in redness even without Brimonidine; (3) increasing the CMC concentration resulted in an increase in eye dwell time.

[0557] A few individuals who are highly reactive to Formulas #15-#17, will darken significantly with 1.53% w / v eucatropine, Formula #19 is an excellent alternative. For those few individuals who are reactive to Formula #19, Formula #20 is an excellent choice. Finally, for those few individuals who are slow to react and have a poor pupillary response to Formula #20, Formula #21 is an excellent choice.

[0558] Example 5: Comparison of the effects of polyoxyl 40 stearate, HRBCO and poloxamer 407

[0559] Table 5. Comparison of the effects of polyoxyl 40 stearate, HRBCO and poloxamer 407.

[0560] #22 #23 #24 Acetidine 1.45％ 1.45％ 1.45％ Tropicamide 0.044％ 0.044％ 0.044％ Brimonidine 0.040％ 0.040％ 0.040％ Macrogol 40 stearate 5.5％ HPβCD 5.5％ Poloxamer 407 5.5％ CMC 0.80％ 0.80％ 0.80％ NaCl 0.037％ 0.037％ 0.037％ EDTA 0.015％ 0.015％ 0.015％ BAK 0.007％ 0.007％ 0.007％ pH 7.00 7.00 7.00 Phosphate buffer 5mM 5mM 5mM Congestion 0.00 0.50 1.50 Pricking 0.25 0.25 0.25 Wetness 4.00 4.00 4.00 Redness 0.25 0.50 0.50 Visual blur (< 15 sec) 0.50 0.50 1.50 Duration 6-8 hrs 6-8 hrs 6-8 hrs Overall 0-4 4.00 4.00 4.00

[0561] Clinical protocol

[0562] Twenty patients with full distance corrected presbyopia each used the above formula (#22-#23). All patients had pre- and post-drops distance and near vision measurements, (Visante is a registered trademark of Carl Zeiss Meditec AG) Optical coherence tomography, axial length and contrast visual acuity testing (i.e. Colenbrander-Michelson 10% Lum target) yielded the following results:

[0563] All patients achieved a pupillary constriction of 1.5 to 2.20 mm;

[0564] No patient experienced ciliary muscle pain, ciliary spasm or induced discomfort;

[0565] All patients achieved 20 / 30+ or better at 14 inches and were very satisfied with the high contrast near vision results and had no significant burning or pain;

[0566] The duration of all cases was 6 - 8 hours;

[0567] Binocular vision provided all patients with 1-1.5 lines of near vision over monocular testing; the last 10 patients were tested at 20 inches (i.e. computer distance, cell phone distance) and all patients achieved 20 / 25 or better for near vision;

[0568] Moderate hyperopia (approximately +2.25 spheres) uncorrected presbyopes were very satisfied with the far vision acuity, the far vision acuity improved to 20 / 25 or better levels in the 20 / 30 range for both distance and near vision acuity; and

[0569] For those patients who choose to have very small refractive errors corrected with a non-standard correction, uncorrected distance visual acuity is usually improved. As can be seen in Table 5, the use of polyoxyl 40 stearate provides the most comfortable formulation of aceclidine with the least visual blurring and redness. To achieve similar results to formulation #22, formulation #23 requires a 10-15% higher concentration of non-ionic surfactant, while formulation #24 requires a 15-20% higher concentration of non-ionic surfactant. HPβCD causes a change in color over time, possibly indicating the presence of oxidation. (Sulfobutyl ether β-cyclodextrin) was found to be similarly substituted.

[0570] Example 6: Adjustment of aceclidine concentration in a preferred embodiment.

[0571] Preferred embodiment:

[0572] 1.35% - 1.55% w / V aceclidine;

[0573] 5.5% w / v polyoxyl 40 stearate;

[0574] 0.037% w / v NaCl;

[0575] A viscosity agent, preferably 0.80% w / v CMC or an amount of 934 or 940 sufficient to achieve a viscosity of about 5 to about 35 cps upon topical instillation, for example, a concentration of about 0.09% to about 1.0% w / v 940;

[0576] 0.015% w / v BAK; and

[0577] about 3 to about 10 mM phosphate buffer, citrate buffer, citrophosphate buffer, or acetate buffer,

[0578] wherein the pH is about 4.75 to about 6.0.

[0579] For 1.35% w / v aceclidine

[0580] Punctate stinging sensation upon topical instillation 0.25 / 4.0 (lasting about 2-5 seconds);

[0581] Redness induced at 10 minutes: 1.0 to 1.5 / 4.0;

[0582] Redness induced at 30 minutes: 0.0 to 0.25 / 4.0;

[0583] Comfort: Very high.

[0584] Wettability: Very high. The eye remained improved in wettability for most of the 24 hours after a single topical instillation.

[0585] Hyperopic addition: Excellent.

[0586] Myopic addition: Excellent.

[0587] Upon testing the above formulation on a plurality of subjects, it was found that the concentration of eucatropine upon which the clinical effect depends exists in a narrow range, with 1.35% to 1.55% w / v of eucatropine being preferred, but with 1.35% w / v and 1.45% w / v being the concentrations that can bring the desired benefit to most subjects.

[0588] Furthermore, it was found that the clinical effect of 1.35% w / v eucatropine can be improved by instillation in the following manner:

[0589] 1) Baseline effect: 1 drop per eye.

[0590] 2) Augmented effect: 2 drops per eye.

[0591] 3) Greater effect: After 2) above, repeat 1) above.

[0592] 4) Maximum effect: After 2) above, repeat 2) above.

[0593] Example 7: Use of preferred embodiments to extend contact lens wear time.

[0594] Preferred embodiments:

[0595] 1.45% w / v eucatropine;

[0596] 5.5% w / v polyoxyl 40 stearate;

[0597] 0.037% w / v sodium chloride;

[0598] A viscosity agent, preferably 0.80% w / v CMC or an amount of 934 or 940 sufficient to achieve a viscosity of about 5 to about 35 cps upon topical instillation, e.g., a concentration of about 0.09% to about 1.0% w / v of 940;

[0599] 0.02% w / V BAK; and

[0600] about 3 to about 10 mM phosphate buffer, citrate buffer, citrophosphate buffer or acetate buffer,

[0601] wherein the pH is about 4.75 to about 6.0.

[0602] As a baseline, subjects who typically wear their contact lenses daily experienced blurred vision Air Optix is a registered trademark of Novartis AG) overnight. Upon waking each morning, the subjects' vision was blurred and the contact lenses needed to be removed and cleaned of the film and deposits that had formed overnight. Average distance vision: 20.60; average vision near the Michelson contrast vision chart: 20.80.

[0603] Then, the formulation described above was instilled in a single dose between 7 AM and 10 AM each day for 7 consecutive days. The subjects wore lenses and wore the lenses overnight. Upon waking each morning, the subjects' vision was: 20.20+; uncorrected vision was near 20.40 (consistent with the subjects' baseline presbyopia, when the subjects did not wear contact lenses overnight, but wore the lenses upon waking).

[0604] Example 8: Comparison of the effects of polyoxyl 40 stearate and sulfobutyl ether β-cyclodextrin

[0605] Table 6. Comparison of the effects of polyoxyl 40 stearate and sulfobutyl ether β-cyclodextrin

[0606]

[0607] As shown in Table 6, the exclusion of EDTA resulted in a reduction in redness and the best overall rating for the polyoxyl 40 stearate compositions (Formulations #25 and #26) when polyoxyl 40 stearate was used as the surfactant. The addition of cocamidopropyl betaine ("CAPB") further reduced redness, but caused significant stinging (Formulation #31). Replacing polyoxyl 40 stearate with sulfobutyl ether β-cyclodextrin and adding mannitol resulted in a similar reduction in redness as adding CAPB to the polyoxyl 40 stearate, but without the stinging, resulting in the highest overall rating for the brimonidine compositions (Formulation #32). After several weeks, the formulation containing sulfobutyl ether β-cyclodextrin was orange, possibly indicating oxidation.

[0608] Example 9: Preferred cold chain composition

[0609] Composition

[0610] brimonidine at a concentration of about 1.40% - 1.80% w / v; and

[0611] tolcapone at about 0.42% w / v;

[0612] Polyethylene glycol 40 stearate at a concentration of about 5.5% w / v;

[0613] Mannitol at a concentration of about 2.5% to 4.5% w / v;

[0614] Carbomer 940 at a concentration of about 0.09% to about 2.0% w / v;

[0615] Optionally, a preservative, such as BAK, at a concentration of about 0.2% w / v;

[0616] Optionally, citrate at a concentration of about 0.1%;

[0617] Optionally, acetate or phosphate buffer at 2-100 mM, more preferably 3-5 mM,

[0618] wherein the pH of the composition is about 4.50 to about 5.0; preferably about 4.75 to about 5.0; and

[0619] wherein w / v means weight / volume

[0620] The above composition was applied to a 62 year old subject. The results were a pupil of 1.8-1.9 mm ou, 20.20+ reading vision and 20.20+ distance vision; while without carbomer 940, the effect was reduced at 2.5% mannitol and there was no near vision effect at 4.0% mannitol. There was no ciliary spasm or loss of distance vision. Onset was within about 15 minutes. There was about 1+ / 4 transient flushing observed within about 20 minutes without an alpha agonist vasoconstrictor. There was no clinical effect with or without BAK for providing an optional preservative.

[0621] Example 10: Stable aceclidine formulation

[0622] Composition tested:

[0623] Aceclidine at a concentration of about 1.50% w / v;

[0624] Tropicamide at a concentration of about 0.042% w / v;

[0625] Polyethylene glycol 40 stearate at a concentration of about 5.5% w / v;

[0626] Mannitol at a concentration of about 2.5% w / v;

[0627] Citrate at a concentration of about 3 mM;

[0628] wherein the pH of the composition is about 4.75.

[0629] The 20 samples of the above composition were each divided and stored at 25 °C and 4 °C. Prior to storage, the initial concentration of eucilidine was measured using high- performance liquid chromatography ("HPLC"). The amount of eucilidine in each solution was calculated by comparing the area under the main peak to a reference solution of eucilidine. The samples were then stored for 3 months. Measurements of eucilidine were taken at 1 month, 2 months, and 3 months. The results of the stability test are shown in Table 7.

[0630] Table 7. Stability of eucilidine in cold-chain storage

[0631]

[0632] As shown in Table 7, the "cold-chain storage" or storage at 2 °C to 8 °C of the eucilidine composition significantly increased the stability of eucilidine at all 3 time points.

[0633] Example 11: Use of compositions containing little or no cycloplegic agent

[0634] The use of eucilidine alone causes severe ciliary spasm (supraorbital neuralgia) and blurring of near vision that mimics migraine. These effects are inversely proportional to age, with subjects 40 years of age reporting the highest incidence and subjects over 60 years of age reporting the lowest incidence. The addition of a cycloplegic agent reduces ciliary spasm and the accompanying supraorbital neuralgia, migraine, compression of the eye with squeezing or other symptoms of ciliary spasm. Surprisingly, the addition of a cycloplegic agent does not reduce the myopic effect of eucilidine. However, the addition of 2.5% w / v mannitol does reduce the myopic effect of eucilidine. Increasing the concentration of eucilidine overcomes the reduction in the myopic effect after the addition of mannitol. Surprisingly, however, the increase in eucilidine does not occur simultaneously with an increase in ciliary spasm. Even more surprisingly, in the presence of mannitol, the concentration of cycloplegic agent can be reduced or even eliminated without an increase in ciliary spasm. Thus, the use of higher concentrations of eucilidine in the presence of mannitol in combination with little or no cycloplegic agent improves myopic acuity without the side effects associated with lower concentrations of eucilidine and higher concentrations of cycloplegic agent.

[0635] Further surprisingly, the addition of a non-ionic surfactant increases the quantitative measure of myopic acuity improvement and the duration. This effect is concentration sensitive. In preferred embodiments, the concentration of non-ionic surfactant is at least 1%, preferably at least 2%, more preferably from about 1% to about 5%, most preferably about 5%. For example, polysorbate 80 or macrogol 40 stearate at a concentration of from about 1% to about 5% w / v results in an improvement of from about 1.5 to about 2.0 lines and a duration of from about 4 to about 5 hours.

[0636] Without being bound by a particular theory, the increase in surfactant concentration can crowd the corneal surface, and at an optimal concentration, this crowding results in a smaller diameter, possibly nanodiameter, which given the bipolarity of the surfactant, non-ionic surfactants are most preferred, enhances corneal uptake of the highly polar aceclidine.

[0637] Adding viscosity agents alone does not increase duration. Surprisingly, adding viscosity agents to formulations with optimal ratios of aceclidine, tropicamide, and non-ionic surfactants can significantly increase duration. For example, a formulation of the present invention comprising 1.75% aceclidine, 2.5% mannitol, 0.01% tropicamide, 5% polysorbate 80 can increase 3 lines of near vision in presbyopic patients for up to about 4 to about 5 hours. Adding 1.4% CMC further improves near vision from about 7 hours to about 10 hours. Without being bound by a particular theory, the threshold above the critical micelle threshold greatly enhances corneal penetration by reducing micelle size from microns to nanometers. See Figure 2 .

[0638] Examples of compositions containing little or no cycloplegic are shown in Table 8 below.

[0639] Table 8. Compositions containing little or no cycloplegic

[0640]

[0641] Table 8. (continued)

[0642]

[0643] Table 8. (continued)

[0644]

[0645] Table 8. (continued)

[0646]

[0647] Table 8. (continued)

[0648]

[0649] Table 8. (continued)

[0650]

[0651] Table 8. (continued)

[0652]

[0653] Table 8. (continued)

[0654]

[0655] All concentrations are by volume,

[0656] mm means millimeter,

[0657] cm means centimeter,

[0658] min means minute.

[0659] %* means the amount can optionally vary between about 0.01% to about 1% w / v.

[0660] # means the formulation can include polysorbate 80 or exclude polysorbate 80.

[0661] Ciliary spasm score corresponds to the following: 0 = no discomfort; 0.5 = slight pricking sensation; 1 = distinct squeezing / discomfort; 2 = pain for less than 30 minutes; 3 = pain for 1 hour or more; 4 = severe to unbearable pain.

[0662] Efficacy index is shown as Figure 3 Briefly, the score is calculated by multiplying the improvement in near visual acuity by the number of hours the improvement lasts. For example, 5 points equals an improvement in near visual acuity of +1 line for 5 hours; 10 points equals an improvement in near visual acuity of +1.5 lines for 6.7 hours; 15 equals an improvement in near visual acuity of 2 lines for 7.5 hours; 20 equals an improvement in near visual acuity of 2.5 lines for 8 hours; 25 equals an improvement in near visual acuity of +3 lines for 8.3 hours; and 35 equals an improvement in near visual acuity of +3.75 lines for 9 hours.

[0663] By comparing the reading at baseline 40 cm and the efficacy index for Formulas #L33-#L37, the formulas containing 1.40% or more of aceclidine are more suitable for correcting presbyopia than the formula containing 1.25% of aceclidine. Conversely, the lower concentrations of aceclidine bring better overall comfort to the user. The addition of 2.5% of mannitol and 1.45% of aceclidine in the formula improves the overall comfort, but at the expense of a decrease in the presbyopia correction effect (compare #L37 with #L47). This decrease in near visual acuity is exacerbated after the addition of 4.0% of mannitol (compare with #L47 and #L48). Increasing the concentration of aceclidine to 1.65% or 1.75% overcomes the decrease in near visual acuity after the addition of mannitol (compare with #L47, #L49, and #L50).

[0664] In addition, the formulations containing 1.75% of aceclidine and 2.5% of mannitol had higher efficacy and duration of action in the treatment of presbyopia, which was inversely proportional to the increase in the polysorbate 80 content to 5.0% and then to the decrease in the CMC content from 1.45% to 1.40% (compare formulations #L66 to #L78). #L77, #L78 and #L85-#L94 demonstrated the best formulations, each having a maximum improvement in reading at 40 cm of 3.5 to 3.75 visual acuity and the highest efficacy index score of 25 to 34 and the longest duration of 7 to 9 hours. The increase in effectiveness and duration of action of formulations #L66 to #L78 was also inversely proportional to the decrease in the content of tropicamide from 0.0275% to 0.01%. The same trend was also demonstrated by the increase in effectiveness (i.e. reading compared to baseline at 40 cm) comparing #L85 to #L94.

[0665] This data demonstrates that mannitol can effectively reduce the ciliary spasm induced by aceclidine, thereby reducing the need for a cycloplegic agent such as tropicamide. In addition, this data demonstrates that the addition of a non-ionic surfactant and a viscosity agent can further improve the efficacy and duration of action of a composition comprising aceclidine, mannitol and tropicamide. This data also demonstrates that in an aceclidine composition comprising polysorbate 80 and CMC, the use of a cycloplegic agent near 0.006% is more advantageous and beneficial to the correction of presbyopia than near 0.025%. Finally, this data demonstrates that a composition comprising aceclidine and mannitol is sufficient to correct presbyopia and has tolerable pain.

[0666] Example 12: Use of high content tropicamide formulations

[0667] The following examples are aceclidine formulations containing greater than 0.03% of tropicamide.

[0668] Table 9. High content tropicamide formulations

[0669]

[0670] Ciliary spasm score corresponds to the following: 0 = no discomfort; 0.5 = slight pricking sensation; 1 = clear squeezing / discomfort; 2 = pain for less than 30 minutes; 3 = pain for 1 hour or more; 4 = severe to unbearable pain.

[0671] As shown in Formulations #L39-#L41, formulations containing about 1.40% to about 1.45% of aceclidine, about 0.035% to about 0.04% of tropicamide, about 5.5% of polyethylene glycol 40 stearate, and about 0.75% of CMC are almost as effective as formulations comprising about 1.65% to about 1.75% of aceclidine, about 2.5% of mannitol, about 5% of polysorbate 80, about 1.40% of CMC in treating presbyopia, with a slight decrease in efficacy. This efficacy is greatly reduced when tropicamide is increased to about 0.05% to about 0.08%.

[0672] Example 13: Use of mannitol containing compounds

[0673]

[0674] Method:

[0675] Two drops of the above formulation were instilled into each eye of the subject and the excess formulation was wiped off from the eyelids and eyelashes.

[0676] Results:

[0677] Within 20 minutes, approximately 3 lines of near vision were observed to be improved and a very slight dimming occurred. The near vision remained enhanced throughout the day and there was no loss of distance vision. In addition, if the subject had any mild refractive error previously, the distance vision was improved. Over 5 to 8 hours, the pupils started to recover slightly and after a few hours, the minimal dimming phenomenon was no longer present. As the pupils started to increase in size from the minimal size earlier in the day, the near vision kicked in and the near vision could still be slightly improved.

[0678] Example 14: Preferred embodiments to optimize the use of tropicamide and hydroxypropyl methylcellulose

[0679] Composition

[0680]

[0681]

[0682] Method

[0683] Two drops of the above formulation were instilled into each eye of the subject, as 1 drop per eye, and a second drop was added after 5 minutes.

[0684] Results:

[0685] Assess comfort, duration of effect, and efficacy. Stinging during the infusion and first hour was minimal, scoring 0.25 / 4. Redness was also mild during the first hour, scoring 0.5 / 4 at 20 minutes. Improvement in vision began within the first 20 to 25 minutes after infusion. Baseline myopia (i.e., 40 cm) improved by 3.5 lines. Near vision improvement lasted 8.5 hours. The efficacy index score was 29.75 when the formulation was compared to Table 8. Replacing 1.80% w / v HPMC with 1.68% w / v HPMC resulted in a slight decrease in near vision improvement to 3.25 lines and a slight decrease in duration of effect to approximately 6+ hours. The efficacy index score was 19.5 when the formulation was compared to Table 8.

[0686] Example 15: Use of compounds containing mannitol and various nonionic surfactants

[0687] Composition

[0688] Table 10 lists the active ingredients, excipients, and their concentrations in test and prediction examples of compositions containing nonionic surfactants.

[0689] method

[0690] Two drops of the above composition were instilled into each eye of the subject independently, and excess preparation was wiped off the eyelids and eyelashes.

[0691] result

[0692] All nonionic surfactants tested showed significant improvement in near vision. In the case of only... Among the subjects tested (35%), those in a marginal state experienced significant corneal irritation, hyperemia, and shortened duration of hyperemia. Polysorbate 80 and poly-35 castor oil were the most preferred, while polyethylene glycol 40 stearate and poloxamer 407 were also very good. However, polyethylene glycol 40 stearate caused precipitation reactions with cellulose viscosities and increased other stability issues.

[0693] The comfort and duration of each nonionic surfactant were also tested and are listed in Table 10. Stinging and redness were rated from 0 to 4, where 0 represents none and 4 represents the most severe. (Except for...) Outside of 35°C, stinging and redness were mild to almost nonexistent. The duration of stinging was excellent for the nonionic surfactants tested for each type.

[0694] Table 10. Comparison of efficacy and comfort of various nonionic surfactants

[0695]

[0696] Example 16: Use of additives and concentrations of compounds containing optimized non-ionic surfactants and antioxidants

[0697] Compositions

[0698]

[0699]

[0700] Methods

[0701] Two subjects instilled 2 drops of the above formulation in each eye every 5 minutes apart.

[0702] Results:

[0703] Comfort, duration, and efficacy were assessed. For each subject, the stinging sensation after instillation and the first hour was minimal, scoring 0.50 / 4, lasting about 15 seconds. For each subject, the redness was also minimal in the first hour, scoring 0.25 / 4 at 20 minutes. Vision started to improve in the first 20 to 25 minutes after instillation. For subject 1, the baseline near vision (i.e., 40 cm) improved by 4.0-4.25 lines of vision and lasted for 11.5 hours. For subject 2, the baseline near vision improved by 3.5 lines and lasted for 9.5 hours. The efficacy index scores were 47.38 and 33.25, respectively, achieving the highest among all formulations.

[0704] Example 17: Vecamylidene compositions for cold chain storage (predictions)

[0705] Table 11. Cold chain storage compositions

[0706]

[0707]

[0708] Table 11. Cold chain storage compositions (continued)

[0709]

[0710] Table 11. Cold chain storage compositions (continued)

[0711]

[0712]

[0713] Methods

[0714] Velticine cold chain storage compositions CS#1-5 and 11-20 were filled in vials under nitrogen blanket and then purged with nitrogen to the remaining headspace. CS#6-10 were filled in vials under ambient air and headspace. One vial of each composition was kept at 25 degrees Celsius and the other at 5 degrees Celsius.

[0715] Results

[0716] Table 12. Stability of velticine cold chain storage compositions

[0717]

[0718] Table 12. Stability of velticine cold chain storage compositions (continued)

[0719]

[0720] As shown in Table 12, CS#3-5 containing 0.10% sodium ascorbate, 0.10% sodium bisulfate or 0.10% sodium metabisulfite were stable for about 2 months at 25 degrees Celsius and about 26 months at 5 degrees Celsius. Figure 4 As shown in Table 12, filling vials under nitrogen blanket and headspace nitrogen purge resulted in an increase in cold storage stability of 4-5 months. Addition of HPMC increased stability by another 3 months; sodium citrate, sodium bisulfate or sodium metabisulfite increased stability by another 3 months; further addition of sorbic acid and BAK increased stability by another 2 months. CS#20 increased stability to 22 months.

[0721] Example 18:

[0722] Stability of Lined Bags Velticine formulations of the present application were placed in containers and subsequently placed in bags lined with biaxially stretched polyethylene terephthalate at -20°C, 5°C and 25°C for up to 3 months. Total related substances of velticine were recorded at 1 month, 2 months, 3 months and 6 months. The results of this study can be seen in Table 13 below.

[0723]

[0724] Used as a source of biaxially stretched polyethylene terephthalate. Mylar is a registered trademark of DuPont Teijin Films US Limited and is available from DuPont Teijin Films US Limited. Table 13. Total Related Substances of Velticine After Storage

[0725]

[0726] ​

[0727] As shown in Table 13, using a bag lined with The bagging can help maintain the potency of aceclidine by reducing the rate of degradation. Specifically, compare the total percent change of 4.46% at room temperature (25 °C) without bagging to the total percent change of -0.05% and 0.041% at room temperature (25 °C) with bagging.

Claims

1. A method of stabilizing a composition comprising aceclidine, the method comprising storing the composition in a container having a headspace at a temperature of about 2 degrees Celsius to about 8 degrees Celsius.

2. The method of claim 1, wherein, The composition is filled into the container under an inert gas blanket.

3. The method of claim 2, wherein, The headspace is purged with an inert gas.

4. The method of claim 1, wherein, The container comprises a closure and a vessel, wherein part of the closure and part of the vessel are sealed with a tamper resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene and aluminum foil.

5. The method of claim 1, wherein, The container is placed inside a second container formed of or lined with a tamper resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene and aluminum foil.

6. A method of stabilizing a composition comprising aceclidine, a viscosity agent and a non-ionic surfactant, the method 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 a nitrogen gas blanket and the headspace is purged with nitrogen gas, wherein the composition provides a low shear (1 / sec) viscosity of about 50 to about 1000 centipoise and a high shear (1:1000 / sec) viscosity of about 0.5 or less centipoise.

7. A method of stabilizing a composition comprising aceclidine, hydroxypropyl methylcellulose, polysorbate 80, mannitol, sorbate and an antioxidant selected from the group consisting of sodium ascorbate, sodium bisulfite, sodium metabisulfite, n-acetyl cysteine or a combination thereof, the method 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 a nitrogen gas blanket and the headspace is purged with nitrogen gas.

8. A container comprising aceclidine, prepared by a process comprising the steps of: a) providing a container; b) filling a composition comprising aceclidine into the container under an inert gas blanket; c) purging a headspace formed during the filling step b) with an inert gas; d) capping the container.

9. A composition comprising about 0.25% to about 4.0% w / v aceclidine and one or more methods of stabilizing the composition selected from the group consisting of filling the composition into a container under an inert gas blanket and purging the headspace created upon filling with an inert gas, the total viscosity of the composition is at least 50 centipoise or more, adding a preservative to the composition and the preservative is selected from the group consisting of sorbate, benzalkonium chloride, sodium ascorbate, sodium bisulfite, sodium metabisulfite, n-acetyl cysteine and combinations thereof, wherein the composition is stored at a temperature of about 2 to about 8 degrees Celsius and wherein w / v means weight per total volume of the composition.

10. A method of stabilizing a composition comprising aceclidine, the method comprising storing the composition in a container having a headspace at a temperature of about 22 degrees Celsius to about 25 degrees Celsius, wherein the container comprises a closure and a vessel, wherein part of the closure and part of the vessel are sealed with a tamper-evident material selected from the group of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil, and / or, placing the container within a second container formed from or lined with biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil.

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