CA3195422A1 - Compositions and methods for storage stable ophthalmic drugs - Google Patents

Compositions and methods for storage stable ophthalmic drugs

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Publication number
CA3195422A1
CA3195422A1 CA3195422A CA3195422A CA3195422A1 CA 3195422 A1 CA3195422 A1 CA 3195422A1 CA 3195422 A CA3195422 A CA 3195422A CA 3195422 A CA3195422 A CA 3195422A CA 3195422 A1 CA3195422 A1 CA 3195422A1
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Prior art keywords
concentration
container
aceclidine
degrees celsius
sodium
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CA3195422A
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French (fr)
Inventor
Gerald Horn
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Lenz Therapeutics Operations Inc
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Lenz Therapeutics Inc
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Priority claimed from US17/069,155 external-priority patent/US11273150B2/en
Application filed by Lenz Therapeutics Inc filed Critical Lenz Therapeutics Inc
Publication of CA3195422A1 publication Critical patent/CA3195422A1/en
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention is related to methods of stabilizing an ophthalmic drug by adding a surfactant and a viscosity enhancer to the ophthalmic drug to create a composition wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 centipoise or more at shear rate of 1 per second at 25 degrees Celsius, filling the composition into a container; and storing the container at a temperature from about 2 degrees Celsius to about 25 degrees Celsius, The present invention is further directed to a container prepared by the methods of the present invention.

Description

COMPOSITIONS AND METHODS FOR STORAGE STABLE OPHTHALMIC DRUGS
BACKGROUND OF THE INVENTION
[001] Several ophthalmic drugs must be. diluted just prior to instillation or if pre-foiniulated have a limited shelf life or require cold storage. Current ophthalmic drugs that suffer from stability issues include aceclidine, latanoprost, latanoprost-timolol, ehloramplienicol, azasite, cyclopentolate, proteins, peptides, amino acids and their derivatives.
[002] Aceolidine has been shown effective f:-tr the treatment of glaucoma Current aceelidine, formulations require lyophilization of the aceclidine and mixing with a diluent just prior to Aceclidine has also been demonstrated to treat presbyopia, an eye condition that effects almost every person starting around 40 years of age. See US Patent Nos. 9,089,562;
9,314,427; 9,320,709; 9,833,441; 9,844,537; 9,968,594; 10,052,313; 10,064,818;
10,307,408;
10,617,763 and 10,959,990.
[003] Latanoprost has also been shown to effectively treat glaucoma. Like aceclidine, latanoprost requires Gold storage due to a limited shelf life at room temperature.
[004] The instability of these ophthalmic drugs including aceclidine and latanoprost cause inconvenience, reduced efficacy and increased costs for both the subjects in need of these treatments and the companies that manutheture, sell and package these drugs,
[005] Thus, there is a need in the art for a method of stabilizing ophthalmic drugs such that an increase in shelf lite is achieved.
SUMMARY OF THE. INVENTION
[006] In certain other embodiments, the present invention is directed to a method of stabilizing an ophthalmic drug comprising the following steps:
a) adding a surfactant and a viscosity enhancer to the ophthalmic drug to create a composition wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 centipoise or more at shear rate of 1 per second at 25 degrees Celsius;
b) filling the composition from step a) into a container; and c) storing the container at a temperature from about 2 degrees Celsius to about 25 degrees Celsius, preferably from about 2 to about 8 degrees Celsius and more preferably at about degrees Celsius.
[007] In certain other embodiments, the ophthalmic drug is selected from the group consisting of aceclidine, latanoprost, latanoprost-timolol, chloramphenicol, azasite, cyclopentolate, proteins, peptides, amino acids, salts thereof, derivatives thereof and combinations thereof'.
[008] In certain other embodiments, the container of the present invention comprises a closure and a vessel wherein a portion of the closure and a portion of the vessel are sealed with an anti-leaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil, preferably biaxially-oriented polyethylene terephthalate.
[009] in certain other embodiments, the container of the present invention is disposed in a second container that is formed with or lined with an anti-leaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetrafluoreth.ylene and aluminum foil, preferably biaxially-oriented polyethylene terephthalate.
[010] In certain other embodiments, the present invention is directed to a method of stabilizing a composition comprising aceelidine comprising storing the composition in a container having a headspace at a temperature from 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 an anti-leaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil and/or the container is disposed in a second container that is formed with or lined with biaxially-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil.
[011] In certain other embodiments, the second container comprises a second closure, wherein the second closure provides an airtight seal.
[012] In certain other embodiments, the the airtight seal is resealable.
[013] In certain other embodiments, the ophthalmic drug is aceclidine is at a concentration from about 0.25% to about 4.0% w/v aceclidine,
[014] In certain other embodiments, the methods of the present invention provide at least 90%
stability of the ophthalmic drug 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 or at least 24 months.
[015] In certain other embodiments, the compositions of the present invention have a viscosity of about 0.5 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 150 centipoise or more, preferably 300 centipoise or more at at shear rate of I
per second at 25 degrees Celsius.
[016] In certain other embodiments, the compositions of the present invention has a viscosity from about 75 to about 1,000 centipoise at a shear rate of 0.
[017] In certain other embodiments, the present invention is directed to a method of stabilizing a composition comprising aceclidine, hydroxypropylmethyl cellulose, polysorbate 80, mannitol, sorba.te and an antioxidant selected from the group consisting of sodium asc,orbate, sodium bisulfate, soidum inetabisulfite, n-acetyl cysteine or a combination thereof comprising storing the composition in a container having a head.space at a temperature from about 2 degrees Celsius to about 8 degrees Celsius, wherein the composition is filled into the container under an inert gas overlay, preferably nitrogen and the headspace is purged with an inert gas, preferably nitrogen.
[018] In certain other embodiments, the aceclidin.e is at a concentration from about 0.25% to about 4.00% w/v, the hydroxypropylmethyl cellulose is at a concentration from about 0.75% to about 1.25% w/v, polysorbate 80 is at a concentration from about 2% to about 4% w/v, mannitol is at a concentration from about 2% to about 4% w/v, sorbate is at a concentration from about 0.10% to about 0.12% w/v and the antioxidant is at a concentration from about 0.10% to about 0.25% w/v.
[019] In certain other embodiments the present invention is directed to a container comprising an ophthalmic drug prepared by the process comprising the steps of:
a) providing a container;
b) filling the container with a composition comprising an ophthalmic drug, a surfactant and a viscosity enhancer, preferably under an inert gas overlay, preferably nitrogen, wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1./1000 per second at 25 degrees Celsius and a viscosity of about 70 centipoise or more at shear rate of I per second at 25 degrees Celsius;
c) optionally, purging a hea.dspace created during the filling step b) with an inert gas, preferably nitrogen;
d) capping the container; and e) optionally, storing the container at a temperature from about 2 to about 25 degrees Celsius, preferably from about 2 to about 8 degrees Celsius and more preferably at about degrees Celsius.

1020] In certain other embodiments, the present invention is directed to a method of stabilizing a composition comprising aceclidine comprising storing the composition. in a container having a headspace at a temperature from about 2 degrees Celsius to about 8 degrees Celsius, preferably at about 5 degrees Celsius.
[021] lii certain other embodiments, the compositions of the present invention are tilled into the container under an inert gas overlay, preferably nitrogen, preferably the headspace is purged with an inert gas overlay, preferably nitrogen.
[022] In certain other embodiments the present invention is directed to a composition comprising from about 0.25% to about 4.0% WA/ aceelidine and one or more means of stabilizing the composition selected from the group consisting of filling the composition into a container .under an inert gas overlay, preferably nitrogen and purging a hea.dspace created during filling with the inert gas overlay, preferably nitrogen, having a total viscosity of the composition of at least 50 eentipoise or more, adding a preservative to the composition selected from the group consisting of sorbate, benzalkonim chloride, sodium ascorbate, sodium 'bisulfate, sodium metabisulfite, nsacetyl cysteine and a combination thereof, wherein the composition is stored at a temperature from about 2 to about 8 degrees Celsisus and.
wherein w/v denotes weight by total volume of the composition.
[023] In certain other embodiments, the present invention is directed to a method of treating presbyopia comprising administering to a subject in need thereof a composition of the present invention.
[024[ In certain other embodiments, the present invention is directed to a method of treating a refractive error of the eye in a subject in need thereof comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a composition of the present invention wherein the refractive error of the eye is selected from presbyopia, myopia, hyperopia, astigmatism or a combination thereof [025] The present invention is further directed to a method of increasing the visual depth of field (i.e. depth of focus) secondary to pupil miosisõ comprising administering to a subject in need thereof a pharmaceutically effective amount of an ophthalmological composition of the present invention.

10261 The present invention is further directed to a method of reducing the side effects of ophthalmic aceclidine administration by modulating the agonist effect on the ciliaiy body of the eye such that ciliary spasm, ciliary induced brow ache, and/or ciliary induced headache are substantially reduced or eliminated.
[027] The present invention is further directed to at method of allowing binocular physiologic topical presbyopic correction.
10281 The present invention is further directed to a method of eliminating the need for monocular /imitation due to distance blur, or reduced to treatment of mild hyperopes to counteract induced myopic blur, as typically associated with pilocarpine, or pilocarpine and alpha agonist combinations.
[029) The present invention is further directed to a method of improving near vision by increasing accommodation without reduction in distance vision sharpness. This is achieved by simultaneously increasing incremental accommodation, modulated so that while sufficient to provide additive near vision enhancement, it remains at a rate of induction and total degree of accommodation such that the associated myopic blur does not break through the ability of the simultaneously induced pupil miosis pinhole effect to filter the refractive error and maintain distance sharpness.
[030] The present invention is further directed to a method of increasing the visual depth perception upon improving near vision unaided comprising administering to a subject in need.
thereof a pharmaceutically effective amount of an ophthalmological composition of .the present invention in both eyes (binocular vision), wherein such binocularity further enhances near vision beyond that of either eye separately.
[031] The present invention is further directed to a method of improving vision in a subject with ammetropia (vision abnormality), comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition of the present invention.
[032] The present invention, is further directed to a method of improving vision in a subject with ammetropia, comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition of the present invention, wherein ammetropia is selected from the group consisting of nearsightedness, farsightedness, regular astigmatism, irregular astigmatism and high degrees of regular astigmatism.

[033] The present invention is further directed at eliminating optical aberrations induced by corneal irregularity, opacities, or very high degrees of regular astigmatism that include regions adjacent or peripheral to the central 1.5 nun optical zone, and thereby inducing improved visual acuity and quality of vision by filtering out these aberrant optics in those suffering from irregular astigmatism or high degrees of more regular astigmatism, such as occurs in conditions such as .keratoconus, photorefractive keratectomy induced corneal haze, diffuse lamellar keratitis ("DLK") (post-lasik DLK), other iatrogenic corneal induced irregularity such as cataract incision, glaucoma -filtering blebs, implanted glaucoma valves, corneal inlays with or without removal, ectasia post corneal surgery (lasik), and secondary to infection.
(034] The present invention is further directed at improving acuity relative to existing uncorrected refractive error. Upon this improved acuity, patients now requiring toric contact lenses for astigmatism with reduced comfort and optics that may shift during each blink may in many cases require only non-toric soft contact lenses or no contact lenses.
Further, those requiring gas permeable contact lenses may no longer require contact lenses or only require much more comfortable soft contact lenses. Patients with high degrees of astigmatism may now require no correction or reduced astigmatic correction. Patients with small to moderate degrees of nearsightedness may require less correction or no longer require correction. Patients with small to moderate degrees of hyperopia (farsightedness) may require no correction or reduced correction.
[035] The present invention is directed to methods and ophthalmological compositions for improving eye sight. In a preferred embodiment the present invention is directed to methods and ophthalmological compositions for the treatment of presbyopia. In a more preferred embodiment the present invention is directed to ophthalmological compositions comprising aceclidine.
(036] The present invention is directed to methods of treating irregular astigmatism, keratoconic e.ctasia, and low myopia, or hyperopia, with or without astigmatism, comprising administering to a subject in need thereof an ophthalmological composition of the present invention.
[037] The present invention is further directed to a method of stabilizing aceclidine comprising providing a first composition comprising about 135% w/v aceclidine and about 2.5% w/v mannitoi in a first chamber and a second composition comprising about 0.01%
w/v tropicamide, about 4.0% w/v polysorbate 80, about 1.25% %iv/qv hydroxypropylmethyl cellulose, 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 optionally, about 0.1% w/v sodium citrate or citrate buffer in a second chamber, wherein upon mixing the first composition and the second composition the efficacy of aceclidine is maintained for at least one month.
10381 The present invention is further directed to a method of stabilizing aceclidine comprising storing a composition of the present invention at from 0 degrees Celsius to 8 degrees Celsius.
BRIEF DESCRIPTION OF THE FIGURES
[039] Figure 1 is a graphical representation of the effects of pilocarpine and aceclidine with or without tropicamide and with or without a carrier on near and distance vision in. a patient over the age of 45.
1040] Figure 2 is a graphical representation of the effects of addition of non-ionic surfactants and viscosity agents on near vision acuity and duration of effect. Line-Hours denotes lines improved times duration of effect.
[041] Figure 3 is a graphical representation of the Efficacy Index for formulas #1,33-#L94.
Box color denotes a comfort level of good for white, fair for cross-hatched and poor for black.
19421 Figure 4 is a graphical representation of percent stability of aceclidine cold storage compositions at 5 and 25 degrees Celsius over 30 months.
DETAILED DESCRIPTION OF THE INVENTION
[043] The present invention is directed to compositions and methods of stabilizing an ophthalmic drug by formulating the drug in a combination of surfactants and viscosity agents that achieve a nonlinear viscosity for the composition arid storing the composition in a container.
Definitions 10441 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 a combination of the. specified ingredients in the specified amounts.
[045] The term "stabilizing", as used herein, refers to any process which facilitates and/or enables an active agent to remain in solution. The term "stabilizing", as used herein, also refers to any means or process which inhibits and/or reduces the tendency of an active agent including a musearinie agonist, including aceclidine, to degrade.
[046] As used herein, all numerical values relating to amounts, weights, and the like, that are defined as "about" each particular value is plus or minus 10%. For example, the phrase "about 5% w/v" is to be understood as "4.5% to 5.5% w/v." Therefore, amounts within 10% of the claimed value are encompassed by the scope of the claims.
10471 As used herein "% w/v" refers to the percent weight of the total composition.
[0481 As used herein the term "subject" refers but is not limited to a person or other animal.
[049] As used herein, the term "container" refers to a pharmaceutically acceptable container comprising a chamber suitable to house a liquid drug product. Containers include, for example, vials, syringes, capsules, and ampoules.
[050] As used herein "headspace" refers to the area within the chamber of the container between the composition and the cap when the cap is oriented away from the pull of gravity.
[051] As used herein, the term "cap" or "closure" refers to any article capable of preventing the composition from exiting the container.
[052] The tenni muscarinic receptor agonist ("muscarinic agonist") encompasses agonists that activate muscarinic acetylcholine receptors ("muscarinic receptors").
.Muscarinic receptors are divided into five subtypes named MI -M5. Muscarinic agonists of the present invention include those muscarinic agonists that preferentially activate Ml and M3 receptors over M2, M4 and M5 receptors ("Ml /M3 agonists"). Ml /M.3 agonists include but are not limited to aceelidine, xanomeline, talsaclidine, sabcom.eline, cevimeline, alvameline, arecoline,, milameline, SOZ-210-086, YM-796, RS-86, CDD-0102A (54.3-ethy1-1,2,4-oxasdiazo1-5-y11-1,4,5,6-tetrahydropyrimidine hydrocholoride), N-arylurea-substituted 3-morpholine arecolifieS
VU0255-035 (N43-oxo-344-(4 -pyridiny1)- I -piperazinyl]propy1]-2,1,3-benzothiadi azole-4-sulfonamide), benzylquinolone carboxylic acid (BQCA), WAY-132983, AFB267B
(NGX267), AC-42, AC-260584, chloropyrazines including but not limited to L-687, 306, L-689-660, 774,1-1-28-.1 , LY593039, and any quinielidine ring with one or more carbon substitutions particularly that include an ester, sulfur, or 5 or 6 carbon ring structure including with substituted nitrogen(s) and or oxygen(s), or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof A preferred Ml/M.3 agonist is aceclidine. In a preferred einbodiment, muscarinic agonist of the present invention include those muscarinic agonist that preferentially activate MI and M3 over M2, M4, and M5; and even more preferably activate MI
over M3. In a more preferred embodiment muscarinic agonist of the present invention include those muscarinic agonists that only activate MI.

[0531 The term "aceclidine" encompasses its salts, esters, analogues, prodrugs and derivatives including, hut not limited to, aceclidine as a. racemic mixture, aceclidine enantiomer, aceclidine enantiomer, aceclidine analogues, including, but not limited to, highly MI selective 1,2,5 thiadiazole substituted analogues like those disclosed in Ward. J.S. et al., 1,2,5-Thiadiazole analogues of aceclidine as potent ml muscarinic agonists, J Ailed Chem, 1998, Is.m 29, 41(3), 379-392 and aceclidine prodrugs including but not limited to carbamate esters.
[054] The term "selective a-2 adrenergic receptor agonists" or "0,-2 agonist"
encompasses all a-2 adrenergic receptor agonists which have a binding affinity of 900 fold or greater for a-2 over a-1 adrenergic receptors, or 300 fold or greater for a.-2a or a--2b over a--1 adrenergic receptors.
The term also encompasses pharmaceutically acceptable salts, esters, prodrugs, and other derivatives of selective a-2 adrenergic receptor agonists.
10551 The term "inert gas" refers to gases that are chemically inert and do not react with other compounds. Inert gases include, but are not limited to, helium, neon, argon, krypton, xenon, radon and nitrogen.
[056] The term "low concentrations" or "low-dose" of alpha-2 adrenergic receptor agonists refers to concentrations from between about 0.0001% to about 0.065% w/v; more preferably, from about 0.001% to about 0.035% w/v; even more preferably, from about 0.01%
to about 0.035% w/v; and even more preferably, from about 0.03% to about 0.035% w/v, 10571 The term "brimonidine" encompasses, without limitation, brimonidine salts and other derivatives, and specifically includes, but is not limited to, brimonidine tartrate, 5-bromo-6-(2-imida.zo1in-2-yl.ainino)quinoxa1ine D-tartrate, and Aiphagan .
[058] The terms "treating" and "treatment" refer to reversing, alleviating, inhibiting, or slowing the progress of the disease, disorder, or condition to which such terms apply, or one or more symptoms of such disease, disorder, or condition, [059] The. term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable (i.e. without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner).
[0601 As used herein, the tenn "pharmaceutically effective amount" refers to an amount sufficient to effect a desired biological effect, such as a beneficial result, including, without limitation, prevention, diminution, amelioration or elimination of signs or symptoms of a disease or disorder. Thus, the total amount of each active component of the pharmaceutical composition or method is sufficient to show a meaningful subject benefit. Thus, a ".pharmaceutically effective amount" will depend upon the context in which it is being administered. A
pharmaceutically effective amount may be administered in one or more prophylactic or therapeutic administrations.
[061] The term "prodrugs" refers to compounds, including, but not limited to, monomers and dimers of the compounds of the invention, which have cleavable groups and become, wider physiological conditions, compounds which are pharmaceutically active in vivo.
[062] As used herein "salts" refers to those salts which retain the biological effectiveness and properties of the parent compounds and which are not biologically or otherwise harmful at the dosage administered. Salts of the compounds of the present inventions may be prepared from inorganic or organic acids or bases.
[063] The term "higher order aberrations" refers to aberrations in the visual field selected from starbursts, halos (spherical aberration.), double vision, multiple images, smeared vision, coma and trefoil.
[064] The term "cold chain" refers to storage at temperatures from about 2 to about 8 'V from manufacture to immediately prior to administration.
[065] The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids or bases. The phrase "pharmaceutically acceptable salt" means those salts which 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. Pharrnaceutioa SeienCd8.: .1977, 66: 1 et seq.
[066] The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a 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-hydroxyethansulfbnate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, pe.rsulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and &amyl sulfates; long Chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others.
Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, h.yaluronic acid, malic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, malic acid, maleic acid, methanosulfonic acid, succinic acid and citric acid.
[0671 Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts include, but are not limited to, cations based oil alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methy lammoni um , di m et hylamm onium , trimethy I
ammonium, triethylammoniumõ diethylammonium, and ethylammonium among others. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolarnine, diethanolamine, piperidine, piperazine and the like.
[0681 The term "ester" as used herein is represented by the formula -----0C(0)A1 or -- C(0)0A1, where Al can be alkyl, cycloalkyl, alkenyi, cycloalkenyl, alkynyl, cycloalkynyl, aryl, a heteroaryl group or other suitable substituent, = Methods of the Invention [069] In certain embodiments, the present invention is directed to a method of stabilizing an ophthalmic drug comprising the following steps:
a) adding a surfactant and a viscosity enhancer to the ophthalmic drug to create a composition wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 centipoise or more, preferably of about 150 centipoise or more and more preferably at about 300 centipoise or more at at shear rate of 1 per second at 25 degrees Celsius;
filling the composition from step a) into a container; and c) storing the container at a temperature from about 2 degrees Celsius to about 25 degrees Celsius, preferably from about 2 to about 8 degrees Celsius and more preferably at about degrees Celsius.
[0701 In certain other embodiments, the compositions of the present invention are filled into the container under an inert gas overlay, preferably nitrogen, preferably the headspace is purged with an inert gas overlay, preferably nitrogen.
[071] In certain other embodiments, the ophthalmic drug is selected from the group consisting of aceclidine, latanoprost, latanoprost-timolol.õ c..hloramphenicol, azasite, cyclopentolate, proteins, peptides, amino acids, salts thereof, derivatives thereof and combinations thereof [072] In certain other embodiments, the container of the present invention comprises a closure and a vessel wherein a portion of the closure and a portion of the vessel are sealed with an anti-leaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil, preferably biaxially-oriented polyethylene terephthalate.
[073] In certain other embodiments, the container of the present invention is disposed in a second container that is formed with or lined with an anti-leaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, poly tetraftuorethylene and aluminum foil, preferably biaxially-oriented polyethylene terephthalate.
[074] In certain other embodiments, the present invention is directed to a method of stabilizing a composition comprising aceclidine comprising storing the composition in a container having a headspacc at a temperature from 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 an anti-leaching material selected from the group consisting of biaxialty-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil and/or the container is disposed in a second container that is formed with or lined with biaxially-oriented polyethylene terephthaiate, polytetrafluorethylene and aluminum foil, [075] In certain other embodiments, the second container comprises a second closure, Wherein the second closure provides an airtight seal.
[0761 In certain other embodiments, the the airtight seal is resealable.
[077] In certain other embodiments, the ophthalmic drug is aceelidine is at a concentration from about 0.25% to about 4.0% w/v aceclidine.
[0781 In certain other embodiments, the methods of the present invention provide at least 90%
stability of the ophthalmic drug for at least 7 months, at least 8 montlis, at least 12 months, at least 15 months, at least 18 months, at least 20 months or at least 22 months or at least 24 months.
[079] in certain other embodiments, the compositions of the present invention have a viscosity of about 0.5 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 150 centipoise or more, preferably 300 centipoise or more at at shear rate oil per second at 25 degrees Celsius.
[0801 In certain other embodiments, the compositions of the present invention has a viscosity from about 75 to about 1,000 centipoise at a shear rate of 0.
[081] In certain other embodiments, the present invention is directed to a method of stabilizing a composition comprising aceclidine, hydroxypropylinethyl cellulose, polysorbate 80, mannitol, sorbate and an antioxidant selected from the group consisting of sodium ascorbate, sodium bisulfate, soidum metabisulfite, n-acetyl cysteine or a combination thereof comprising storing the composition in a container having a headspace at a temperature from about 2 degrees Celsius to about 8 degrees Celsius, wherein the composition is filled into the container under an inert gas overlay, preferably nitrogen and the headspace is purged with an inert gas, preferably nitrogen.
[082] In certain other embodiments, the aeeclidine is at a concentration from about 0.25% to about 4,00% w/v, the hydroxypropylmethyl cellulose is at a concentration from about 0.75% to about 1.25% w/v, polysorbate SO is at a concentration from about 2% to about 4% w/v, mannitol is at a concentration from about 2% to about 4% w/v, sorbate is at a concentration from about 0.10% to about 0,12% w/v and the antioxidant is at a concentration from about 0,10% to about 0.25% w/v.

[083] In certain other embodiments the present invention is directed to a container comprising an ophthalmic drug prepared by the process comprising the steps of:
a) providing a container;
b) filling the container with a composition comprising an ophthalmic drug, a surfactant and a viscosity enhancer, preferably under an inert gas overlay, prefereably nitrogen, wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 eentipoise or more at at shear rate of 1 per second at 25 degrees Celsius;
c) optionally, purging a headspace created during the filling step b) with an inert gas, preferably nitrogen;
d) capping the container; and c) optionally, storing the container at a temperature from about 2 to about 25 degrees Celsius, preferably from about 2 to about 8 degrees Celsisus and more preferably at about degrees Celsius.
[084] In certain other embodiments the present invention is directed to a composition comprising from about 0.25% to about 4.0% w/v accelidine and one or more means of stabilizing the composition selected from the group consisting of filling the composition into a container under an inert gas overlay, preferably nitrogen and purging a headspace created during filling with the inert gas overlay, preferably nitrogen, having a total viscosity of the composition of at least 50 centipoise or more, adding a preservative to the composition selected from the group consisting of sorbate, benzalkonirn chloride, sodium ascothater sodium bisulfate, sodium inetabistiffite, n-acetyl systeine and a combination thereof, wherein the composition is stored at a temperature from about 2 .to about 8 degrees Celsisus and wherein wlv denotes weight by total volume of the composition..
Compositions of the Invention [085] Ophthalmic drugs suitable for use in the present invention include, but are not limited to, aceelidine, latanoprost, latanoprost-timolol,, cbloramplienicol, azasite, cyclopentc.date, proteins, peptides, amino acids, salts -thereof, derivatives thereof and combinations thereof.
10861 Surfactants suitable for use in the present invention include nonionic, ionic and amphoteric (zwitterionic) surfactants. In a preferred embodiment, the surfactant used in the present invention are at a concentration above the critical mieellar concentration for that surfactant.
[087] Nonionic surfactants suitable for the present invention include cyclodexuins, polyoxyl alkyls, poloxamers, polysorbates or combinations thereof. Preferred embodiments include Poloxamer 108, Poloxamer 188, Poloxamer 407, Polysorbate 20, Polysorbate 80, tonically charged (e.g. anionic) beta - cyclodextrins with or without a butyrated salt (Captis" 2-hydroxypropyl beta cyclodextrin ("1-1P13CD"), alpha cyclodextrins, gamma cyciodextrins, Polyoxyl 35 castor oil, and Polyoxyl 40 hydrogenated castor oil or combinations thereof.
Further, substitution of other nonionic surfactants compatible with ophthalmological use allows for similar formulation advantages, which may included but is not limited to one or more of a nonionizing surfactant such as poloxamer, poloxamer 103, poloxamer 123, and poloxamer 124, poloxamer 407, poloxamer 188, and poloxamer 338, any poloxamer analogue or derivative, polysorbate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, any polysorbate analogue or derivative, cyclodextrin, hydroxypropyl-P- cyclodextrin, bydroxypropyl-eyclodextrin, randomly methylated p-cyclodextrin, ri-eyelodextrin sulfebutyl ether, le-cyclodextrin sulfobutyl ether or glucosyl- r- cy-clodextrin, any cyclodextrin analogue or derivative, polyoxyethylene, polyoxypropylene glycol, an polysorbate analogue or derivative, polyoxyethylene, hydrogenated castor oil 60, polyoxyethylene (200) , poiyoxypropyiene glycol (70), polyoxyethylene hydrogenated castor oil, polyoxyethylerie hydrogenated castor oil 60, polyoxyl, polyoxyl stearate, nonoxynol, octyphenol ethoxylates, nonyl phenol ethoxylates, capryols, lauroglycol, polyethylene glycol ("PEG"), Brij 35, 78, 98, 700 (polyoxyethylerie glycol alkyl ethers), gl-yceryl laurate, lauryl glucoside, decyl glucoside, or cetyl alcohol; or zwitterion surfactants such as palmitoyl earintine, cocarnide DEA., cocamide DEA derivatives cocamidopropyl betaine, or trimethyl glycine betaine, N-2(2-acetamido)-2-aminoetbane sulfbnic acid (ACES), N-2-acetamido iminodiaeetic acid (ADA), N,N-his(2-hydroxyethyl)-2-aminoethane sulfonic acid (BES), 2-[Bis-(2-hydroxyethyl)-amino]-2-hydroxymethyl-propane-1,3-diol (Bis-Tris), 3-cyclohexylamino-l-propane sulfonic acid (CAPS), 2-eyclohexylamino-1-ethane sulfonic acid (CHES), N,N-bis(2-hydroxyethy1)-3-atnino-2-bydroxypropane sulfonic acid (DIPSO), 4-(2-hydroxyethyl)-1-piperazine propane sulfonic acid (EPPS), N-2-hydroxyethyipiperazine-M-2-ethane sulfonic acid (HUES), 2-(N-morpholino)-ethane sulfonic acid (MES), 4-(N-morpholino)-butane sulfonic acid (MOBS), 2-(N-morpholino)-propane sulfonic acid (MOPS), 3-morphohno-2-hydroxypropanesulfonic acid (MOPS0), 1,4-piperazine-bis-(ethane sulfonic acid) (PIPES), piperazine-N,N1-bis(2-hydroxypropane sulfonic acid) (POPS0), N-tris(hydroxy,-methyptnethy1-2-aminopropane sulfonic acid (TAPS), N-[tris(hydroxymethyptnethyli-3-amino-2-hydroxypropane sulfonic acid (TAPS0)õ N-tris(hydroxymethyl) methy1-2-aminoethane sulfonic acid (TES), 2-Amino-2-hydroxymethyl-propane-1,3-diol (Tris), tyloxa.pol, Solulanim C-24 (2-al 0,13-dimethy1-17-(6-methylheptan-2-y1)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro- I H-cyclopenta[a]phenanthren-3-y oxy]ethanal) and Span 20-20 (sorbitan monolaurate, sorbitan monopaimitate, sorbitan mcniostearate, and sorbitan monooleate) in other embodiments the addition of polysorbate 80 is preferred. In addition to the above nonionic surfactants any nonionic surfactant is suitable for use in the present invention as long as the concentration of the nonionic surfactant is such that it is above the critical micellar concentration for that non-ionic surfactant. Preferably, the nonionic surfactants used in the present invention achieve submicron diameter micelles, more preferably less than 200 nanometers and more preferably less than 150 nanometers in diameter.
[088] Ionic surfactants suitable for use in the pesent invention include, but are not limited to, anionic surfactants and cationic surfactants. Anionic surfactants suitable for use in the present invention include, but are not limited to, ammonium lauryi sulfate, dioctyl sodium sulfosuccinate, sodium laureth sulfate, linear alkylbenzene sulfonate, sodium dodecyl sulfate, perfluorooctariesuifonate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pared' sulfate, sodium stearte, lignosuifonate, sodium lauryl sulfate, a olefin sultanate, ammonium laureth sulfate and sodium esterilauryl sulfate. Cationic surfactants suitable for use in the present invention include, but are not limited to benzalkonium chloride, benzetbonium chloride, methylbenzethonium chloride, cetylpyridinium chloride, alkyl-dimethyl dichlorobenzene ammonium chloride, dequ,,ilinium chloride, phenamylinium chloride, cetyl -trimethylammonium bromide, cetyl trimethylammonium chloride, cetrimonium bromide and cethexonium bromide.

10891 Amphoteric (zwitterionic) surfactants are any surfactant simultaneously carrying an anionic charge and a cationic charge. Amphoteric surfactants suitable for use in the present invention include, but are not limited to, alkyl or alkenyl-amphoacetates or ampho-diacetates, alkylampho-propionates or -dipropionates, alkyl amphohydroxypropyl suitaines wherein the alkyl groups contain 8 to 24 carbon atoms such as coco or lauryl.
(0901 Surfactants may be used in the present invention at a concentration above their critical 'Medlar concentration. The critical micellar concentration for any particular surfactant may be calculated by a person of skill in the art In a preferred embodiment, the concentration of surfactants in the present invention is from about 1.5% to about 7% w/v. The selection of nonionic, cationic, or anionic surfactants is based largely on I) drug interaction; and 2) ability to permeate the cornea; where the surfactant quality combined with a viscosity agent is key to the nonlinear (non-newtonian) viscosity created.
[091] Ophthalmological in situ gels which may be substituted for or added in addition to one or more surfactants include but are not limited to gelatin, earbomers of various molecular weights including carbomer 934 P and 974 P. xanthan gums, a.lginic acid (alginate), guar gums, locust bean gum, chitosan, pectins and other gelling agents well known to experts in the art.
[092] In other preferred embodiments, the nonionic surfactant is polysorbate 80 at a concentration from about 0.5% to about 10% w/v, more preferably from about 1%
to about 7%
w/v and even more preferably from about 2% to about 5% w/v, yet more preferably from about 2.5% to about 4% w/v and most preferably at about 2.5% or 2,75% or 3% or 4% or 5% w/v.
1093] Viscosity agents suitable for the present invention include, but are not limited to gums such as guar gum, hydroxypropyl-guar ("hp-guar"), and xanthan DIM, alginate, chitosan, gelriteõ
hyauturonic acid, dextran, Carbopol (poiyacrylic acid or carbomer) including Carbopole 900 series including Carbopol 940 (carbomer 940), Carbopol 910 (carbomer 910) and Carbopol 934 (carbomer 934), cellulose derivatives such as carboxymefhyl cellulose ("CMC"), methylcellulose, methyl cellulose 4000, hydroxymethy/ cellulose, hydroxypropyl cellulose, hydroxypropyimethyl cellulose, hydroxyl propyl methyl cellulose 2906, carboxypropylmethyl cellulose, hydroxypropylethyl cellulose, and hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, gellan, carrageenan, aiginic acid, carboxyvinyl polymer or combinations thereof.

10941 Viscosity agents may be used in the present invention at a concentration necessaiy to achieve a viscosity of about 0.5 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 150 centipoise or more, preferably 300 centipoise or more at at shear rate of 1 per second at 25 degrees Celsius when combined with a surfactant above its critical micellar concentration.
[095] In certain other embodiments, the compositions of the present invention has a viscosity from about 75 to about 1,000 centipoise at a shear rate of 0.
1096/ in another embodiment the viscosity agent will have an equilibration viscosity less than 100 cps, preferably from about 15 to about 35 cps, and most preferably at about 30 cps. In a preferred embodiment the viscosity agent is Carbopol. 940 (carbomer 940) at a concentration from about 0.05% to about 1.5% w/v, preferably from about 0,09% to about 1.0%
w/v, more preferably at 0.09%, 0.25%, 0.5%, 0.75%, 0.9% or 1.0% w/v. In certain combinations it has been surprisingly discovered nonionic surfactant ./ viscosity combinations may result in phase separation over time with precipitate formation. in such situations, particularly for polyoxyis, in a preferred embodiment polyoxyl 40 stearate, and cellulose derivatives, particularly hydroxypropylmethyl cellulose, use of a nonpolysaccharide derivative for viscosity enhancement, such as polyacrylic acid derivatives (carbomers, carbomer 934 or 940 in preferred embodiments) may prevent such separation; or alternatively use of a non polyoxyl nonionic surfactant, such as polysorbate 80 with either a cellulose derivative or noncellulose derivative viscosity agent may be substituted, 1097/ In another preferred embodiment, the viscosity agent is carboxymethy I
cellulose at a concentration from about 1% to about 2% w/v, more preferably from 1.35% to about 1.45% w/v and most preferably 1.42% w/v or 1.40% w/v.
1098) in another preferred embodiment, the viscosity agent is hydroxypropylmethyl cellulose at a concentration from about 0.5% to about 1.75%, and more preferably about 0.75% or 1.5%, still more preferably from about 1.0% to about 1.5%, and most preferably at about 1.25%.
10991 Compositions of the present invention may further comprise cryoproteetants, polyols, bulking agents, solubilizers, antioxidants, tonicity adjustors, preservatives, Cryoprotectants are compounds that either prevent freezing or prevent damage to compounds during freezing. As used herein, the term "cryoprotectant" or "cryoprotectants" include lyoprotectants.
Cryoproteetants suitable for use in the subject invention include, but are not limited to, a polyol, a sugar, an alcohol, a lower alkanol, a lipophilic solvent, a hydrophilic solvent, a bulking agent, a solubilizer, a surfactant, an antioxidant, a cyclodextrin, a maltodextrin, colloidal silicon dioxide, polyvinyl alcohol, glycine, 2-methy1-2,4-pentanediol, cellobiose, gelatin, polyethylene glycol (PEG), dimethyl sulfoxide (DiviS0), form.amide, antifreeze protein 752 or a combination thereof.
[0100] As used herein the term "polyol" refers to compounds with multiple lrydroxyl functional groups available for organic reactions such as monomeric polyols such as glycerin, pentaerythritol, ethylene glycol and sucrose. Further, polyols may refer to polymeric polyols including glycerin, pentaerythritol, ethylene glycol and sucrose reacted with propylene oxide or ethylene oxide. In a preferred embodiment, polyols are selected from the group consisting of mannitol, glycerol, erythritol, lactitol, xylitol, sorbitol, isosorbide, ethylene glycol, propylene maltitol, threitol, arabitol and ribitol. In a more preferred embodiment, the polyol is mannitol.
[01011 Sugars suitable for use in the present invention as cryoprotectams include, but are not limited to, glucose, sucrose, trehalose, lactose, maltose, fructose and dextran, [01021 in another preferred embodiment, alcohols include, but are not limited to, methanol.
101031 In one embodiment, the present invention individually excludes each cryoprotectant from the definition of cry oprotectant.
[01041 Cryoprotectants may be at present in compositions of the present invention at a concentration from about 0.1% to about 99% w/v, preferably from about 1% to about 50% w/v, more preferably from about 1% to about 10% w/v.
[0105] As used herein "lower alkanols" include Cl-C6 alkanols. Lower alkanols, suitable for use in the present invention include, but are not limited to, amyl alcohol, butanol, sec-butanol, t-butyl alcohol, n-butyl alcohol, ethanol, isobutanol, methanol, isopropanol and propanol.
[0106] Bulking agents suitable for use in the present invention include, but are not limited to, saccharide, polyvinylpyrrolidone, cyclodextrin and trehalose.
[0107] Solubilizers suitable for use in the present invention include, but are not limited to, cyclic amide, gentisic acid and cyclodextrins.
[0108] In a preferred embodiment, antioxidants suitable for use in the present invention include, but are not limited to, bisulfite, ascorbic acid, disodium- or tetrasodium ethylenediaminetetraacetic acid, citrate, butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), a sulfoxy-late, propyl galiate, an amino acid containing a thio group, and a thiol. In a preferred embodiment the antioxidant is disodium ethylenediaminetetraacetic acid at a concentration from about 0.005% to about 0.50% w/v, citrate at a concentration from about 0.01% to about 0.3% w/w, dicalcium diethylenetriamine pentaacetic acid ("Ca2DTPA") at a concentration from about 0,001% to about 0.2% wlv, preferably about 0,01%
w/v Ca2DTPA
which can be formulated by adding 0.0084% w/v Ca(OH)2 and 0,0032% w/v pentetic acid to the formulation and mixing slowly. Further combinations of antioxidants can be used. Other antioxidants that can be used with the present invention include those well known to experts in the art such as ethylenedianiinetetraacctic acid at a concentration from about 0.0001% to about 0.01. 5% w/v.
[0109] A tonicity adjustor can be, without limitation, a salt such as sodium chloride ("Na0"), potassium chloride, mannitol or glycerin, or another pharmaceutically or ophthalmoiogically acceptable tonicity adjustor. In certain embodiments the tonicity adjustor is 0.037% vviv NaCI, [0110] Preservatives that can be used with the present invention include, but are not limited to, benzalkonium chloride ("BAK"), sorbic acid, oxychloro complex, citric acid, ehlorobutanol, thimerosal, phenylmercurie acetate, disodium ethylenediaminetetraacetic acid, phenylmercuric nitrate, perborate or benzyl alcohol. In a preferred embodiment the preservative is BAK, sorbic acid, oxychloro complex or a combination thereof. In a yet more preferred embodiment BAK is at a concentration of about 0.001% to about 1.0% w/v, more preferably at a concentration of about 0.007%, 0.01% or 0.02% w/v. In another preferred embodiment the preservative is perborate at a concentration of 0.01% to about 1.0% w/v, more preferably at a concentration of about 0.02% W/V.
in I Various buffers and means for adjusting pH can be used to prepare ophthalmological compositions of the invention. Such buffers include, but are not limited to, acetate buffers, citrate 'buffers, phosphate buffers and borate buffers. It is understood that acids or bases can be used to adjust the pH of the composition as needed, preferably of 1 to '10 niM
concentration, and more preferably about 3 mi'vl or 5 mrsel, In a preferred embodiment the pH is from about 4.0 to about 8.0, in a more preferred embodiment the pH is from about 5.0 to about 7Ø
[01121 [0113]
Acedidine 101141 One ophthalmic drug that may be stabilized by the methods of the present invention is aceelidine. Aceelidine is traditionally used as a treatment for glaucoma. When aceclidine is used to treat glaucoma it is normally stored in a two-bottle system; one bottle containing the lyophilized aceclidine and the second bottle containing the diluent necessary to reconstitute the lyophilized aceclidine before topical instillation, Romano J.H., Double-blind cross-over comparison of aceclidine and pilocatpine in open-angle glaucoma, Brit J
OphthalõAlig 1970, 54(8), 510-521. It is a further aspect of the present invention to provide an aqueous aceclidine composition that is stable in combination with cold chain storage. It is yet a further aspect of the present invention to provide a method of stabilizing aqueous aceclidine by combining effective excipients, pH ranges and temperature ranges.
[0115] The compositions and methods of the present invention treat presbyopia by improving depth of focus in patients with presbyopia by administering an ophthalmological composition to the eye that reduces pupil dilation in the dark or in dim light, produces a particular degree and duration ofiniosis without accommodation., provides cosmetic whitening and/or induce redness prophylaxis. The compositions and methods of the present invention also do not cause significant pupil rebound., tachyphylaxis, ciliary spasms, induction of myopia or reduction in distance vision. Additionally, the compositions and methods of the present invention allow fOr the further improvement in visual acuity and depth perception of binocular (both eyes) treatment.
The ophthalmological composition of the present invention surprisingly creates a pupil of from about 1.5 to about 2,4 MITI at the anterior iris plane and about 2.0 mm at the corneal surface. Not wishing to be held to particular -theory the clinical effect appears to involve both with modulated increase in accommodative tone and enhanced pinhole near depth of focus for improved near vision, estimated to be about -1.25 D or less, but restricted in power to remain wihin the range of pinhole correction for distance, found to be about -1.00 I) or less creating a sum increase that may in some eases create a near vision add of +2,00 D or more without distance blur; and with a reduction or ablation of the redness that is otherwise a hallmark of the use of miotic agents. The pupil iniosis of the present invention with such modulation and restriction of peak accommodative tone is superior to the pinhole effect of the Kamra and Flexivue Microlens cortical inlays, allowing binocular treatment without peak din-lining. Pupil miosis of the present invention with modulated accommodation is also superior to inlays because the constriction of the actual pupil does not result in the attendant severe night vision disturbance caused by the light scattering borders of the pre-corneal pinholes created by the inlays.
Further pupil miosis provides a greater field of vision and transmission of more tbcused light, and in a discovered optimal pupil range of about 1.5 mm to 2.1 mm using fbrmulation discoveries of the present invention does so with negligible to mild and very tolerable dimming and enhanced contrast, distance vision, reduced glare at night, and improved near vision.
[0116] The use of aceclidine has a minimal effect on the longitudinal ciliary muscle, thus reducing risk of retinal detachment when compared to the use of general muscarinic agonists such as pi loctupine and carbachol. The further inclusion of a cycloplegic agent resulted in only 0.04 mm of anterior chamber shallowing. Aceclidine, particularly as enhanced for the present invention, also has greater magnitude, duration, and control of minimum pupil diameter than conventional pilocarpine with or without alpha agonists, and less anterior chamber inflammation with chronic use. Compositions of the present invention achieve these advantages by allowing both pinhole near vision depth perception benefit and modest accommodative increase below the.
threshold of induced myopic distance blur through the miotic pupil, whereby, not wishing to be held to particular theory, it is believed the rate of miosis and the rate of accommodative increase maintain a synchronous balance in preferred embodiments allowing pinhole correction of otherwise induced accommodative blur in prior art applications of miotics for presbyopic correction. This combination thus is found to avoid the distance blur typically seen in patients as a response to pilocarpine and/or carbachoi induced miosis without the formulation discoveries of the present invention, as well as the excessive accommodative myopia and ciliary spasm manifested as brow ache or generalized migraine-like headache.
[01171 Such conventional formulations of pilocarpine, in order to effect any reasonable duration of effect, are still restricted to less than or equal to about 4 flours in most cases, as the high ratio of accommodation to pupillaiy miosis requires minimal concentrations of pilocarpine of about 1.0% to minimize but not eliminate distance induced myopic blur and ciliary spasm. Further pilocarpine must be instilled monocularly to minimize intolerable distance blur to a still bothersome 2-3 lines of distance blur. Even instilled monocularly, pilocarpine still may create bothersome attendant distance blur and must be restricted to about 1.0%. Upon instillation of 1.0% pilocarpine pupil size is about 2.3 mm or larger in most subjects and thereby restricts any significant pinhole depth perception benefit as well as any pinhole filtering of induced myopic rays. The restriction to about 1.0% for these conventional formulations of pilocarpine with the attendant short duration and still bothersome but reduced distance blur in eminetropes or myopes (somewhat neutralized in low hyperopes) are attempts to prevent extremely strong accommodation of 5D to 11 D well known to occur at higher concentrations of pilocarpine.
101181 Any effects on accommodation may be further reduced or totally eliminated in preferred embodiments by combining a miotic with a cycloplegic agent in a narrow and particular ratio of miotic to cycloplegic, where such ratios as discovered for US 9, 089,562, such as about 35:1 for a preferred embodiment, become greatly increased for the present invention in the presence of cryoprotectant as to a factor of about 300% - 700%. Aceclidine is capable of producing the increased depth of focus by both pupil miosis below 2.3 mm and modest accommodation described in the present invention. Particularly enhanced miosis occurs with use of compositions of the present invention. This enhanced miosis makes it possible to use an a-2 agonist at very low concentrations if desired to reduce mild eye redness. Other combinations of inactive ingredients reduce or effectively eliminate induced redness without such agonists. Further, due to the apparent and surprisingly selective nature of aceclidine, and the commercially stable aceclidine formulation discoveries of the present invention, administration to the eye of compositions of the present invention result in a net strongly enhanced near vision acuity from both pupil miotic, pinhole effect and moderate modulated ciliary accommodation. These beneficial effects are accompanied by a filtering pupil effect, which eliminates any distance blur from the accommodation, correcting residual refractive error and optical aberrations as may exist to in ninny cases improve distance vision as well. Thus, the administration of aceclidine results in pupil miosis without excessive accommodation and attendant distance blur.
However, aceclidine alone may cause substantial redness and brow ache. Without formulation enhancement of the present invention such as requiring cycloplegic agent, cryoprotectant or both, aceclidine may produce either less than optimal pupil miosis at low concentrations or at higher concentrations require more than desired peak miosis to attain satisfactory duration of greater than 3-4 hours. However the use of a cycloplegic agent has been found to be highly sensitive to other inactive ingredients in the formulation not usually associated with effects on active agents, and particularly for cryoprotectants as found to be preferred commercially for aceclidine reduce or eliminate the need for this cycloplegic requirement to extremely low concentrations in a preferred embodiment, rendering 0.042% sufficiently high when a cryoprotectant is present (e.g.
a polyol such as mannitol) to cause substantial loss of efficacy. Further, aceclidine without formulation enhancements of the present invention causes dimming of vision in dim or absent lighting as well as ciliary pain above a reasonably tolerable threshold that may last for an hour or more and be similar to a severe migraine headache.
[01191 Certain embodiments of the present invention enhance the discovered preferred degree of pupillary miosis by providing a consistent range of effect of about 1.50 ¨
2.20 mm for most patients using a preferred embodiment of a nonionic surfactant and viscosity agent. Similar benefit may be achieved using other permeation enhancers, particularly :hydroxypropylmethyl cellulose, high viscosity carboxymethyl cellulose, Carbopol (polyacrylic acid or carbomer), and various viscosity additives that increase drug residence time, such as xanthan gums, guar gum, alginate, and other in situ gels well known to experts in the art. It is well known to experts in the art that the exact concentration of a specific viscosity agent. will depend on both the molecular weight for that agent selected and the concentration, such that for increased molecular weight a reduced concentration can have the same viscosity. The present invention further prevents nasal congestion otherwise occurring when substantial aceclidine levels reach the nasal mucosa, due to the rheologic properties of the preferred embodiment.
[0120] The combination of aceclidine and a low concentration of a selective a-2 adrenergic receptor agonist (a-2 agonist or a-2 adrenergic agonist), such as fadolmidine, brimonidine or guanfacine, allows for the desired miotic effect with diminished or no redness. The use of low concentrations of a selective a-2 agonist results in substantial reduction of hyperemia with greatly reduced risk of rebound hyperemia that is found in concentrations of about 0.06% w/v or more. Furthermore, the. use of low concentrations of selective a-2 agonist does not adversely modify the pupil constriction caused by aceclidine. In contrast, the use of brimonidine 0.20%
w/v, when topically applied for pupil modulation for night vision, result in =tachyphylaxis of pupil modulation due to a-2 receptor upregulation in almost 1.00% of treated subjects within four weeks of use.
101211 Unexpectedly, the addition of a cycloplegic agent results in reduction of any brow ache or associated discomfort by further reducing the degree of ciliary spasms on topical instillation without impairing the miotie response. More unexpectedly and surprisingly, the ratio of 1.40%
aceclidine to about 0.040% tropicarraide in a preferred embodiment of U.S.
Patent No. 9,089,562 (35:1) becomes about 1.75% aceclidine to about 0.004% to 0.010% tropicamide (350:1, 175:1 respectively) in the presence of marmitol, where 2.5% provides better effect than 4.0%.

[0122] The lack of impairment of the miotic response is an unexpected surprising discovery, as particular cycloplegic agents, such as tropicamide, have known pupil dilating effects at concentrations as low as 0.01% w/v (Granberger J. et al.. The pupillary response test as a method to differentiate various types of dementia, Neuropsychiatr, 2009, 23(1), pg 57). More specifically cycloplegic agents cause pupil mydriasis (i.e. dilation of the radial muscle. of the iris). Further, the addition of a cycloplegic agent to the miotic agent unexpectedly increases the time at which the pupil maintains the desired size range Without becoming too restricted. Peak miotic effect at 30 ¨ 60 minutes can be titrated in inverse relation to the cycloplegic concentration. The concentrations of tropicamide discovered in the present invention apparently cause more relaxation of the ciliary muscle than the iris radial musculature.
In fact, iris mydriasis is discovered to be suppressed by the addition of tropicamide to compositions containing concentrations of aceclidine used in the present invention, with instead a more consistent level of miosis for the duration of the miotic effect. Additionally and quite surprisingly, unexpectedly, and beneficially the addition of tropicamide can reduce the degree of peak pupil miosis without inducing mydriasis thereby creating a more constant and ideal pupil size throughout the drug induced miosis. This more consistent pupil size allows for beneficial near and distance vision without the adverse dimming or loss of resolution due to diffraction limits at the very reduced pupil sizes seen at peak pupil miosis (e.g. 1.25 mm).
101131 Previously, in US 9,089,562, it was staprisingly found that the addition of at least 0.04%
w/v cycloplegic agent resulted in an abatement of ciliary side effects caused by the administration of aceclidine (1.40%) to the eye, in a preferred embodiment, but such formulations are not as constituted sufficiently stable for commercial use, and typically have a duration of about five to six hours maximum.
[0124] Several additional discoveries of the present invention allow for commercially stable aceclidine formulations with enhanced efficacy and duration.:
[0125] Equally or more surprising than the synergistic effects of cyloplegies of 0.040% added to aceclidine 1.40%, is the discovery of the present invention that combination of aceclidine 1.50%
-2.0%, and preferably about 1.75% and a cryoprotectant, preferably a polyol, in a preferred embodiment mannitol, particularly at 0.5% to 4.0% and most preferably about 2.5%, can achieve a similar pupil range with reduced or absent ciliary side effects. The cryoprotectarn when combined with aceclidine can then be combined to allow lyophilization without degradation of aceclidine and simultaneously further reduce or eliminate the need for a cycloplegic agent for the present invention vs. the teachings of cycloplegic concentration ranges required in US 9,089,562.
Optionally, the addition of a cryoprotectant can therefore also be used to greatly reduce (i.e. no more than 0.025% w/v cycloplegic agent, preferably 0.004% to 0.015% and most preferably 0.005% to 0.010%) the concentration of cycloplegie required to further eliminate mild, but potentially bothersome, ciliary side elects particularly in younger presbyopes and further modulate pupil rniosis over aceclidine and a eryoproteetant combinations alone, reducing and in most cases eliminating any bothersome peak concentration dimming, as found in preferred embodiments of the present invention. In preferred embodiments it is discovered that aceclidine about 1.50% - 2.0% and more preferably 1,75% and mannitol about 0,5% - 4.0%
and more preferably 2.5% provide optimal concentration combinations for the present invention, that are necessary but not sufficient for about 3 lines of near improvement and 5 or more hours duration desired for an effective topical presbyopic composition, where additional formulation discoveries can further enhance the desired clinical near improvement magnitude and duration;
[01.26] It is surprisingly discovered that adding a viscosity agent to compositions described in a.
above only modestly improves magnitude and duration, however when first adding a nonionic surfactant, such as polyoxyl stearate or polysorbate 80, optimal concentrations are discovered that provide greatly improved magnitude and duration for the present invention, to which viscosity may then provide added duration much more substantially than when added alone. For polysorbate 80 or polyoxyl 40 stearate concentrations of 1.0% to 10.0%, and more preferably about 2.5% to 5.0% w/v have been found to be beneficial;
[01271 When formulation improvements of a. and b, above are combined, preferred embodiments such as aceclidine 1.75%, marmitol 2.5%, and polysorbate 80 2.75%
result.
Viscosity agents such as high viscosity carboxymethyl cellulose ("CMC") are surprisingly discovered to moderately enhance magnitude and greatly enhance duration, unlike with formulations in a. above alone. High molecular weight (MC concentrations of 0.75% to 1,75%, and most preferably about 1.40%, or hydroxypropylmethyl cellulose ("FIPMC") at about 0.25%
to 2.0%, more preferably about 0.50% or 1.50%, and most preferably about 1 INJ
to 1.23%, when combined result now in about -4-3 lines of near vision improvement or greater, at a duration of 5 ¨ 1.0 hours, at a mean of about 7 hours or greater vs. pilocarpine 1..0%
of about less than 4 hours;

[01281 Not wishing to be held to particular theory citrate in combination with EDTA as a preferred embodiment buffer appears to 1) reduce redness; 2) enhance sorbate preservative shelf life, and in combination of the above with BAK 0.005% to 0.02% (0.02%
preferred) further enhances near vision lines to about 4 lines and duration to about 8 to 12 hours.
[0129] Additionally 0.5% or 1.5% sodium chloride is added in a preferred embodiment.
Optionally, sodium chloride may be substituted with boric acid, preferably at 035% or potassium borate, preferably at 0.47%;
[01301 Not wishing to be held to particular theory, it appears the addition of nonionic surfactant at optimized concentration of about 2.5% to 5.0% enhances permeation of aceclidine into the eye, Which may relate to optimal micellar size particularly once of micromieallar or nanomicellar ranee. This increased permeation coincides with the desirable increase in magnitude and.
duration and absent tropicamide but in the presence of mannitol with slight increases in ciliary sensation and dimming. Therefore in the presence of the combined formulation enhancements of a-d, above, where a cycloplegic agent is no longer required for a-d, above, addition of a nonionic surfactant at concentrations found to be preferred may be further improved with much lower concentrations of a cycloplegic agent than those found in US 9.089,562, such as the use of about 0.042% tropicamide with aceclidine 1.40%. For the present invention then preferred embodiments include aceclidine of about 1,75%, mannitol 2.5%, polysorbate 80 of about 2.5% to 5.0%, CMC of about 1.42%, or HPMC of about 1.8% and tropicamide of about 0.004% -0.010%, more preferably about 0.005% to 0.007%, and most preferably about 0.005% - 0.006%.
Micelle formation above the critical micellar concentration may allow for micelles to spread across the tear film surface and spread at low concentrations to cover this surface, While at higher concentrations these micelles becoming increasingly contracted and "squeezed"
along the surface. Not wishing to be held to particular theory, it is believed at an optimal concentration a minimal micelle diameter is achieved before significant multiple lamellae (layering) occurs. It is believed that at the optimal concentration nanomicelles of about 100 to 250 nm along, the surface are achieved surrounding the highly charged and hydrophilic aceclidine, facilitating its penetration through the very lipophilic epithelium;
[01311 Not wishing to be held to particular theory the addition of BAK 0.02%
to sorbate about 0.10%, EDTA about 0.10%, in a preferred composition of aceclidine 1.75%, mannitol 2.5%, tropieamide 0.01%, and citrate buffer (1 to 100 mIVI 3-5 raM preferred) is above the BAK. critical micellar concentration. BAK, being a cationic surfactant, and BAK micelles, creating an ionic micellar gradient with + charge N1-14+ quaternary nitrogen bring on the polar heads aggregating outside and lipophilic alkyl chain on the hydrophobic tails aggregating on the inside may cause significant similar aceclidine alignment due to its dipole with quaternary NT-Li nueleophilic or NI-14 protonated nitrogens oriented along the outside polar heads and more hydrophobic carbonyls Car,0 along hydrophobic BAK micellar tails these preventing, greatly reducing, or moderately reducing collisions of any nonionic aceclidine molecules - the nucleophiles which if oriented in solution such that randomly they collide with another aceclidine carbonyl will result in chemical conversion of that aceclidine via nucleophilic attack at its targeted carbonyl, which can recur from such nucleophiles to other aceciidines so oriented repeatedly and cause loss of stability without such BAK orientation via 0.005% and preferably 0.01% to 0.02% most preferred micelles. The concentration of such nonionic nucleophiles at a preferred pH in the preferred embodiment is relatively low, but the ability of these nonionic nucleophiles to destabilize adjacent aceclidines repeatedly without themselves degrading is otherwise high. The result may be improved potency for 1 month plus of a mixed solution once opened in a dual chamber bottle and mixing occurs of lyophilized aceclidine/ma.nnitol with the remainder of the formulation in the diluent and or improved stability sufficient for commercialization in solution, either at room temperature or via cold chain;
[01321 it is discovered that BAK alone does not provide sufficient bacterial and fungal.
preservative efficacy but that BAK and sorbate, or sorbate alone satisfactorily preserve diluent and or mixed solutions of the invention;
[0133] Not to be wishing to be held to particular theory preferred embodiments of the present invention such as containing 1.25% h.ydroxypropyl methyl cellulose may have a viscosity of about 400 cps prior to instillation, yet unlike conventional high viscosity artificial tear formulations such as Celluvisc at about 400 cps, which may blur vision for 10-
20 minutes or Liquiger at about 100 cps, which causes similar but slightly reduced blurring causes only about 60 seconds of blur dissipating rapidly with an influx of tear secretion; where both a nonnewtonian reduction in viscosity at high shear (such as about 1/1000 sec during a blink, and.
aceclidine parasympathetic trigger of tear secretion as a. sialogen may contribute, [0134] General miotic agents, such as pilocarpine, carbachol and phospholinc diesterasc, are capable of causing pupil miosis resulting in improved near vision of presb-yopic patients.

However, there is an inverse reduction in distance vision associated with these general miotic agents from miosis at peak effect and accommodation that is not seen with aceclidine. The co-administration of a cycloplegic agent with aceclidine surprisingly results in an attenuation of this reduction in distance vision.
[0135] Comfort, safety, and efficacy of a preferred embodiment of an ophthalmological composition of the present invention results from the presence of a nonionic surfactant, such as cyclodextrin alpha, beta, or gamma chains, preferably 2-hydrox.ypropyl beta-cyclodextrin ("HPPCD"), and, sulfobutyl ether derivative of P-cyclodextrin (Captisole), a polyoxyl alkyl such as polyoxyl 40 stearate and polyoxyl 35 castor oil, or a poloxamer such as poloxamer 108 and poloxamer 407, a polysorbate such as polysorbate 80 or Brij 3.5(3rij is a registered trademark of liniqema Americas LLC); a .viscosity enhancing agent, such as carboxymethyl cellulose ("C.MC"); a tonicity adjustor, such as sodium chloride; a preservative, such as benzalkonium chloride and a pH from about 5.0 to about 8Ø Further, an increase in the concentration of the nonionic surfactant may result in reduced redness. Specifically, increasing polysorbate from 0.10% to 0.50 - 1.0% results in reduced redness. Further, increasing CMG or Carhopol 940 from 0.50% to 1.5% w/v (preferably 1.40 --- 1.43% w/v) results in enhanced near vision, both quantitative improvement and duration improvement.
[01361 The viscosity of compositions of the present invention comprising a viscosity agent may be from about I to about 10,000 cps prior to topical instillation in the eye.
As a result of the shear force applied to the composition as it exits the device used for administration the viscosity is lowered to a range from about 1 to about 25 cps at the high shear of blinking, and 50 (.7ps to 200 cps at the low shear between blinks, allowing greater drop retention with less spillage and less nasolaerimal drainage and systemic absorption upon topical instillation.
[0137] In one embodiment, the present invention is directed to an ophthalmological composition comprising aceclidine. In a preferred embodiment, aceclidine is at a concentration from about 0.25% to about 2.0% w/v, more preferably from about 0.50% to about 1,90% w/v, still more preferably from about 1.65% to about 1.85% w/v, and most preferably about 1.75% w/v. As aceclidine is a tertiary amine with asymmetry, both a + and --- optical isomer exist (where in some studies ( ) is more potent and in others it is felt (-) may be more potent).
For the above concentrations polarimetry demonstrated an exactly equal ratio of (-1-) and (.--) isomer for these concentrations. Altering this ratio could therefore alter this concentration range proportional to a change in ratio.
[0138] It is a discovery of the present invention that several modifications may singly or in combination be used to enhance cold chain stability storage, including in addition to in a preferred embodiment aceclidine L40% - 1.75%, tropicamide 0.025% - 0.10% and optionally a nonioinic surfactant such as polyoxyl 40 stearate 0.5%-10%, preferably 5.5%
one or more of (See Table 1):
101391 Acidic pH, preferably less than 5,5, preferably less than 5.0 and most preferably at a pH
of about 4.75;
[0140j Viscosity agent, preferably at 25C viscosity of about 15-50 cps, and more preferably 20-45 cps, where a preferred embodiment is carbomer 940 0,09% - 1.5%;
10141] Addition of a cryoprotectant, in a preferred embodiment a polyolõ
preferably Mannitol 2,5% - 4.0%;
[0142] Addition of a buffer, where acetate or phosphate buffers are preferred, 2-100 nirnole range with 3-5 mmole is preferred; and [0143] Addition of a preservative, where BAK 0.015% is preferred.
Muscarinic Agonists 101441 The present invention is further directed to an ophthalmological composition comprising a muscariuic agonist, preferably a nonionic surfactant above its critical micellar concentration for the composition, and a viscosity enhancing agent; or alternatively an in situ gelling agent. In preferred embodiments the initial viscosity of the composition on topical application is above 20 cps, preferably 50 cps, and more preferably above 70 cps at low shear (1/s).
101451 Muscarinie agonists include selective a-2 agonists, which may be included within the composition of the present invention or applied topically preferably just minutes before or less preferably just minutes afterward if additional means to reduce nasal congestion or redness is desired for sensitive subjects. Selective a-2 agonists suitable for the present invention have minimal a-1 agonist activity at low concentrations. For example, for brimonidine or fadolmidine, 1% to 2% w/v is considered extremely high, 0.5% to 1.0% wlv still highly inductive of a-1 receptors and toxic for purposes of the present invention.
Further, 0.10% to 0.5% w/v is still too high and even 0.070% to 0.10% w/v is associated with a higher than preferred incidence of rebound hyperemia (however, for dexmedetomi dine, its greater lipophilicity and intraocular penetration reduces rebound risk in this range).
Only 0.065% w/v or below is potentially acceptable, where for most a-2 agonists, depending on degree of selectivity 0.050% w/v or even more preferably 0.035% w/v or less is desired. On the other hand some degree of useful activity may occur at one or more orders of magnitude further reduction of concentration. The preferred embodiments, brimonidine, fadohnidine and guanfacine, of the present invention preferentially stimulate a-2 adrenergic receptors, and even more preferably a-2b adrenergic receptors so that a-1 adrenergic receptors are not stimulated sufficiently enough to cause excessive large vessel arteriolar constriction and vasoconstrictive ischemia. in addition, it has been discovered that preventing or reducing redness for drugs that otherwise. directly induce redness, such as the acetylcholine agonist, aceelidine, enhances compliance for sensitive subjects that. may have induced redness or nasal congestion even with formulations of the present invention that do not include an a-2 agonist. However, because a-2 agonists are shifted to their ionized equilibrium an acidic pH is somewhat offset by the fact such agonists exert greater affect at neutral or alkaline pH. Therefore each a-2 agonist has a preferred pH range depending on its lipophilicity and pKa value when added to the inventive compositions with aceclidine. For the present invention while pH range of 5.0 to 8.0 is tolerated, preferred embodiments are at pH 5.5 to 7.5 and more preferably 6.5 to 7Ø Further, it has been discovered that cyclodextrins and/or polyoxyl 40 stearate as a nonionic surfactant component or as the sole nonionic surfactant, result in a greater whitening effect when the a-2 agonist is included in the composition rather than poloxamer 407. The a-2 agonist may optionally be applied separately or in certain preferred embodiments with formulations of the present invention that do not include an a-2 agonist, such as those formulas with polyoxyl 40 stearate 5.5% w/v as the non-ionic surfactant, although the a-2 agonist is not required except for occasional sensitive subjects.
Fadolmidine represents the a-2 agonist with highest hydrophilicity and therefore high surface retention for the present invention.
Guanfacine is also highly selective and hydrophilic. Brimonicline is highly selective with moderate lipophilicity. Finally, dexmedetomidine has high selectivity with high lipophilicity that may be used with less efficacy for reducing redness for the purposes of the present invention (although possibly inducing fatigue as a side effect in some patients). in a preferred embodiment using polyoxyl 40 stearate 5.5% wlv; CivIC 0.80% w/v; Na.C.l 0,037% w/v;
ethylenediaminetetraacetie acid ("EDTA") 0.015% w/v, borate buffer 5 rn.M and BAK 0j)07%

w/v results in redness of about 1.0 to 1.5 out of 4 which is transient lasting about ten minutes, and by 30 minutes returns to about baseline.
[01461 In one embodiment, the selective a-2 adrenergic receptor agonist is a compound .which has binding affinity of about 900 fold or greater, even more preferably about 1000 fold or greater, and most preferably, about 1500 fold or greater.
[01471 The selective a-2 adrenergic receptor agonist may be present at a concentration from between about 0.0001% to about 0.065% w/v; more preferably, from about 0.001%
to about 0.035% w/v; even more preferably, from about 0.01% to about 0,035% w/v; and even more preferably, from about 0.020% to about 0.035% w/v.
[0148] in one embodiment, the selective a-2 adrenergie receptor is selected from the group consisting of brimonidine, guanfacin.e, fadolmidine, dexmedetomidine, (+)-(S)-4-[1-(2,3-dimethyl-pheny1)-ethy -1,3-dihydro-imidarole-2-thione, 1-1(imidazolidin-2-ypiminolindazole, and mixtures of these compounds. Analogues of these compounds that function as highly selective u-2 agonists may also be used in compositions and methods of the present invention.
101491 In a more preferred embodiment, the selective a-2 agonist is selected from the group consisting of fadolmidine, guanfaeine and brimonidine. In a yet more preferred embodiment the selective a-2 agonist is brimonidine in the form of a salt at a concentration of 0.025% to 0.065%
w/v, more preferably from 0.03% to 0.035% w/v. In a preferred embodiment, the salt is a tartrate salt.
[0150] In another yet more preferred embodiment, the selective a-2 agonist is fadolmidine at a concentration from about 0.005% to about 0.05% w/v, more preferably from 0.02%
to about 0.035% w/v in the form of a hydrochloride ("1-IC1") salt.
101511 In another yet more preferred embodiment, the selective a-2 agonist is guanfacine at a concentration from about 0.005% to about 0.05% w/v, more preferably from 0.02%
to about 0,035% w/v in the form of an HCI salt.
[0152] In another yet more preferred embodiment, the selective a-2 agonist is dexmedetomidine at a concentration from about 0.005% to about 0.05% w/v, more preferably from 0.04% to about 0.05% w/v in the form of an FICA salt.
[0153] In another preferred embodiment a pH less than physiologic pH. is found to enhance the whitening effect for brimonidine, preferably pH 4.5 to 6.5, and more preferably pH 5,5 to 6Ø
However, redness reduction is achieved at all pHs, and enhancement of aceelidine absorption occurs at alkaline pH, such that more effect occurs from a given concentration, and therefore while effective at pH ranges from 4.5 to 8.0, pH range of 6.5 to 7.5 is preferred for the present invention, and 7.0 to 7,5 most preferred.
[0.154] The present invention is further directed to an ophthalmological composition comprising a muscarinic agonist and further comprising a cycloplegic agent. It is a surprising and totally unexpected discovery of the present invention that certain cycloplegic agents can be combined with miotic agents, particularly for the present invention, accelidinc, without reducing miotic onset, magnitude, or duration; and further blunt the normally attendant spike in miotic effect coinciding with time of peak absorption in aqueous formulations to provide a constant miosis versus time after onset from 15 to 30 minutes to 6 to 10 hours depending on the desired formulation. The addition of the cycloplegic agent also reduces any residual associated discomfort that may otherwise occur soon after topical instillation, which presumably is a result of ciliary spasms or excessive pupillary miosis.
101551 Cycloplegic agents suitable for the present invention include, but are not limited to, atropine, Cyclogy(cyclopentolate hydrochloride), hyoscine, pirenzepine, tropical-nide, atropine, 4-diphenylacetoxy-N--methylpiperidine methobromide (4-DAMP), AF-DX 384, methoetramine, tripitramine, darifenacin, solifenacin (Vesicare), tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium (Spriva), and otenzepad (a.k.a. AF-DX 116 or II-- [2-(diethylamino)methy i]-1--piperi dinyi) acety1]-5,11-dihydro-61-1--pyrido [2,3b] [I ,4]henzodiazepin e-6-one). In a preferred embodiment the cycloplegic agent is tropicamide at a concentration from about 0.004% to about 0. 025% w/v, more preferably from about 0.005% to about 0.015% w/v and still more preferably from about 0.005% to about 0.011% w/v, from about 0.005% to about 0.007% w/v and from about 0.005% to about 0.006% w/v. In another preferred embodiment the cycloplegic agent is a mixture of tropicamide at a concentration from about 0.04% to about 0.07% w/v or pirenzepine or otenzepad at a concentration from about 0.002% to about 0.05%
w/v.
[01561 In a preferred embodiment, tropicamide 0.01% w/v was found to slightly reduce brow ache, 0,030% w/v to further reduce brow ache and from 0.04% to about 0.07% w/v to completely eliminate brow ache without reduction of the average pupillary miosis diameter over duration of effect. Tropicamide in preferred embodiments has demonstrated completely unexpected sensitivity of effect, where at about 0.04% wiv unexpectedly and very effectively reduces or eliminates brow ache and ciliary spasm pain, becoming very noticeably further reduced at 0.042% w/v and absent at 0.044% w/v in a preferred embodiment with no cycloplegia (sin-prising due to its common use as a pupil dilating agent). Yet, tropicamide did not reduce the mean degree of pupil miosis, the time of onset of pupil miosis or the subsequent visual benefits. On the contrary, tropicamide blunted the peak iniosis seen in aqueous formulations to create a smooth consistent miotic effect over time. It allowed modulation of peak pupil miosis to achieve a more even effect over time with no dilation as has been thund with its prior use. Specifically, tropicamide is useful to prevent transient constriction below 1.50 mm at 30 to 60 minutes following aceclidine i.n some embodiments and to reduce transient excessive and undesirable dimming of vision that may otherwise occur at peak onset of about 30 minutes.
As an example, an ophthalmological composition comprising 1.53% w/v aceclidine, 5% w/v HPPCD, 0.75% w/v CIVIC, 0.25% w/v NaC1 , 0.01% w/v BAK and a phosphate buffer at pH 7.0; or 1.45% w/v aceclidine; 5.5% w/v poiyoxyl 40 stearate; 0.80% w/v CIVIC; 0.037% w/v NaCI;
0.015% 'Ws, EDTA, 0.007% wtv BAK and 5m1V1 phosphate buffer at a p1-1 7.0; was varied from 0.040% w/v tropicamide, where moderate dimming was noted, to 0.044% w/v tropicamide where dimming became almost undetectable other than in extremely dim light conditions. This additional pupil size modulation with a cycloplegic agent allows aceclidine concentrations sufficient for prolonged effect while blunting the attendant peak excessive constriction that is undesirable as well as any uncomfortable brow ache. Surprisingly and due to its short-acting nature, tropicamide achieves this blunting effect without causing mydriasis. Further, in a preferred embodiment, -tropicamide 0.014% w/v was found to reduce brow ache, 0,021% -w/v to further reduce brow ache and from 0.028% to 0.060% w/v and in some embodiments up to 0.09% w/v to completely eliminate brow ache without cycloplegia (i.e. paralysis of ciliary muscle of the eye).
[011571 It has been found for a racemie 50:50 mixture of (+) and (a) aceclidine optical isomers (where in some studies (-4-) is more potent and in others it is felt (a) may be more potent) tropicamide effects may vary depending on the ratio of aceclidine to tropicamide. For example, in an. ophthalmological composition of the present invention comprising 1.55%
w/v aeeclidine, 5.5% w/v liPPCD or in a preferred embodiment polyoxyl 40 stearate, 0.75% w/v CIVIC (1% ¨
2,500 eentipoise), 0.25% w/v Nan, and 0.01% w/v BAK and at pH 7.5, 0.042% w/v tropicamide can be differentiated from even 0,035% w/v, with the former demonstrating normal indoor night vision and the latter slight dimming that becomes more noticeable at still lower concentrations.

At higher concentrations, such as from about 0.075% to about 0.090% w/v tropicamide, loss of optimal range pupil constriction 1.50 mm to L80 mm. range begins, and frank mydriasis at higher concentrations begins to occur. As isomer ratio may alter the effective concentration, this must be factored into the clinical efficacy anticipated using aceclidine; for preferred embodiments of the present invention a polarimeter was used to determine an exact 50:50 isomer ratio was used (personal communication Toronto Research Chemicals).
[01581 Ha 1 shows the effect of a miotic agent with or without a cycloplegie agent and with or without a carrier. Subject is an emmetrope over the age of 45 with a baseline near vision of 20.100 and baseline distance vision of 20.20. Topical administration to the eye of 1% w/v pilocarpine in saline solution results in an improvement of near vision to 20.40 (8a), however this improvement comes at the expense of a reduction in distance vision to 20.100 (813). The addition of 0.015% w/v tropicainide results in an improvement of near vision to 20.25 (9a) and a lessening of the reduction of distance vision to 20.55 (9b), though in certain instances with some induced irregular astigmatism (mildly blotched areas in reading field of vision). Topical administration of 1.55% w/v aceclidine in saline solution results in an improvement of near vision to 20.40 for an extended time period of 6 hrs (10a) without any effect on the baseline distance vision (lob). 10c and 10d show the effects of administering aceclidine in a carrier composed of 5.5% w/v 2-hydroxypropyl beta cyclodextrin, 0.75% w/v CMC (1% =
2,500 eentipoise), 0.25% w/v NaCI, and 0.01% wily BAK. As seen in 10c the carrier increases the beneficial effect of aceclidine resulting in better than 20.20 near vision. As seen in 10d a similar increase in distance vision occurs. 10e and 10f show the effects of adding 0.042% w/v tropica.mide to the aceclidine in the carrier. As seen in 10e near vision is improved to 20.15 with a quicker onset of maximum visual acuity. As seen in 10f a similar improvement is seen in distance vision. Taken together, FIG. 1 shows that aceclidine is capable of temporarily correcting near vision in a presbyopic subject without affecting the baseline distance vision.
Similar results can be achieved with a different miotic agent, pilocarpine, with the addition of a eyeloplegic agent such as tropicamide. A proper drug carrier can also have a beneficial effect.
101591 It is a surprising and unexpected discovery that topical formulations of the present invention, particularly one of the preferred embodiments comprising aceclidine 1.35% to 1.55%
w/v; 5.5% w/v polyoxyl 40 stearate; 0.80% w/v CMC; 0.037% w/v Mel; 0.015% w/v EDTA;
0.007% w/v BAK; and 5rnIVI phosphate buffer at pH 7.0 result in considerably prolonged contact lens wear and comfort after a single topical instillation daily. The single daily use of the preferred embodiments allowed a subject with dry eye to sleep in his lenses for one week. periods where previously even after a single night vision would be blurred and contact lenses coated with film requiring removal and cleaning or replacement (see Example 7).
L01601 In preferred embodiments, an ophthalmological composition of the present invention comprises aceclidine, a cryoprotectant, optionally a cycloplegic agent, a nonionic surfactant at a concentration from about 1% to about 5% wiv and a viscosity agent at a concentration of about 0.75% to about 1.6% wtv, preferably about 1.25% to about 1.5% w/v.
[0161] The following representative embodiments are provided solely for illustrative purposes and are not meant to limit the invention in any way.
REPRESENTATIVE EMBODIMENTS
[01162] In one embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75%w/v; and mannitol at a concentration of about 2.5% w/v.
101631 in another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75%w/v;
mannitol at a concentration of about 2.5% w/v; and tropicamide at a concentration of about 0.02% w/v.
[0164] In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75%w/v;
mannitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 5.0% w/v;
carboxymethyl cellulose at a concentration of about 1.4% w/v;
BAK at a concentration of about 0.015% w/v; and optionally, phosphate buffer at a concentration of about 3 InNI, wherein the pH is about 5.
[0165] In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about I .75%w/v;
marmitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 0.5% w/v;
NaC.1 at a concentration from about 0.10% to about 0.50% w/v;

Carbopolg 940 at a concentration of about 0.95% w/v;
BAK. at a concentration of about 0.01% w/v; and.
optionally, phosphate buffer at a concentration of about 3 rnM, wherein the pH is about 5.
[01661 in another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about I.75%w/v;
mannitol at a concentration of about 2.5% w/v;
po]ysorbate 80 at a concentration of about 2.0% w/v;
NaC1 at a concentration of about 0.50% w/v Carbopol 940 at a concentration of about 1.5% w/v;
BAK at a concentration of about 0.015% w/v; and.
optionally, phosphate buffer at a concentration of about 3 miVi, wherein the is about 5.25.
101671 In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75%w/v;
mannitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 0.25% w/v;
N aCi at a concentration of about 0.1% w/v;
boric acid at a concentration of about 0.12% w/v;
Carbopol 940 at a concentration of about 0.95% w/v; and.
BAK. at a concentration of about 0.015% w/v;
wherein the pH is about 5.
101681 in another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1,75%w/v;
mannitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 0.50% w/v;
NaC1 at a concentration of about 0.05% wilv;
boric acid at a concentration of about 0.2% w/v;
Carbopol 940 at a concentration of about 0.95% w/v;
BAK at a concentration of about 0.01% w/v; and optionally, phosphate buffer at a concentration of about 3 MM, wherein the pH is about 5.
[01691 In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1 .75%w/v;
mannitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 0.1% w/v;
boric acid at a concentration of about 0.2% w/v;
Carbopol 940 at a concentration of about 0.9% w/v;
B.AK at a concentration of about 0.05% w/v; and optionally, phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.
[0170] in another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1,75%w/v;
mannitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 0.1% w/v;
NaCi at a concentration of about 0.1% w/v;
boric acid at a concentration of about 0.12% w/v;
Carbopol 940 at a concentration of about 0.95% w/v;
BAK at a concentration of about 0.01% w/v; and optionally, phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.
[0171] in another embodiment, the opinhaimologica[ composition comprises:
aceclidine at a concentration of about 1.75% w/v;
tropicamide at a concentration of about 0.01% w/v;
mannitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 5.0% w/v;
CMC at a concentration of about 1.4% w/v;
BAK at a concentration of about 0.015% w/v; and optionally, Phosphate buffer at a concentration of about 3 mM, wherein the pH is about 5.
[0172] In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75%w/v;

tropicamide at a concentration of about 0.02% w/v;
mannitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 0.25% w/v;
NaC1 at a concentration of about 0.1% w/v;
boric acid at a concentration of about 0.12% w/v;
Carhopol 940 at a concentration of about 0.95% w/v; and BAK at a concentration of about 0.01% w/v.
wherein the pH is about 5.
[01731 In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about I .75%w/v;
tropicamide at a concentration of about 0.015% w/v;
marmitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 0.75% w/v;
NaC1 at a concentration of about 0.05% w/v;
boric acid at a concentration of about 0.2% w/v;
Carbopol 940 at a concentration of about 0.95% w/v;
BAK at a concentration of about 0.01% w/v; and optionally, phosphate buffer at a concentration of about 3 mM.
wherein the pH is about 5.
[01741 In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75%w/v;
tropicamide at a concentration of about 0.025% w/v;
mannitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 0.1% vv/v;
boric acid at a concentration of about 0.2% w/v;
Carbopol 940 at a concentration of about 0.9% w/v;
BAK at a concentration of about 0.05% w/v; and optionally, phosphate buffer at a concentration of about 3 inM.
wherein the pH is about 5.
[01751 In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75%w/v;

-tropicamide at a concentration of about 0.02% w/v;
mannitol at a concentration of about 2.5% w/v;
polysorbate 80 at a concentration of about 0.1% w/v;
at a concentration of about 0.1% w/v;
boric acid at a concentration of about 0.12% w/v;
Carbopol 940 at a concentration of about 0.95% w/v;
BALK at a concentration of about 0.01% w/v; and optionally, phosphate buffer at a concentration of about 3 turvi.
wherein the pH is about 5.
191761 in another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v;
.tropicamide at a concentration of about 0.040% w/v;
polyoxyl 40 stearate at a concentration of about 5.0% w/v;
mannitol at a concentration of about 2.5% w/v;
optionally, acetate or phosphate buffer at a concentration of about 3.0 mM.;
and BAK at a concentration of about 0.01% w/v, wherein, said composition has a pH of about 4.75.
101771 In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.55% w/v;
tropicarnide at a concentration of about 0,040% w/v;
polyoxyl 40 stearate at a concentration of about 5.0% w/v;
citric acid moraohydrate at a concentration of about 0.1% w/v;
mannitol at a concentration of about 4.0% w/v;
Carbopoll0 940 at a concentration of 0.09% w/v; and optionally, acetate or phosphate buffer at a concentration of about 3,0 niM;
wherein said composition has a pH of about 5Ø
[0178] In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.50% w/v;
tropica.mide at a concentration of about 0.042% w/v;
polyoxyl 40 stearate at a concentration of about 5.5% w/v;
mannitol at a concentration of about 2.5% w/v;

optionally, phosphate buffer at a concentration of about 3.0 InIVI;
Carbopol 940 at a concentration of about 0.85% wlv; and BAK at a concentration of about 0.01% w/v, wherein said composition has a pH of about 4.75.
10179] In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.45% w/v;
tropicamide at a concentration of about 0.042% w/v;
polyoxyl 40 stearate at a concentration of about 5.5% w/v;
chric acid monohydrate at a concentration of about (11% w/v;
optionally, acetate buffer at a concentration of about 3.0 riti\n; and Carbopola 940 at a concentration of about 0.75% w/v, wherein said composition has a pH of about 4.75.
[0180] In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1..45% w/v;
tropicamide at a concentration of about 0.042% w/v;
polyoxyl 40 stearate at a concentration of about 5.5% w/v;
mannitol at a concentration of about 2.0% w/v;
citric acid monohydrate at a concentration of about 0.1% w/v;
optionally, phosphate buffer at a concentration of about 3.0 mIVI: and.
Carbopol 940 at a concentration of about 1.0% w/v, wherein said composition has a pH of about 4.75.
[0181] In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine;
about 2.5% w/v mannitol;
about 2.75% w/v polvsorbate 80; and about 1.25%; 1.0% - 1.80% w/v hydroxypropylmethyl cellulose (depending on its molecular weight).
101821 In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine;
about 0.005% to about 0.011% tropicamide;
about 2.5% w/v mannitol:

about 2.75% wily polysorbate 80; and about 1.25%; 1.0% - 1.80% w/v hydroxypropylmethyl cellulose (depending on its molecuJar weight).
[0183] In another embodiment, the ophthalmological composition comprises:
about 1.75% .w/v aceclidine;
about 0.010% w/v tropiearnide;
about 2.5% w/v mannitol;
about 5.0% w/v polysorbate 80;
about 1.40% w/v carboxymethyl cellulose high viscosity;
optionally, about 3 inIVI phosphate buffer; and about 0.010% BAK = as preservative;
with a pH of about 5Ø
[0184] In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine;
about 0.006% w/v tropicamide;
about 2.5% w/v mannitol;
about 2.5% w/v polysorbate 80;
about 1.25%; 1.0% - 1.80% w/v hydroxypropylmethyl cellulose (depending on its molecular weight);
optionally, about 3 miNil phosphate buffer; and about. 0.020% BAK = as preservative, with a pH of about 5Ø
[0185] In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine;
about 0.006% w/v tropicamide;
about 2.5% w/v mannitol;
about 2.5% w/v polysorbate 80;
about 1.25%; 1.0% - 1.80% w/v hydroxypropylmethyl cellulose (depending on its molecular weight);
optionally, about 3 miVil phosphate buffer;
about 0.50% wb.; NaCl; and -about 0.020% BAK = as preservative, with a pH of about 5Ø
[0186] In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine;
about 2.5% w/v mannitol;
about :3.5% w/v polysorbate 80;
about 1.25%; 1.0% - 1.80% w/v hydroxypropylmethyl cellulose (depending on its molecular weight);
optionally, about 3 rriPvl phosphate buffer;
about 0.50% w/v NaCI; and about 0.020% BAK or 0.15% sorbic acid as preservative, with a pH of about 5Ø
[0187] In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine;
about 2.5% w/v mannitol;
about 3.5% w/v polysorbate 80; and about 1.25%; 1.0% - 1.80% w/v hydroxypropylmethyl cellulose (depending on its molecular weight);
in another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine;
about 2.5% w/v mannitol;
about 3.5% w/v polysorbate 80;
about 1.25%; 1.0% - 1.80% v.:iv hydroxypropylmethyl cellulose (depending on its molecular weight); and one or more excipient selected from the group consisting of about 0.50 % w/v sodium chloride, about 0.02% w/v benzalkonium chloride, about 0.10% w/v sorbate, about 0.01%
w/v ethylenediaminetetraacetic acid (EDTA) and 0.10% w/v citric acid.
[0188] In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine;
about 2.5% w/v marmitol;
about 0.01% w/v tropicarnide;

about 0.1% .w/v sodium citrate, anhydrous;
about 0.02% w/v benzalkonium chloride;
about 0.12% w/v sorbic acid;
about 0.1% w/v disodium edetate dihydrate;
about 4.0% w/v polysorbate 80; and about 1.25% w/v hydroxypropylmethyl cellulose, wherein the pH is about 5Ø
[01891 In another embodiment, the ophthalmological composition comprises:
about L75% w/v aceclidine;
about 2.5% w/v mai-mac*
about 0.01% w/v tropieamide;
about 0.1% w/v sodium citrate, anhydrous;
about 0.02% w/v benzalkonium chloride;
about 0.1% w/v sorbic acid;
about 0.1% w/v EDTA;
about 3.5% w/v polysorbate 80; and about 1.25%; 1,0% - 2.25% w/v hydroxypropylmethyl cellulose (depending on its molecular weight), wherein the pH is about 5Ø
10/901 In another embodiment, the ophthahnoiogical composition comprises:
about 1.75% w/v aceciidine;
about 2.5% w/v mannitol;
about 0.01% w/v tropicamide;
optionally, about 3m1V1 phosphate buffer;
about 0.02% w/v benzaikonium chloride;
about 0.1% w/v sorbic acid;
about 0.1% w/v citrate;
about 3.5% w/v polysorbate 80; and about 1.25%; 0.25% - 2.25% w/v hydroxypropylmethy/ cellulose (depending on its molecular weight);
wherein the pH is about 5Ø

10191.1 In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.5% w/v, mannitol at a concentration of 2.5%
w/v.
[0192] in another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.55% wtv, mannitol at a concentration of 2.5% w/v.
[0193] in another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.6% w/v, mannitol at a concentration of 2.5%
w/v.
[0194] In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.65% w/v, mannitol at a concentration of 2.5% w/v.
[0195] In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.7% w/v, mannitol at a concentration of 2.5%
w/v.
101961 In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.75% w/v, mannitol at a concentration of 2.5% w/v.
[0197] In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.80% w/v, mannitol at a concentration of 215% w/v and Carbopol 940 at a concentration of 0.09% who [0198] in another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.48% w/v, mannitol at a concentration of 1.5% w/v and Carbopol 940 at a concentration of 0.50% w/v, [0199] in another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.80% wtv, marmitol at a concentration of 2.5% w/v and Carhopol 940 at a concentration of 0.9% w/v.
[0200] In certain preferred embodiments, the present invention is directed to compositions for the treatment of presbyopia comprising about 1.75% w/w aceclidine, about 4.0%
w/w polysorbate 80, about 2.5% wlw mannitol, about 1.2% w/w h.ydroxypropylmethyl cellulose, about 0.1% wlw ethylenediaminetetraacetic acid, about 0.02% w/w benzalkonium chloride, about 0.12% w/w potassium sorbate and about 0.077% w/w citrate, wherein the composition has a pH of about 5Ø
[0201] In certain preferred embodiments, the present invention is directed to compositions for the treatment of presbyopia comprising about 1.75% w/w aceclidine, about 4.0%
w/w polysorbate 80, about 2.5% .w/w marmitol, about 1.2% w/w hydroxypropylmethyl cellulose, about 0..1% w/w ethylenediaminetetraacetic acid, about 0.02% w/w benzalkonium chloride, about 0.12% w/w potassium sorbate and about 0.1% w/w citrate, wherein the composition has a pH of about 5,0.
[0202] In certain preferred embodiments, the present invention is directed to compositions for the treatment of presbyopia comprising about 1.40% w/w aceclidine, about 2.0%
w/w polyoxyl stearate, about 2.5% w/w mannitt-A, about 0.1% w/w ethylenediaminetetraacetic acid, about 0.02% w/w benzalkonium chloride, about 0.12% w/w potassium sorbate and about 0.1% w/w citrate, wherein the composition has a pH of about 5Ø
102031 The :following Examples are provided solely for illustrative purposes and are not meant to limit the invention in any way.
EXAMPLES
Example .1 Effect of aceclidine on vision of subjects aged 47 to 67 years [0204] Table 1 demonstrates the effect on the near focus ability of presbyopic subjects before and after ophthalmological administration of a composition containing aceclidine. Each composition included aceclidine in the concentrations indicated and 5.5% wiv HPpCD, 0.75%
w/v CAC, 0.25% w/v NaCI and 0,01% wiv BAK. Additionally compositions administered to subjects 4 and 5 included 0.125% wiv tropicamide. As aceclidine is an enantiomer, the clinical effectiveness may vary with different ratios. For the present studies a nearly exact 50:50 ratio of stereoisomers was measured as best determined by polarimetry.
Table I. Effects of aceclidine on vision of presbyopic patients.
Date, # .ege M0f0i: ........................
Vision 5aseline PotGtt15 Effect i)*
R Pre Dist L Pre Dist R Pre Near L. Pre Near R Post Dist iPostDst R Post Near; L Post Neafl .. 67 1 .5 2020. 2Ø3d 2a60 2001 2070 20.20 20,15 20.15JO
22/20 N. :3 2 S2 ...b 2030. 20;30 20.50 2025. 20.25 YØ25; 1040 &O
Slat2i)32:: 3 61 1.5 20A0 20.30 20.60 20:5 20,20 20.25 2a15, 20.15 :8:00 4/23/2013, .1 61 Li 20.20 ] 20.25 20.80 20,50 20.1s:
20.15 3* 2o- 20.15 12.00 ... 7 .
8/23/2013 S 53 1.1 702J 2020 20.60 .7,0,15;
zatk.
8/24/2013 6 47 1.5 20,25 2Ø2.5, 4)1.00 2o.loo 2Ø20 õ 2021': 7)15 7O3. 8.00 8/25/2013 7 58 1.5 20.30 20.200F 20..100 ..2. 20.25 20.301 20.20 20,40 8.00 [0205] As seen in Table 1 all subjects had less than perfect near vision (20.20) in both the left and right eye (object at 15 inches from the eye) and most subjects had less than perfect distance vision be-fore administration of the composition. After administration of the composition all subjects experienced an improvement in their near vision that lasted from 7 to 12 hours.
Surprisingly, the majority of subjects also experienced improvement of their distance vision for the same time period. Still more surprisingly the improvement in near point was much closer than 16" typically required for comfortable reading, in some cases to about 8.5" more commonly seen in individuals 30 or less. The addition of tropicamide, a cycloplegic agent, had no additive or deleterious effect on vision correction.
Example 2 Effect of of concentration of aceclidine and tropicarnide Table 2: Effect of concentration of concentration of acecli dine and tropiearaide.
---:4 ill ......... 43 : g-di #5 (Op) a?-5, (OS): 114 L___ in ,4 Britaoakr= 0_03% 0,03% 0_03% . 0.03% 0_03%, : 0_03% .
0,03% I....
Pobtartmc 4411 15%
:
.
.
¨ . ... ___ = ..................
_________________ BPBCD
15% 55% 53% ' 55% 5_5% 55% 55% ' ¨
15% 15% 0.75% .. I_1% 1_1% 1_1% 1_1% LI%
= = =
Tropic:mile 0_014% 0_021% 0_0.M% 0_042%
0_062%
_________________ EfaC1 025% 025% 0.25% 0 __________________________________ 75% 015% 025% 025% 025%
_ . ________-4- ,-CMC 035% 0:15% 035% ---------------------------------------- 0_75% 035%
0.75% 035% .. 0,15%
13AK 0_ ¨ 1% 0_1% 01% -1 0.1% 0.1% 0.1.%
0_1% :; 0_1%
_ ____________________________________________ ¨;_ Retimss (15 rtk) 3+ 1 03 : , 0_5 0 0 0 Madness (30 re) 15 -- 1 05 025 = . 0.25 0 ... .. 0 .... . .. 0 .. 0 .. ..
---t.
Brow- Athe (60 tn) 2+ 1 2+ 2 0_5 _______________________________________________________________________________ _____ .
St*Atts, , 10 210 2 I 2 . 03 = 0 0 0 BD-OD 2020 i 2020 2020. . !=== 2020 2020 2020 2020 . 20.20 BD-OS .. 20.25 1 20_25 2025. 2025 1 20.25 20.25 20)5 2025 BN-OD .. F_Itl . 1. 0 pt ---------------------- 3 pt ,.....4_ a pt. _ _ a pt a pt 8 Itt a pt _________________ BN.OS 7 pt i. 7t __ 7ril 1 7pt , 7pat 7$
7$ I 7$
BP-Owt10pic 3 racist .. 3 mai _____________ 3 not I 3 ram 3 man 3 roatt a wca 3 ratat ¨ .
_ . BP-Ink 1. 5 smirti 5 tItsa 5 tnat 1 5 nta/ , , 5 Mak S mil 5 AXUs. L 5 man.
Mimit; Alla (m) l ....... 15 15 15 15 15 15 15 , Tvras. (01.1) (1k) 1_63 trat 1,61 um. 21-2_51Xigra 1_63 tamk. 1_63 mm 1_63 mm 1_63 salm L70 masaL, .Dilame (t3U) (20 am) 20/0 2020 20.20 20/0 2020 20_20 20_20 20_20 1 Damte (01)) (1k)._, 20_15+2 20_1512 , 20.20 20.15-a2 201542 20_15+2 20_15a2 20_15+2 i Diatztoce (OS) (lhar) 20_15+2 20.15+2 20.20 2015+2 20_15+2 20_1512 20_15+2 20_15+2 1 ¨
Thisatw.e (01.1) OW 20104 2010-3 .. 20_15 20_04 2010-3 . 2010-3 2010-3 ... 1 I
Nmar (OD) (20 m) 4$ 4$ : 4pt J 4$. 4pt I
4pt 4pt. 4pft 1 . .
matt ent) . 125 . 12.5 : 0_5 ' .. 11 ............... 10 10 L

.... . = .
[0206] Abbreviations: (C) indicates corrected vision, (m) indicates minutes, (hr) indicates hour, mm indicates millimeters, BD indicates baseline distance vision; EN indicates baseline near vision. BP indicates baseline pupil size, OD indicates right eye; OS indicates left eye and OU
indicates both eyes.
[0207] All percentages are w/v. "pt" reflects size of print. materials, 4 being equivalent to 20/20 vision and 3 to 20/15 vision.
[0208] Time refers to duration of the effect.

[02091 As seen in Table 2 aceclidine at a concentration of at least 1.1% w/v was able to reduce the size of the pupil to 1.63 mm 1 hour after topical instillation resulting in corrected near and distance vision for at least 10 hours. Lowering of the concentration of aceclidine to 0.75% w/v (formula 43) reduced the miotic effect to 2.0-2.5 mm after 1 hour and vision correction lasted.
only 6.5 hours. The addition of 0.03% w/v brimonidine reduced redness of the eye (4 out of 4 without brimonidine, not shown.) to 1.5 out of 4 within 30 minutes after topical instillation which was maintained for the. entire time vision was corrected. Switching the nonionic. surfactant to HPPCD (formulas #2-6) further reduced the redness of the eye. Lowering of the concentration of aceclidine to 0.75% w/v (formula 11.3) further reduced eye redness but as mention above also reduced the vision correction duration of the formula.
102101 A brow ache and stinging in the eye were noticeable in formulas 41-3 with a 2 out. of 4 level of pain which was also associated with feelings of slight nausea, upset stomach and fatigue.
Surprisingly, the addition of a cycloplegic agent, tropicarnide, reduced brow ache and stinging to 0.5 out of 4 and 0 out of 4 respectively with brow ache dissipating after 60 minutes (formula 4 4). Further, the raising of the concentration of aceclidine to 1.1% w/v restored the longer duration of corrected vision seen in formulas 41-2 without increasing eye redness. However, .upon re-topical instillation of formula 44 at the end of the 10 hours noticeable brow ache occurred. Topical instillation of formula 45 (01)) and (OS), with increased tropicamide concentrations, following formula #4 relieved the brow ache experienced with re-installation of formula #4. Upon a 3"1 topical instillation, at the end of the effective duration of formula #5, re topical instillation of formula 45 again led to considerable brow ache. Once again, in formula 46, raising the concentration of tropicamide was able to overcome the brow ache. Additionally.
and unexpectedly, tropicamide, despite being a cycloplegic agent, had no effect on pupil miosis or vision correction. Surprisingly, the addition of tropicamide resulted in a prolonged duration of optimal pupil size constriction.
[02111 To determine the effect of brimonidine on pupil miosis, formula #7, was administered.
Administration of formula 47 resulted in only a slight decrease in pupil miosis to 1.70 mm with identical distance and near vision improvement to that of formula 45. A 2-3+
conjunctival injection was noted.
[02121 All baseline vision data was based on -vision corrected with distance contact lenses. Near vision was noted by subject as outstanding from 8 inches to the horizon at 1.5 hours after installation. A Marco Autorefractor with infrared camera and superimposed pupil calibration scale was used for all pupil size measurements. Once an image was selected it remained on screen allowing accurate calibration.
Example 3 Effect of concentration of aceclidine, brimonidine, guanfacine, ,./adolmidine, tropicamide and additives Table 3: Effect of concentration of aceclidine, brimonidine, guanfacine, fadointidineõ tropicarnide and additives.
AB2T AB4T t AB6T. ABUT i' ABUT 'PROP1113 .,,,. .....
=
i...5S i..55 : 1_55 1.85 1.55 = ................................. ..... -= .-------:. =-- ... : . ;-õ:-----: -.; ,, iirnuon.wone ......... I-, 037 0.037 0.037 0.037 MIIIIIIIII.
-.
Fadolmaine .1i I 0.037 1 1-32BCD 5.5 5.5 S..5 5,5 Tropkarnide 0.043 0.043 0,043 0.043 , 0.042 0.043 CMC' 0.075 0 07-5 0.0/5 : 0.075 ... .......... .... ...:
_ 11, __ 0..075 1: 0.075 LL____ ............................................................ 10.025 0.025 0.025 Tii 025 : 0025 ! 0025 .....
BAK - 0.01 : 0,01 0.01 . 0.01 0101 0.01 cs4,c.mr, ____________ : 0.1 : 0.1 . 0.1 -= = __ = . -'Poloxashcr 1 :PoIvoxy1 40 stswate. ...... : 0.05 ............ .. ..
......... .. pH s._ 6..5 . 7.5 . 7.5 7.5 7.0 73.. .

Aasa1,couges1tion 0 0 . 0 .... _ _ 0.75 0 : 1.5 33 0 1.5 -. - - ________ -ting,itig., 3 rain 0.5 õ 0 i 0 wash out 0 0 rCADCS.5 iaiai. - 0 i 0 ! 1 at .. 1 I

redness 15 rthi 0 0 0 :. VC 0 0 whiter ' 0 .i 0 0 111C 1..5 1.5 -- _ paia ___________________ 0 0 0 :. at 0 . : a ..4 _ . ... .
viSio-17.-P;...ar- .......................... I iii7.307 ' .i.b.f.s ...E.-.?.
s. ' at 20.15 --vision distaace 20.20 ____ 20.20 20.20 .: ________ DIC ...
20.20 : 20.20 t ---,,,- i:
- oastt 6:gin) .. . _______ 20 12 16 ... i......D/C
.. 12 . 16 duration (hrs) $.5 : 7,5 7.5 D/C
...._ 7.5 7.5 r I

____________ color . clear yellow yellow yellow vegow ! yellow t ...
1 OVERAWE: 2.5 1 3.9 1 3.8 0 4 : 3.9 . .. -----1.- ..,...---- ., [0213] *1% = 2,500 cps [02141 Ali percentages are why. Scores for nasal congestion, stinging initial, stinging, 3 min, redness initial, redness 15 min, whitening, pain and overall are out of 4.

10215] "pt" reflects size of print materials, 4 being equivalent to 20/20 vision and 3 to 20/15 [0216] Baseline vision was 20.20 both eyes for distance; 20,70 right eye unaided for near; 20.80 left eye for near (best @ 16").
[0217] DC stands for discontinued after eye washing due to intolerable stinging, [0218] Aneclidine at a concentration of 1.55% w/v was able to reduce the size of the pupil to about 1.63 mm 30 minutes after -topical instillation resulting in corrected near and distance vision to 20.20 or better for at least 6 hours, with noticeable affect lasting about 7.5 hours as seen in Table 3. Lowering of the concentration of aceclidine to 1.25% w/v (not shown) resulted in useful near vision improvement to about 20.25 ---- 20.30, but not as effective as at the higher dose range alkaline pH resulted in quicker onset, longer dura don, and greater effect. The addition of 0.037% w/v brimonidine reduced redness of the eye (4 out of 4 without brimonidine, not shown) to baseline within 15 minutes after topical instillation which was maintained for the about the entire time vision was corrected. Adding glycerin 0.10% w/v noticeably reduced stinging.
Adding instead poloxamer 188 0.05% w/v and poiyoxyl 40 stearate 0.05% w/v however reduced initial stinging further but was more viscous. The combination of glycerin 0.1% w/v, poloxamer 188 0.1% w/v at a pH of 6,5 was noticeably reduced in onset, duration, comfort and effectiveness. ABll T did not include glycerin, poloxamer 188, or polyoxyl 40 stearate, which resulted in substantial stinging and discontinuation of the experiment with eye flush irrigation immediately after topical instillation. Substitution of guanfacine 0.037% w/v in AB12T for brimonidine resulted in minimal initial redness with prolonged redness reduction and some degree of whitening, and. appeared to provide overall the best cosmesis though requiring slightly higher aceclidine concentration for optimal effect.
10219] All baseline vision data was based on vision corrected with distance contact lenses. Near vision was noted by subject as outstanding from 8 to 10 inches to the horizon at. 30 minutes after installation for A134T and AB6T.
[0220] .AB4T and AB6T were repeated both monocularly and binocularly.
Substantial improvement in depth perception, near point acuity to 3 pt (20,15), and near point distance (8", 20.20) was noted when both eyes were treated vs. monocular treatment.
Monocular treatment resulted in worsening of vision with both eyes open versus testing only the treated eye.
Example 4 Effect of concentration of aceclidine, brimonidine, tropicamide, and additives Table 4: Effect of concentration of aceclidine, brimonidine, tropicamide, and additives, = ;z:==9 1 710 711 712 1: 713 714 715 716 717 I 718 719 1 720 a,21 Aseckine : 1.61% = 1.61% 1.61% 1.61% 1.61% 1.53% 133% 1.53% 1_53% 1_53% I
L53% 1.415% 1.63% 1.75%
Tropical-nide ! 0.042%: 0.042%1 0.042% 0,042% 0.042% :0.044% 0,044µ4. 0.044%
0.044% 0.044% 1, 0,044% (04:1=M111,044% 0.015%
Briaionidiae 0_042% 0.042%1 0.042% '0.042% bv,clis;i: 0.042% 0.042%::
.
1,0.042% 00,q.;1113:44284-. 0.042%
CMC 0.75%: 0.75%1 010% :: 0.07% 0.75% 0.75%0.75% 0.80%: 0.80%
010% 0.80% 0.75% 035% 0.75%
Wag:1 025% 0.25% 0.50% I! 0.50% 0.25% : 0.50% 0,50% 0.30% 0,75% !
0.75% 1.00% 0.25% = 0.25% 0.25%
BAK 0.01% 0.01% t 0.01% : 0.01% 0.01% :0.01% 0.01% 0.01% 0.01%
0.01% 0.01% 0,01% 0.01% 0_01%
PH 7,00 7.00 1: 7.00 7.00 0.00 7.00 7.00 7,00 7.00 8.00 7,00 7.00 7.00 0.00 phosphaxe buffer 5 vtal = 5 xa.M 5 InNit , 6 at:N 3 :DM
5iAC 5 ta,1 5 la{ 5 .0713.. 1 ! 5 %AM 5 tat 5m21 6m11.1 berate buffer : 5 OFS5L1 cm 15 13 15 15 15 15 15 15 15 15 Duration Ors) 7 7 10-12 10-12 7 : 9 7 10-12 9 Pupa range Own) 1.3-1, 1.5-1,7 : 13-1.7 13-13 : :1.8-2.0 :13-2.0 1.840 L8-2.0 1.0-2.0 1.8-2.0 13-2.1: 13-2.1 Dicrarriatg 0-4 13 1.5 13 13 13 0.5 1 0.5 0.5 :
0.5 03 0.503 03 Stirg 04 1 1 1 1 1 E 1 1 1 1 I

Ache 0-4 0.25 0.25 025 0,25 0.25 0.00 0.00 0.00 0.00 0,00 0.00 0.00 0.25 0.00 Realism 0-4 0.5 0.5 0.5 0.5 1.3 1.0 0-5 : 0.5 0.5 1.0 0.5 0.5 0.3 0-5 Otattr u=atery. watery 81 did= sl residut. warrffy õwatery watery-thicker dicker Wateryi waterytwawy Overa110-5 1: 3.5 3.5 : 4 4 23 4.5 4.75 5 5 5:
4 1 4 4 : 4 102211 As seen in Table 4, formulas #8-9, an increase in brimonidine to 0.42%
\mix, resulted in redness reduction to 0.5, while 0.75% wiv CMC resulted in a watery consistency. Unexpectedly, increasing CMC from 0.75% w/v to a range of 0.80% w/v to 0.87% NO/ and increasing NaCi from 0.25% w/v to 0.75% w/v in formulas 410-11 resulted in a thicker consistency and an increased residence time from 7 hours to 10-12 hours and decreased the amount of drug that drained into the nasolacrimal duet. This decreased drug delivery to the nasal passages results in less nasal congestion.
102221 In formulas 413-18 a decrease in the amount of aceelidine from 1.61% to 1.53% wiv resulted in a pupil size range from 1.8-2.0 mm. Dimming as a result of the restriction of the pupil decreased linearly from 1.5 to 0.5 with the decreased amount of aceclidine, Specifically, the 1.8 to 2.0 mm pupil created 41% more light than the 1.5 to 1.7 mm pupil.
Surprisingly, the 1.8 to 2.0 mm pupil had a near depth increase of 1.75 D. This is only a 0.25 D
loss from the beneficial 2.001) seen with the 1.5-1.7 mm range. Thus, the 1.80 to 2.0 mm range produces 41% more light while still allowing the full benefit of increased near vision in individuals under 60 years of age; whereas, individuals 60 years of age and over still experience total computer benefit and some increased near benefit.
102231 The increase in tropicamide concentration from 0.042% w/v (formulas #8-#11) to 0.044% w/v (formulas #13-#18) resulted in a decrease in ache to negligible amounts. The amount of ache may also be correlated with the age of the individual. For those individuals under the age of 45, an increase of tropicamide concentration to a range from 0.046% to 0.060%
w/v may be preferred.
102241 Further, Table 4 shows an unexpected result seen in formulas #13 and 417 where the increase of NaC1 from 0.25% w/v to a range of 0.50 to 0.75% w/v resulted in an acceptable redness score of only 1.0 even without the addition of the redness reducing agent brimonidine.
[02251 Formulas #15, 416 and 417 each result in an overall maximum rating of 5 by combining the benefits of: (1) reduced aceelidino concentrations to improve the amount of light produced without significantly affecting the near vision benefits seen in formulas #8 -#12; (2) increased NaC1 concentrations resulting in a further reduction in redness even in the absence of brimonidine; and (3) increased CMC concentrations resulting in longer residency time on the eye.
[02.261 Formula #19 is an excellent alternative for the minority of individuals that are high responders to formulas #15-- #17 and get noticeable dimming with 1.53% w/v acedidine.
Formula #20 is an excellent alternative for the minority of individuals that are low responders to formula 419. Lastly, Formula #21 is an excellent alternative for the minority of individuals that are low responders and get poor pupil response with Formula #20.
Example 5 Comparison of Effects of Polyoxyl 40 Stearate, IfFVCD and Poloxamer Table 5. Comparison of Effects of Polyoxyl 40 Stearate,IIPPCD and Poloxamer 407, 5?

............................. : ___________ 422 #23 024 "
etti4J:ne 1,45% I .45% 1A5%
........................................... Tropicarlide 0.044% 0..04-4%
I 0.044%..

trimonidine 0.040% 0,040% .0040%
Polyoxyl 40 Ste-aate 5.5%
, - =
1113f3CD 5.5%
Poloxarnwr 407 ............................. . 5.5% .
CMC 0.80% 0.80% 00%: 10.037% 0.037%
0.037'...=;3=
EDTA 0.015% 0.015% 0.015%
BAK 0.007% 0.007% 0.007%
p}:1 On 7 7.00 ... 7.00 . . = - :
phosphate buffer 5 irtlg .54111µ,A 5rnMI
Nasal Congesrim 0.00 0.50 1.30 S$1.51.j-tw: 0.25 1 0.25 4_25 Wettirm : 4,00 ;: 4.00 4.00 Redtriess 0.25 I 0,50 . :
Vonal. Blur (< 15 sec) 0.50 . 0..50 1.50 Duration 6-8 hrs 6-8 hrs ................. hrs Overall. 0-4 4.00 Clinical Protocol [0227] 20 presbyopic patients with full distance correction were each given one of the above formulas (#22 - 423). All patients received pre- and post-drop distance and near acuity measurement, Zeiss Visantee (Visante is a registered trademark of Carl Zeiss Meditec AG) optical adherence tomography, axial length and contrast acuity testing (i.e.
Coleribrander-Michelson 10% Lim target) with the following results:
all patient achieved a miotic pupil of 1.5 to 2.20 mm;
no patient experienced ciliary ache, ciliary spasm, or induced accommodation;
all patients achieved 20/30-4- visual acuity or better at 14" and were very satisfied with their high contrast near vision results and there was no significant complaint of burning or aching;
the duration of effect lasted 6 -8 tars in all cases;
binocular vision afforded all patients 1 - 1.5 additional lines of near acuity over monocular testing;
the last 10 patients were tested at 20" (i.e. computer distance, cell phone distance) and all achieved 20/25 or better near visual acuity;

moderately hyperopic (approx. +2.25 sphere) uncorrected presbyopes were very satisfied with distance visual acuity that improved to a 20/25 or better level at distance and near vision in the 20/30 range; and uncorrected distance acuity was often improved for those patients who chose not to routinely correct a small refractive error.
[02281 As seen in Table 5, the use of polyoxyl 40 stearate provides the most comfortable aceclidine formulation with the least amount of visual blur and redness. To achieve similar results to that of formula #22, formula #23 requires 10-15% higher concentrations of the non-ionic surfactant and formula 424 requires 15-20% higher concentrations of the non-ionic surfactant. lippcD induced a color change over time, possibly indicative of oxidation. Captiso16 (sulfobutylether p-cyclodextrin) was substituted with similar findings.
Example 6 Modulation ofAceclidine Concentrations in a Preferred Embodiment.
[02291 Preferred embodiment:
Aceclidine 1.35% - 1.55".4 w/v;
Polyoxyl 40 stearate 5.5% w/v;
NaCI 0.037% w/v;
a viscosity agent, preferably CMC 0.80% w/v or an amount of Carbopol 934 or 940 sufficient to achieve a viscosity of from about 5 to about 35 cps upon topical instillation, such as Carhopolg 940 at a concentration from about 0.09% to about 1.0% w/v;
B.AK 0.015% w/v; and optionally, a phosphate, citrate, citrophosphate, or acetate buffer from about 3 to about 10 mIVI, wherein the pH is from about 4.75 to about 6Ø
[0230] For 1.35% w/v aceclidine ¨
[0231] Stinging on topical instillation 0.25 /4.0 (lasting about 2-5 seconds);
(02321 induced redness at 10 minutes: 1.0 to 1.5 / 4.0;
[0233] Induced redness at 30 minutes: 0.0 to 0.25 / 4.0;
[0234] Comfort: very high.
[0235] Wetting: very high, the eye maintaining sensation of improved wetting for most of a 24 hour period after a single topical instillation.
[02361 Depth of Focus distance: excellent, [0237] Depth of Focus near: excellent.

[02381 In testing the above formulations on several subjects it was discovered that there is a slight range in clinical effect depending on the concentration of aceclidine, where 1.35% - 1.55%
w/v aceclidine is preferred, but for which 1.35% wtv and 1.45% w/v confer the desired benefits on most subjects.
[0239] Further, it is discovered that the clinical effect of 1.35% w/v aceelidine can be improved when instilled as follows:
1) baseline effect: 1 drop to each eye.
2) enhanced effect: 2 drops to each eye.
3) greater effect: after 2) above repeat 1) above.
4) maximum effect: after 2) above repeat 2) above.
Example 7 Use of a preferred embodiment to prolong contact lens wear.
[0240] Preferred embodiment:
Aceclidine 1.45% w/v;
Polyoxyl 40 stearate 5.5% wiv;
NaC1 0.037% w/v;
a viscosity agent, preferably CMC 0.80% w/v or an amount of Carbopol 934 or 940 sufficient to achieve a viscosity of from about 5 to about 35 cps upon topical instillation, such as Carbopol 940 at a concentration from about 0.09% to about 1.0% w/v;
BAK. 0.02% w/v; and optionally, a phosphate, citrate, citrophosphate, or acetate buffer from about 3 to about 10 mM, wherein the pH is from about 4.75 to about 6Ø
102411 As a baseline, the subject, who normally wore extended wear lenses (Air Optix ; Air Optix is a registered trademark of Novartis AG) for daily wear only, slept in these lenses overnight. On arising each morning the subject's vision was blurred and the contact lenses required removal and cleaning of film and deposits that had formed overnight.
Average vision on arising at distance; 20.60; average vision at near on a Michelson contrast acuity chart: 2080..
[02421 Then, for seven consecutive days the above formulation was instilled between 7 am and am. each day as a single dose. Subject wore the Air Optix lenses throughout each day and slept in the lenses overnight. Upon arising each morning the subject's vision at distance: 20.20+;
vision at near 20,40 unaided (consistent with subject's baseline presbyopia when the subject did not wear the lenses overnight and instead inserted the lenses upon arising).

Example 8 Comparison of Effects of Polyoxyl 40 Stearate and Captisol (sulfobutylether /3-cyclodextrin Table 6. Comparison of Effects of Polyoxyl 40 Stearate and Captisole (sulfobutylether 5-Qiclodextrin).
#2,,..1. *26 #27 Ian .29 030 it32 ,31 ;.! ' #33 = -1 Aceclia4. 1.35 ..-1, ", l.:3.5/:1: 1.33% 1.,Y.j,/,:,.
13_=_-;,..,, 1.35% 1,35% 1.55% I_ _______________________________________________________ :::- .. 0, Tropicamidn. L 0,044c I' o 044 A.::: 0:01µr:.1z 01.14,-1-'0 0,0,;,::,,,=0.0-44i0 0.04-.4% 0 0 .044% .044%
,. .,.
Polvoxyl 40 stearate 5.5% ___________________________ 5.5% 5.5% 5,5%
':;.5% 1 5,5% 5.5%
. . am : -,-----1 I
Captiso1' 5.50.;
' 5.5%
I Cci...-zamidopropyl bezaine. I MB ....:1 .
:j 0.10% ____________________________________________________________________ ..,. ==
1 ' ..
gDTA ...
10015% 0.015% 0.,005%,0.005%1 0,005% 0005% 0.015%
:
I CMC 2.500 cps 080% 0_80% 0,80% ' 0.80'I-, 00%l080% GM% 1; 0.0%
i------ .
NaCI 0..037% 0.037.4' 0.037% 0,07% 0,037% 0,03.P.:1 0431/%1 0,037% 0.0,Y.P.^Ag..
.............-4.-NiatIlliall _______________________________________________________________ 4%
.. . .,. ...,- .. .
BAX ______________________ 0.007% 0007% 0.007%!0.007%
_______________________________ 0.007% 0.007%; 0_007% 0.007% 0.00.7%j = =,..." ., Btrate buffer (m.M.) 4 4 .: 4 : 4 4 ';
4 . 4 1 : ..,.
plaiy,Thzie buffer - (4LINI).: 4 4 .. . . ,..._ j ... .. .
............................. . .
pH .: 7 7 7 '7 7 7 ____ 7 7 ... .. .
.
...............................................................................
..
! Redness, 10 ral....si l 1.25 1.25 2 2 1.75 1.75 0 0 0 i . " ...= õõ-A
Redness, 30 thin !E 0 .. 0 ! 1,5 . ... -.. = :.
1,5 1.25 1.25 0 0 ...õ, ........ ,.. -7,7, . õ -=
! PulA, 30 rain (trim) ',L <2 : e,2 <2 , <2 <2 <2 .
< ' <2 13/1.r. on instil (sec) 10 :: 10 10 10 10 : 10 ! 10 10 1 10 !
Athe ..................... 0 :! 0 0 0 0 1 0 :. I
' 0 1 0 .!
Ratiu4 ! 4.00 4.00 1 2.00 . 2,00 2,50 I 2.50 ! 1.00 5.00 ----A,-,--f0243j As seen in Table 6, when using polyoxyl 40 stearate as the surfactant the exclusion of EDTA results in reduced redness and best overall rating among polyoxyl 40 stearate compositions (Formulas II-25 and 426). The addition of eocamidopropyl betaine ("CAPB") further reduces redness however results in significant ache (Formula 431), Replacing polyoxyl 40 stearate with Captisol (sulfobutylether P-cyclodextrin) and adding lil annitol achieves similar results in redness reduction as the addition of CAM to polyoxyl 40 stearate but without the attendant ache resulting in the highest overall rating among aceclidine compositions (Formula 432), After several weeks formulations with Captiso0) (sulfa.)butyl ether p-cyclodextrin) had an orange hue, possibly indicative of oxidation.
Example 9 Preferred Cold Chain Composition 102441 Composition accciidine at a concentration of about 1.40%-1,80% vi/v; and tropicamide at about 0A2% wiv;

polyoxyl 40 stearate at about 5.5% w/v;
marmitol at a concentration of about 2.5% to 4.5% w/v;
carbomer 940 at a concentration of about 0.09% to about 2.0% w/v;
optionally, a preservative such as BAK at a concentration of about 0.2% w/v;
optionally citrate at a concentration of about 0.1%;
optionally with acetate or phosphate buffer at 2-100 mM, more preferably 3-5 naM
wherein said composition has a p1-1 of about 4.50 to about 5.0; and preferably, about 4.75 to about 5.0; and wherein w/v denotes weight by volume [0245] .A composition as described above was administered to a 62 year old subject. It resulted in pupils of 1.8-1.9 mm ou., 20.20 + reading vision, and 20.20 + distance vision; whereas without carbomer 940 reduced effectiveness resulted at 2,5% ma.nnitol, and no near vision effect resulted at 4.0% mannitol. No ciliary spasm or loss of distance vision resulted. Onset was within about 15 minutes. Transient redness of about 1+ /out of 4 was noted for about 20 minutes without alpha agonist vasoconstrictor. The presence or absence of BAK. had no clinical effect, and was used to provide an optional preservative.
Example 10 Stabile Aceclidine Formulations Composition Tested:
aceclidine at a concentration of about 1.50% w/v;
tropicamide at a concentration of about 0.042% w/v;
polyoxyl 40 stearate at a concentration of about 5.5% w/v;
mannitol at a concentration of about 2.5% w/v;
citrate at a concentration of about 3 rnM;
wherein said composition has a of about 4.75.
[02416] 20 samples of the above composition were divided evenly and stored at 25 "C. and 4 C.
Prior to storage, initial concentrations of aceclidine were measured using high-pass liquid.
chromatography ("I-1.11.:C"). The amount of aceelidine in each solution was calculated by the area under the. principal peak compared to a reference solution of aceclidine.
Samples were then subject to storage for 3 months. Aceclidine measurements were taken at 1, 2 and 3 months, Results of the stability test are shown in Table 7, Table 7. Stability of Aceclidine in Cold Chain Storage 25 C 4 C ..
initial 100% .100%
I month 92% 93%
2 months 75% 92%
3 months 50% 88%
[0247] As seen in Table 7 "cold chain storage" or storage of the aceclidine composition at from 2 "C to 8 'V resulted in a significant increase in stability of aceclidine at all 3 time points.
Example 11 Use of compositions containing little or no cycloplegic agent 102481 Aceclidinc.', alone causes incidence migraine-like severe ciliary spasm (brow ache) and myopic blur. These effects are inversely con-elated to age with subjects age 40 reporting the highest incidence and subject age 60+ reporting the lowest incidence, The addition of a cycloplegic agent reduces ciliary spasms and attendant brow ache, migranious headache, squeezing pressure around eyes or other symptoms of ciliary- spasms. The addition of the cycloplegic agent, surprisingly, does not reduce the myopic effect of aceclidine. The addition of 2.5% w/v mannitol however does reduce the myopic effect of aceclidine.
Increasing the aceclidine concentration overcomes this reduction in myopic effect seen with the addition of mannitol. Surprisingly, however, the increase in aceclidine is not coincident with an increase in ciliary spasm. Even more surprising, the concentration of the cycloplegic agent can be reduced or even eliminated in the presence of mannitol without an increase in ciliary spasm. Thus, combining a higher concentration of aceclidine with little to no cycloplegic agent in the presence of mannitol results in an improvement of near vision acuity without attendant side effects on par with lower concentrations of aceclidine and higher concentrations of the cycloplegic agent in the absence of a cycloplegic agent.
[0249] Further and unexpectedly, the addition of a nonionic surfactant increases both the quantitative measure of near vision improvement and the duration. This effect is concentration sensitive. In a preferred embodiment the non-ionic surfactant is at least 1.%, preferably at least 2%, more preferably from about I% to about 5%, and most preferably about 5%.
For example, polysorbi.,,te 80 or polyoxyl 40 stearate at a concentration from about 1% to about 5% w/v results in about 1.5 to about 2,0 lines of improvement and a duration. from about 4 to about 5 hours.
[0250] Not to be held to particular theory, the increase in concentration of a surfactant may crowd the surface of the cornea, and at an optimal concentration this crowding result in small and probably nanometer diameters, which. given the dual polarity of surfactants, where nonionic are most preferred, enhances corneal absorption of the entrapped highly polar aceclidine molecules.
10251] The further addition of a viscosity agent by itself does not enhance duration.
Surprisingly, the addition of a viscosity agent in a formulation with optimal ratios of aceelidine, tropicamide and a non-ionic surfactant dramatically improves duration. For example, a formulation of the present invention comprising 1.75% aceclidine, 2.5%
mannitol, 0,01%
tropicamide, 5% polysorbate 80 improves near vision in a presbyopic patient by up to 3 lines of vision acuity for about 4 to about 5 hours. The addition of 1,4% CMC further increases the near vision improvement to from about 7 to about 10 hours, Not to be held to a particular theory, a threshold above the critical micediar threshold greatly enhances permeation through the cornea by reducing micelle size from micrometers to nanometers. See Figure 2.
[0252] Examples of compositions containing little or no cycloplegic agent are shown in Table 8 below.
Table 8. Compositions containing little or no cycloplegic agent . .......
41,1 #L2#L3 #L4 L5 ilL6 41;7 41_8 I41,9 41,10 1.75% 1.75% 1.75% 1.75% ,1.75%
1,75% 1.75% 1.75% 1.75% 135%
.......................................................... 0 LP% 0 07% 0.02%
0.02% 0.02%
Mannitol 2,5% 2.5%
2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5%

Potisorbate SO 4.75% .Ø25% 0.25% 0,1% 0.1%
0.5%11 0.25% 0.25% 0.1% Ø1%
Carhopola) 940 or CIVIC 0.95% 0,95% 0.95% 0.9% 0.95% 0.95W 0.95%* 0.95%* 0.9%*
0.95%*
Glxcerine ........ Phosphate buffer 3mM - 3mM 3mM 3mM j 3mM - 3mM 3m1V1 mV
------------ NaC1 ---- 0.5% 0.1%...õ 0.05% 01% 0.5%'' 0.1% 0.05%
0.1%
Boric acid ... Ls, 0.12% 0.2% ..... 0.23/4 0.12% 0.12%
0.2% 0.2% 0.12%
BAK 0.015%1 0:01%
0.01% 0.05% 0.01% 0.015% 0.01% Ø01% 1 0.05%1 0.01%
pH 5,0 : 5,0 5.0 , 5.0 5.0 1 5.0 5.0 5.0 5,0 5.0 Table 8. (continued) ........................ . 43..11 ... #1,12 in...13 1411..14 )41.15 41,16 1 #1.17 ii1018 , H1,19 i 10..20 i #1.21 - 1 .. 0 -Aceclidine 1.65% 1.65% 1.75% 1.75%
1.65% 1.75% 1.75% 1.73% 1.75% 1 1,75%! 1.75%
Troilicamide ...,. 0.01% r - -:;-.
: 0.025% 0.025% 0.025% i 0.{y2.5% 0.025% 0.025% 0.015%i Ø015%
Marmitol 2.5% .- 2.5% . 2.5% . 2.5% 2.5% . 23% [
2.5% 2.5% 2.5% .2.5%1 2.5%
P6173Orklate 80 2".4, .2%
i% 0.10% i 2.50% 2.50% j 3.00% 2.50% 2.50%, 2.50% 2.50% ' earbopoW 040 1 i or CMC
0.75% 0.75% 0.'75% 0.73% ! 0.75% 0.75% 0.75% ! 1.50% 0.75% 0.75% 0.75%

+ n (ilycenne 0.10% 0.10% LiU0% 0.10% ] 0.10% 0.10% ..Ø10% i 0.10% 0.20% 0.20%
0.20%
. .. . ... ....
Phosphate buffer 3 mM 3 mM
3 mM..õ,3 rnM ! 3 mM 3 rriltL .3 .mM I. 3 mM 3 raM 3 m1V1 3 mM _ ..................... Nael - .. . -- . - --Boric acid 1i , ,-- - .. - - -, I .,.... Ø
_ - - , -BAK
, 0.01% 0.01% 0.01% 0.01% j 0,015% Ø0!5% 0.015% 0.015% 0.015%
0.015% 0.015% I
i -pH ..................... 1 5.0 5.0 5.0 - 5.0 ! 5.2.5 5.25 5.25 5.23 5.25 5.25 5.25 ==. === .
._,.

Tab]e 8. (continued) ..................... #122 I, iii...23 1 #1,24-1 #1.2.5 I #1õ26 si #1_27 .
#1,28 1 #129 #1.30 1. #1,31 i #1-7,-/Y2 Amclidine 1.65% . 1.75% = s= 1.75%
1.75% 1. 1.75% 1 1.65% 1.75% 1 1.75% 1.75% = 1.75 4 i 1.75% ., ...........
Tro kamide 0.025%. 0.275% 0.020% Ø015% 0.027% i 0.0275%
0.0275%1 0.0275% 0,025% 0.022%1 t, (H 75%
l- .,. .. -Mannitol 2.5% 2.5% 2.5% 2.5%
2.5% ' 2.5% 2.5% I t 2.5% . 15% 2.5% 1 2.5%
......... Polvsorbate 80 z 5% 5% 5% 5% 5% 5% %
5% : .5%
.
5% = 5% i 5%
.
.. -, CarbopolV 940 1 t __________________ or CMC
' 1.25% 1.15% .. 1.45% 1.45% liffill 1.2.54 LIAO% i 1.40% 1.50% 1.40% .
1.50% .
Olveerine _____________________ - = - ..= IIIIIII = NM
= .. --1 Phgv.Date buffer 3 InM 3 inNI .. 3 mM
..3 friM 3 triM 3 mh4 3 m1V1 4.. 3 rnM FrEll 3 rriM 3 rriM
' __________ NaC1 - - - -,7. ______ - 1 - - ! - =
- .- -_ .
ftoric acid .-,-= .õ .. - . --- - .- - ' - - . - -BAK 0.01% 0.01% 1 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%
,, 0.01% I 0.01%
, 1 .pH 5.0 .. 5.0 4-.. 5.0 5.0 = 6.0 5.0 5.0 5.0 5.0 = 5.0 i .00 ..
..
Pupil .Size (rum) = . 11.111111 = .
....... ---1 Reading Vs.
3+ 3+ 3+ 3+ 3+ 3+ 3+ . 3+
3+ 1 Baseline 40 cm ................................. . ...
= -I
Duration (hours) 7 10+ 10+ lQ 1 10+ 7.0 10+ 10+
1 10+ i e' . Ciliary Spasms 0.0 . tr 1 0.5 1.0 1 1.0 0.0 it 0.5 = 1.0 1.0 --.........
Stin 'ng 0.5 : 0.5 0-5 IIMINIMII 0,5 0.5 0.5L 0 5 ...
Blur (min) 1 1 1 1 1 1 j 1 1 . .. 1 .
Distance Blur .
IIIIIIIIII
.. ..................................................... -I. ..
Onset (mil) . 20 L 20 20 1 20 0 j 20 26 Redness 1hr "0-4) 0.5 j 0.5 0.5 . 0.5 0.5 0.5 .
0.5 0.5 ; 0.5 .4....,... ..................................................................

Redness 4h3(0-4) . . = .
Overall CorfIfOrt Amick), si sticky I sl stklt.zr :4 stickv sl sticky si stic = 1 31 sticky si sticicy sl sticky Osmoiarity 1 Efficacy index: = .
1 :

resedtw = ................ :
________ ..................................... _ OVERALL (1-5 L best best [ best i best best . best , best best , best ia.13)e 8, (continued) - . ..
#1,33 #1.,34 #1,35 I. #1.36 #1,37 111,38 . #1.47 . MI 48 1 41.49 T #1,50 i' #1..51 ,-- -I A cec i idim.; 1.75% ..........................................
1.40% 1.40% i 1.25% : 1.45% : 1.45% : 1.45% i 1.55% 1 1.65% 1.: 1.75%
1.65%
- I,-1 =
Tropic an-de , 7 ' - -0.(1200% 111..111:0.0200%10.0300%i0.0300% 0.0200%.:
=
Brimoniclint: I - -.J - --, 7 ........................................................... - :. , - -t I ,- 1 4 ---, .......... Monnihli - IIIIIII - I - '' :7 : 2.5% 4.0% 1 2.5% 2.5% : 2.5%
, " = .
Pulysorbute 131.). ________ . - . .- -: : - =
5.00%
LP,olvoxyl 40.,Sie2,rate - - . .. -- :== 5.5% 5,5%
: 5.5% 5.51/., I 5.5% .õ: 5. 5rY; :
. Citrat, 0 10% 0 10% 0.10%
:, 0.1f00 : 0.10% : 0.10% .: 0.10% : 0,1064 I 0.10% .- 0. 10%
. -...
= = = =
0.10%_ 0.10% i 0,10% 0, IQ% LO.10% ! 0.10% 0.10% 0.10%1 0.10% 0.10% :
CMC .................. == : 1.45%
0.75%5 , : 0.85% 1 0.75% 0.75% :: 0,75% , 0.75% 0 75 1) 0,75% :
HPMC 1 - ': 1' - i ... :: L õ
_______________________________________________________________________________ _____ i Carbov.)10 940 I __ - , õ. . - = 1 z , ..
, .. ' = - 1 = .. t_ .. .; ...... i ' NaCi ,....Ø75% ...9....:75% :: 0.50% ' 0.50% 0.50% 1 0.50% ': 0,50% 0.50% 0_50%. 0.50 ' 0.00% 1 :.
Bork Acid 1 . .
Po:ÃÃÃ3ssinra Borate : -- -.n 7, 7. - 1 Phosphate buffer 3 3 3 3 I 3 I 3 3 .3 _.. ... .:
Acetate .. . 7 I __ . .= ,, :i - I --, pH : 5.0 1 5.0 5.0 .. 5.0 :1 5.0 5,0 5.0 5.0 . . 5,2 . , . .
.5 50 I 5..0 ' ------------ BAK -- 0.015% z 0.015% 0.015% 0.015%1 0.0154V0 0.0 l 5% 0,015%
0,015% 0.015% 0.015%. : 0.015%
- -.4.
Pupil Size, (rum) A-t [ 1 1111111 .. õ
............................ -------,----- -- --- ....... -RE.Hditlg vs. 1 , Baseline 40 em 3 : 3.25 3 2 ' 3 : 2.5 ),.5 0.5 i 1,5 1.5 1 = + =
1)uration (hours) 4 :: 7 ... 4.5 6..5 : ifl; 3 -) 4 4 1: 2 - .
CT `-' ... õL.ar..-zi .:UtSITIS 4 4 :-Ã 2 1 3 '2, 0.5 0.5 1 0.5 0.5 a5 StinPirto- 1.0 1,0 __ [ 1.0 1.0 1 Ã 0.5 1 1 :
,. ..
. :
Blur (ruin) ............................................ I
DisUznc;e bitÃt none none none none none : none. _1001i0-1 none none none none ..
1.
. Onset (min) Redness ft.(f)-4) 20-11 20-n 1 20-13 20-14 20-15 : 20-16 20-25 I 20-25 20-25 I 20-25 1 20-25 20 ______ i 1 5 0,5 0 5 i. -L-. i 0.5 0.5 1 0.5 05 -... _. , , . : a3 1 Retint;ss 4hr 0-4') . =.LOverall comfort poor poor ?-tor fair .:....)Or.. )oor -ood : Hood good..
pod I gooL, _.-Osrnolarity hi hi hi , hi hi hi hi N :: hi hi hi .
...... .. ....... ,: .. 1. :
Efficacy index:
read*dur 12 23 14 0 , 20 15 5 1 6 6 .. 2 OVERALL (175) I** 1/2 1 4' ..,..... - .' 1 .,'= õ *
' -----.-----Table, 8. (continued) , 41,52 1 41-53 #1_54 :: #1,55 41.56 #1.57 #1,58 1 #1.59 41-60 . #1.61 L,62 I
. . ..
Aceclidine 1.65% 1 1.65% : 1.65% 1.75% 1.75% i 1.65%
1.65% D.65% 1,651? 1.656,4 "1ionic-amide 0.0100% 0.0250% 00003%u0000% 0.0250%j 0,0250% 0,0250% 0.0150% 0.0400%
:).0250% :0.0300%
Brinonicline . .. . . ,. .. .: : - .- .. ,- , ..... ...:
..,.._ Mannitol 2.5% 2,5% 15% 2..5% 2.5% 2.5% 2,5.%
T 2.5%... , 2.5% 2.5% 2.5%
. Polysort?ate 80 2,00%
2.50% 2.00% 1.006 0.10%.. .. 2.00% 2,50% 2.50% 3,50% 150% , 3.50%
Pelyoxyl 40 Stearote - =-, .,.. : ., , - _ - ;.:
- - t Citrate _______________ ::- 0.10( g, ,. _ .. :. . : .;:

......................................................................... ==
.. 1,- .. -Gyeerine __ 0.10% ...................................... 0.10% .. 0.10% 0.10%
0,10% 0.10% 0.10% 0.10% ;1.10% 1: a10% i 0 10%
. ,.
.................
----------- C MC --- 0.75% i a.85 A, 0.85% 0.83% i a85% 0.85% 0.85% 0.75%
0.60% 1 1.60% : a 60%
HP _____________________ MC =,, : -,:. - 7 ...
.
Carbopole 940 - : , - ---------,. -0.75% 0.60%
.1 4 Natl.. 0.50% 0.50% ,-- : ,- .1 - 1 --_,. .1 -_, = ..
Boric, Auk! - -Pus luin B ._- oraM. ..... :,. - 1 , 1 : -,, f .,.:
.......... . _ = =
: .
Phosphate buffer 3 -- 3 -- 1 3 .. 1 1 3 3 3 1 .A,F,:ei=ate - i : -c: - .. - pH t. 5.0 5.0 5.(../ 1 3_3 5.3 : 5.3 : 5.00 5.00 1 5..00 1 f-.7-'30 : 5.00_ BAK 0.015% :: 0.015% 0.015% 0.015% 0,015% = 0.015% 0.015%
0.015%1-0,015% 1 0.015% 0.015%
..
Pup)] Size (nun).
, Reading vs. 1 :1 1-3aseline 40 CM 2.5 3 -- 3 .: 2 1.5 2.5 3 2 1.5 2.3 : 2.5 , =
Duration (hour 4-s) 6 5 6 4 4 .. 6 5.4.; 7 1. 3 7 7 :
- . .. .
, Ciliary Si.'.a.SMS 0.5 a 5 . 2 2 0 0 0 .. 0.5 1 0 0 5 a 5 1 . , , StitighlgI 1 0.5 1 I 0,5 0.5 0.5 .
. 0.5 0.5 I 0,25 0.25 0 25 -I-2 =
Bl = __ :-ur (min) 1 ____________________________ { . 1 5 1 1 -Dnce blur I none none none nom , none none none none none nose none i Onset Ornin) 1 20-25 20-25 20-25 1 20-25 . . 20-25 : 20-25 20725 1 20-25 : 20-25 20725 20-25 1 R.edmss lhr ((-4) 1 0.5 0,5 0.5 : 0.5 1.0 0,5 0.5 ! -- 0.5 0.5 0.5 1 + "- -= -Reoness 4hr (0-4) 1 ................................. i I
T . -- 1 Or ra 1] COtt3i'oEt poor .1:. wor . ax ......,...,,poor ,zood 7 ..spod good gp.).c..... good good g000 1 Osmobrity hi hi ni : __ n1 __ :: .. pl I. ni ni .
n1 iii n1 n1 1 _ - ., :
.........
Efficacy index: .
reacidur 15 : 15 18 8 6 15 /7 14 5 18 18 - .
0VFRA1.1.. (1-5) .1,4, i'.
1 -- I [ ,... `.: ,Z, 4: , * A=N*
µW.,....

Table 8. (continued) i 41,63 #1..611 #1..6i I #1.M #I47 .
#1.68 . #1,69 #1.70 . ii1.71 1 01,72 1 #1.73.

I =
1 Aceclidale 1 1.65% 1.75% 1.65% 1 1.75% 1.75%
1.75% 1.75% I 1.75% 1.75% 1 1.75% i 1.75%
1 == - i =
.Tropiearnide 0.0250% 0 0250% a0250%- 0.0275% a 0275% a 0275% 0.0250%
0.0180% 0.01605.e1'. 0.0160%10.0150%
, t Bririamidine I - .. 1 - . - - - .. - --, =
_______________________________________________________________________________ _____ -Marmite' 2.5% i 2.5% 2.5% t . 2.5% ..2.5%
2.5% 2.5% 2.5% 2.5% 2.5% 2.5%
t.... Polysorbate 80 2.50% 1 3.50% 4.00% .500%. 5.00% 2.00%. 2.00% 2.00% 2.25% ' 4.00%
4.00%
1 Polvoxyl 40 Stearate = - = - .-- - - ..- ---. ,. ..
Citrate - =;.- .: .: -- -1-- . . . . .
I Creerine a 10% - 0.10% 0.10% --- - -. = .: = .: . -............................................ -CMC a 75% : 0.50% 0.75% -1.35% 1.35% 1.45% 1.45% = 1.45% 1.45%
1 ...... . .
IHPMC = ' - .. - .. , = - -Carhopole 940 1 0.50% 1.35% - .-- 1.45% .. , .. -Naa - - - . . . -, .. = - .
Boric Acid - -- -. - - - -Postassitan &nate " 111111111 . ... . . ..
..!: - =

: Phosphate buffer 3 3 t 3 3 3 3.. :
3 3 .333.. t -Acetate t ....- -:.
........... pF1 = 5.00 5.00 5.00 5.0 5.0 . 5.0 .
5.0 ___ 5.0 5.0 . 5Ø
. 1 .5.0 =BAK 0.015% 0.015%. 0.015% 0.015% 0.015% 0.015% Ø015% 0.01:"% 0.01%
0.01% 0.01%
.:= Pupil Size (mm) ' Reading vs.
Baseline 40 cm 2 2 2 i . .. 2.75 2.75 2.75 2.75 2.75 2.75 2.75 3 _ Doratkm (hours) I
Ciliaa Spasms 4 5 0.5 _ . 0.5 t 7 7 6 7 7 ..................................... 1 0.5 1 0.5 0.5 5.5 0.5 0.5 0.5 7 0.5 0.5 7.5 0.5 -Stingin_ 1 Blur (min). 0.5 0.5 0.5 ' 0 5 0.5 .....1.,--..:-.....----i - ................................................ . =0.5 , 1 , IDistance blur . none . none none 1 none none . none none none none none 0I none 1 ....... Onset 'min) 20-25 20-25 20-25 . 20-25 20.25 -. 20-25 i--I Redness Ilir (0-4) 0.5 0.5 0.51 0.5 . 0.5 0.5 - =
I-; .....
t Redness 4hr (0-4) . .t .........................................................
. 4. _______ 1 Overall comfort ood t == good pod .good good good , good , good Nod .1_ pod t i Osniolarity 111 xi: - ni L ttl n1 ni . n1 n1 ril 471-1 nl I Efficacy index: .
' , readtdor 8 0 10 19 19 1 15 17 19 19 ., 19 I 23 L9VERAL1, (1-51 poor 9 - ** 1/2 . .. 44 .
=....,NA. I ..N.NS'..

PCT/US2021/0295.36 Table 8. (continued) =#1,74 #1.75 #1,76 M #1,79 M #1,81 #1.82 s #1..83 #1,84 .
Aeeciidine 1.75% 1.75% 1.75%
1.75% i 1.75% 1.75% 1.75% 1.75% 1.75% 1.65% 1.40%
- - i Tropica al& 0.0150% 0.0150% 0.0120% (0110%00100% 0.0000%
- 0.0100% 0.0150% 0.0000% 0.0000%
.......... --, Brimonidine - i - - 1 - 1 - 0 015% -- .. -Mannitol . 2.5% 2.5% 2.5% 2.5f.va 1 2.5% 2.5%
2.5% 2.5% 2.5% 2.5% 2.5%
. 1 1 Polvsorbate SO 5.00% 5.00% i :5.00% 5.00% 5.00% 5.(k% -: 6.(30% 7.00% 0.00% 0.00%
µ.
Polvoxv140 Stearate -..11111111111111111111111111111111111 - ..5.5%
, - , Citrate .: . 4. : --. . .
..-. =
Glycerine = = - - --, . .. - --CMC 1.45%
1.43% f 1.43% 1.40% 1.40% i 1.40% 1.40% 1.40% 1.40% 0.00% 0.75%
HPMC .. - i - - . - t _ . Carbopole 940 - . -. :5, - -. . .
i ___________ Naa ....... . - - - -0.50% - - 1 .
_ .
Boric Acid - - S. . - =- --+ ,.5, - -Posta ssium Borate. - - - - -,. .. ; ,... - .
.- :-. __ Phosphate buffer 3 3 1 3 3 3 . . 3.. 3 3 i 3 3 . 3 +._.... . . ....... .................... -Ac;ztate : - - - z - ' ' - -......2---.1 ........... pH 5.0 5.0 5.0 5.0 1 5.0 i 5.0 5.0 5.0 i 5.0 5.0 ........... BAK 0.01% 0.01% 0.61% i aoi% i am% 0.01%
= aol% aol% am% o.010%.
. 1 . ; Pupii Seiz (ma ............ i i) .. i I
i R.eading vs.
Baseline 40 cm 3.25 3.25 3.5 3.5 3.75 ').5 2.75 2.5 1 1.5_ . .
Duration (hour 1"
s) i 7.5 7.5 7 -: = 8 9 7 5.5 5 3 3.5 C ilia .ry Spasms 0.5 0.5 1 1 1 7 2 .1 0.5 0.5 ..
Stif1039, __________ 1.
..........................................................
1.0 Blur (min) 1.5 1.5 1.5 - . i Distance none none ',kir ____________________________________ none 1 none -4-: none none none rtOr le . none none i none .. - e ......... Onset (min) 20-25 20-25 20-25 1 2072.5 20-25 20-25 20-25 20-25 20,25 1 20-25 20-25 Redness 11r (0-4) õ 1 i 2 0 ....
Redness 4hr (0-4) 4. ............... I =
1 i ....
Overall comfort ipood-exc 9-ood-exc pod-exel exe ext: fair f 1air uood good 1 . thir .5.: - i , Osmolarity 1 --71-1-nl I ril 1 ni __ ril n1 n1 I ni hi _1 ril n1 .
Efficacy index:
read*dor 24 I .24 0 . __ 25 28 34 18 15 - ..
OVERALL 0.5) 5,44,2.5. I ***** *****1 **MI ! *****!!
*2*44-11.1 *44* *** * ** I I *
_______________________________________________________________________________ __ , . .

Table 8, (continued) ._,.
I
I #1,85 41,86 1 41...57 14..88 -#1..89 #1.90 #1,91 #1-92 #1_93 #1,94 ._____1.
Aceclidine I 1.75% . 075% t ____________ 1.75% 1.75%
1.75% 1.75% 1. 1.75% -1-.75% 1.75% . 1.75%
4 .----7 -,- .
'Tropical-nide 0.0000% 0.0100% 0,0900% 0,0060% 0.0060% 0.0100% 0.0060% 0.0060% 0.0060%
0.0060%
..
I Brimonidine .. - - -. - - - .
, , ..
I- Ma:I:111 1 2.5% - 2,:.5% 1 2.5% 2.5'N . 2.5%
__ 2.5% 2.5% Z5%
Polysorbate 80 5.00% i'' 2 ''.5% 1 2,5% 2. :5% 2-5%
2.50% 2.50% 275% 2.75.5'/0 "3.5 .(PA) 1.
-: - ------------------ - - i Polyoxy: 40 Stearate _07.. _ - 1 .- ___________________ .- -Citrate - . - I = -= - - - I - - - - õ1, - :
Ol,4 s,eerine _ .. ,.. ... :: - .õ.............õ___ .
_ ..
CMC -- : 1,40% -.I --: = --:-1-1P MC ' - 1.75% I 1.75% 3.75% 1.75%
l :
. Carbonole 940 ' - - r - __ -- - 1.75%
1.75% 1. 80% 1.80% [ . 80% I
i.---- .
MICA 0 00", 0.50% - l 0.50% =,.. ' 0.50% 0.50% 0.50% 0.50% 1 0.50% I
õõ...... õ, Boric Acid _ ,-. 0.35% I ................ - - 0.25%
.. . , PostasSiurn Borate ----- - - 0.47% ' - ..... -= ____ 11111111 _ .37% - 1 ..õ,..õõ....
Phosphate buffer 3 3 3 3 4 1 3 -z Acetate - _ - -____________ ell ....... 5.0 5.0 5Ø 5.0 6.0 5.0 5.0 5,0 5.(L 5.0 :
BAK 0,010%
0.0201/0 , 0.020% 0.020% 0.020% 0.02% 0.02% 0.02% 0.02% .,_ 0.0',N, Pupil Size (rim) Reading vs. .
Baseline 40 cm 3.5 3.5 3.5 3.75 3.75 3.5 3.75 3.75 3.75 3.75 - , õõ....
Duration (hours) 7 1 8 7 9 9 7 7 5 8 8.5 C:ilkiry_Spasins 2 (.5 0.5 0.5 ....... 1 0.5 0.5 -- 0.5 .............................................. t Stingina ------------------- 0.5 ................... i 1 __. .................................. . - -k-_________________ Blur (min) 1 Dislance blur 2.0 none none none none , none t none none _ none 130Tle Onset (min) 20-25 1 `,'.0-25 20-2j .. 20-2) 20-25 20-. .,, Redness 1hr (0-4) 1.0 1 .. 1.0 ------- 0.5 0,5 0,5 0.5 i 0.5 I 0.5 0.5 0.5 Redness 41n- (0-4) s. . . .............. ---- -------- _ ... .
Overall -comfort _ good _gpod good __good . good .1 t .
..

Ostnolarity n1 ill nl =. ill .. lo ' Efficacy index:
:
reatPclur 25 28 25 34 34 25 26 30 30 32 õõ_õ, OVERAI.I. (1.-:)).. 1 "" t 1 ..
All concentration in weight by volume.
rum denotes millimeters.
cm denotes centimeters, min denotes minutes.
%* denotes amount can optionally vary from about 0.0113/0 to about 1% wiv.

# denotes formulation can include polysorbate 80 or not include polysorbate 80.
Ciliary spasms scores correspond to the following,: 0=no discomfort;
0.5=slight sting; 1=noticeable squeeze/discomfort; 2¨pain for less than 30 minutes; 3=pain for 1 hour or more; and 4¨severe to intolerable pain.
[0253] The efficacy index is demonstrated in Figure 3. in brief, the score is calculated by multiplying the lines of improvement in near visual acuity by the number of hours the improvement lasts. For example a score of: 5 is equal to +1 lines of improvement in near visual acuity for 5 hours; 10 is equal to +1.5 lines of improvement for 6.7 hours; 15 is equal to 2 lines of improvement for 7.5 hours; 20 is equal to 2.5 lines of improvement for 8 hours; 25 is equal to 3+ lines of improvement for 8.3 hours and 35 is equal to 3.75-1- lines of improvement for 9 hours.
[0254] As demonstrated by comparing the Reading vs. Baseline at 40 cm and Efficacy Indexes of formulas #1,33-#1,37, formulas containing 1.40% or more aceclidine are better at correcting preshyopia than those formulas containing 1.25% aceclidine. Inversely, the lower concentration of aceclidine results in better overall comfort to the user. The addition of 2.5% mannitol to formulas with 1.45% aceclidine improves overall comfort but at the expense of reducing the presbyopic correcting effect (compare #1-37 with #L47.) This reduction in near vision improvement is exacerbated with the addition of 4.0% mannitol (compare #1e47 with 41,48.) Increasing aceclidine concentrations to 1.65% or 1.75% overcome the. reduction in near vision improvement seen with the addition of mannitol (compare #L47 with #L49 and -#1-50,) [0255] Further, formulas containing 1.75% aceclidine and 2.5% mannitol have an increased efficacy and duration in treating presbyopia that is correlated with an increase in polysorbate 80 up to 5.0% and then inversely correlated with a. decrease in CIVIC from 1.45%
to 1..40%
(compare formulas #1,66 to AL78.) Optimal formulations are demonstrated by .#1,77, #1_,78 and #L85-#1,94, which each have the highest improve reading at 40 cm at between 3.5 and 3.75 visual acuity lines and the highest Efficacy Index scores of 25 to 34, and the longest duration from 7 to 9 hours. The increase in effectiveness and duration of formulas from 41-66 to #1_,78 are also inversely correlated with a decrease in tropicamide from 0,0275% to 0.01%. This same trend is demonstrated by the increase in effectiveness (i.e. Reading vs.
Baseline 40 cm) when comparing itL85 through #1-94.
[0256) This data demonstrates that mannitol can effectively reduce ciliary spasms caused by aceclidine, -thus reducing the need for a cycloplegic agent such as tropicamide. Further, this data demonstrates that the addition of a non-ionic surfactant and viscosity agent can further enhance the efficacy and duration of compositions containing aceclidine, mannitoi and low tropicarnide.
This data also demonstrates that the use of a cyclopleg,ic agent in aceclidine compositions containing polysorba.te 80 and CIVIC is most beneficial to presbyopic correction when the cycloplegic agent is closer to 0.006% than 0.025%. Finally, this data demonstrates that compositions comprising aceclidine and marmite' are sufficient to correct presbyepia with tolerable pain.
Example 12 Use of .,fiether high iropieamide fbrmulations 102571 The following examples are of aceclidine formulations containing more than 0,03%
tropicamide.
Table 9. High tropicamide formulations F ! #L39 #1LAO #1.:41 , #1 42 .. 41 4' 41 44 [ #I 4c #L46 __________ .Aceclidine 1 45% 1 -45% ' 1 - , - 40%1,40% 1.40%
1 AO% 1A0% I ...1.40%
Tropicamide 0.035% 0.037% 0.040% 0,050% 0.055% 0.00% E 0.08% 0.04% 1 Polyoxyl 40 Stearate . 5.5% 5.5% 5.5% 5.5% 5.5%
5.5% 5.5% ' 5.5%
Citrate ' 0.10% 0710% 0.10% 0.10%
0.10% 0.10% 0.10% 0,10%
Glycerine 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% ' ----------- CMC ........... 0.75% 0.75% 0,75% , 0.75%
0.75% 0.75% 0.75% ' 0.75%
,_ d=-=
NaC1 0.50% 0.50% : 0.50%
0.50% 0.50% ' 0.50%. ' 0..50% 0.50%
, Phosphate buffer 3 , 3 3 ' 3 3 3 3 " 3 . . -5.0 ............................ 5.0 5.0 _. 5.25 5,5 :
5.25 5.0 5.0 .. HK 0.015% I 0 015% . 0.015% 0.015% 0.015% 0.015%
0.015% 0.015%_.
_ Reading vs, Baseline 40 ern 3.5 3.5 1.5 i, .7: 1 1 :. 1 : 3 , Duration (hours) 6 ': 6 : 6 2 2 1 1 .. : 6 ' Ciliary spasm 1 . 0,5 0.5 0.5 0.5 0,5 :
0,5 ' 0,5 .--Stinging; ............... 1.0 I 1.0 1.0 0.5 , 0:25 0.5 1 Distance blur none none none none none none none none :
,----------- Onset (min). 20-17 20-18 20-19 : 20-20 20-21 ' 20-22 20-23 20-24 Redness 1hr (0-4) ' 0.5 I 0.,5 0.5 0.5 , 0.5 , 0.5 Overall comfort fair good good good 000d ' 000d 000d good -.......r,õõ,õõõõõ .,........r.-_____ ...,,,_ Osmolarity hi hi -- , __ hi hi hi hi hi hi . õ . .. .. :
Efficacy index:: I1.
read*dur 21 21 21 4 2 1 1 OVERALL (i-5) ** *I,* : *** * I4*
. . _____ 34*
' IA* 1 ***
i - - -:

Ciliary spasms scores correspond to the fol lowing: 0¨no discomfort;
0.5¨slight sting; 1¨noticeable squeeze/discomfort; 2=pain for less than 30 minutes; 3=pain for 1 hour or more; and 4=severe to intolerable pain.
[02581 As demonstrated by formulas #L39-#L41 and compared to formulas 111..744#1,78 in Table 8, formulas containing about 1.40% to about 1.45% aceelidine, about 0.035% to about 0.04%
tropicamide, about 5.5% polyoxyl 40 stearate and about 0.75% CIMC2. are almost, but not quite as effective at treating presbyopia as formulas containing about 1.65% to about 1.75% aceclidine;
about 2.5% marmitol, about 5% polysorbate 80, about 1.40% CMC foamulas. This effectiveness decreases dramatically when tropicamide is increased to about 0.05% to about 0.08%
tropicamide.
Example 13. Use of a compound containing mannitol Formulation:
aceelidine 1.75% w/v tropicamide 0.006% wtv mannitol 2.5% w/v polysorbate 80 2.75% w/v NaCi 0.5% w/v hydroxypropylmethyl cellulose 0.5% -1.80% Ws, phosphate buffer 3 naM
pH 5.0, and BAK 0.020% as preservative.
Method:
[02591 The subject instilled 2 drops of the above formulation in each eye and the excess wiped .from lids and lashes.
Results:
[02601 Within 20 minutes, near vision improvement of about 3 lines of visual acuity was noted with very slight dimming. Throughout the day near vision remained enhanced with no loss of distance vision. Further, if the subject previously suffered from any mild refractive errors distance vision was improved. Over a 5-8 hour period the pupil begins to slightly recover, and after a few hours the minimal dimming was no longer noted. Both excellent near vision near onset, and possibly still slightly improved near vision continued as the pupil slightly begins to increase from its minimal size earlier in the day.
Example 14. Use of a preferred embodiment optimizing tropicamide and hydroxypropyl methyl cellulose [0261] Composition Aceclidine 1.75% w/v Tropicamide 0.010% w/v Marmitol 2.50% w/v Potysorbate 80 3.50% w/v NaC1 0.50% w/v HIPMC 1.25% w/v BAK 0.02% w/v Phosphate buffer 3 niM
pH 5.00 Method [0262] The subject instilled 2 drops of the above formulation in each eye as I
single drop each eye and a second drop after 5 minutes.
Results:
[0263] Comfort, duration and efficacy were assessed. Stinging upon instillation and over the first hour was minimal with a score of 0.25 out of 4. Redness over the first hour was also minimal with a score of 0.5 out of 4 assessed at 20 minutes. Onset of vision improvement occurred with the first 20 to 25 minutes after instillation. Baseline near vision (i.e. 40 centimeters) was improved by 3.5 lines of visual acuity, improvement in near vision lasted for 8.5 hours. Comparing this formula to those in Table 8, the Efficacy Index score was 29.75.
Substituting HPMC 1.80% w/v with IIPMC 1.65% w/v resulted in a slight reduction in near vision improvement to 3.25 lines of visual acuity and a slight reduction in duration to just over about 6 hour. Comparing this formula to those in Table 8, the Efficacy Index score was 19.5.
Example 1.5. Use of a compound containing mannitol with various nonionic surfactants Compositions 102641 Table 10 lists the active ingredients, excipients and their concentrations for compositions with both tested and prophetic examples of nonionic surfactants.
Methods [0265] The subject independently instilled 2 drops of the above compositions in each eye and the excess wiped from lids and lashes.
Results [0266] All nonionic surfactants tested demonstrate substantial near vision improvement. Of those tested only Brij 35 was marginal due to the significant corneal irritation, hyperemia and reduced duration that resulted. Polysorbate 80 and poly 35 castor oil were most preferred, polyoxyl 40 stearate and poloxamer 407 excellent as well. However, polyoxyl 40 stearate caused a precipitate reaction with cellulose viscosity agents and added other stability issues.
[0267] Comfort and duration for each non-ionic surfactant were also tested and are noted in Table 10. Stinging and Redness are based on a scale of 0 to 4 with 0 being none and 4 being the most severe. Other than Brij 35 stinging and redness were mild to 'nearly absent. Duration was excellent for each nonionic surfactant tested.

Table 10. Comparing efficacy and comfort of various nonionic surfactants .
_______________________________________________________________________________ __________ =
= , , . .
I
77:.-o cu ,... 'A
.i.-, ta 0, 1.) , .., ,L7 ' -,-; rt.) =I= t' ..--, ',a 0 ':-. .,-) ,0 ,- (...:) ,2 - -.>. -. ,. 7.. 5 lon S:Z1. 'ft -E.D t C., :7*: = =
x rl o. --,-,- ._ T.
- p _ '--3 ;-6, '1; *
& "6 : ,:c E-% wiv ------------------------------------- rZ ..
, , .... ..
Aeeelidine 1.75% 1.75% 1.75% 1.75%
1.75% . 1.75% 1.75% .. 1.75% .. 1.75%
Tropic:amide 0.006% 0.006% 0.005% 0,005% 0.005% 0.006% : 0.006%
1 0.006% 0.006%
Mannitol 2.5% 2.5% 2.5% 2.5% 2.5% 2,5% : 2.5%
2.5% 2.5%
Nonionic surfactant 3.5% 3.5% : 3.5% 3,5% :. 3.5% 3.5%
3.5% 3.5% 3:5% .
NaC1 0.50% 0.50% ! 0.50% 0.50% i 0.50%
0.50% , 0.50% I 0.50% 0.50%
FLPIVIC 1,80% 1.80% . 1_80% 1.80% 1.80%
1.80% 1.80% . 1.80% 1.80%
BA.1c. 0.02% 0.02% 0.02% 0.02% 0.02% 0.02% : 0.02%
0,02% 0.02%
Phosphate buffer 3 naM 3 miV1 3 mM :3 rnIVI 3 iril\4 3 mikeli 3 miM 3 tiiM 3 inM
pH 1 5.00 . 5.00 5.00 5.00 5.00 5.00 5.00 5.00 1 5.00 .................. Stinging 0.25 0 0.5 0.5 ? 0-2 0-2 0-2 I. 072 , ___________________________________________________________ Redness lhr 0.5 0.25 0.75 i 2.5 0.25-0.25-- : 0.25- 0.25-................................... _ _________________________ 2.5 2.5 .
.. 2.5 2.5 -Reading vs. 3.75 3.5 3 3 2 2-3.5 :2-3.5 ' 2-3.5 2-3.5 Baseline (40 ern) Duration (hours) 10 9 , ! 4 4-8 4-3 . . .. .
Efficacy Index 37.5 31.5 21 21 8 8-37.5 8-37.5 8-37.5 8-37.5 1 reaedur 1 Onset (min) , 20-25 20-25 20-25 20-25 30-40 20-40 20-40 20-40 20-40 i Example 16. Use of a compound containing optimizing nonionic surfactant and antioxidant additives and concentrations Compositions Accclidine 1.75% wi'v Tropicamide 0.010% \WA/
Marmite' 2.50% wiv Polyserbate 80 4.00% wiv NaC1 0.00% wiv PIPMC 1.25% wiv (high MW equaling viscosity of about 400 cps units) BAK 0.02% ANA/

Sorbate (112% w/v BAK 0.02% ANA=
EDTA 0.01%
Citrate buffer 3 rnM
pH 5.00 Method [0268] 2 subjects instilled 2 drops each of the above formulation in each eye about 5 minutes apart, Results:
Comfbrt, duration and efficacy were assessed. Stinging upon instillation and over the first hour was minimal for each subject with a score of 0,50 out of 4 for about 15 seconds. Redness over the first hour was also minimal for each subject with a score of 0.25 out of 4 assessed at 20 minutes.
Onset of vision improvement occurred with the first 20 to 25 minutes after instillation. For subject 1 baseline near vision (i.e. 40 centimeters) was improved by 4.0 4.25 lines of visual acuity and lasted for 11.5 hours. For subject 2 baseline near vision was improved by 3.5 lines of visual acuity and lasted for 9,5 hours. The Efficacy index score was 47.38 and 33.25, among the highest achieved for any formulation.
Example 17. Aceelidine compositions.fbr Cold Chain Storage (prophetic) Table 11. Cold Chain Storage Compositions Composition CS#1 CS#2 . CS#3 CS#4 CS#5 CS#6 CS#7 CS#8 Aceclidine L75% 1.75% 2.50% 4.00% 2.00% 1.65% 1.75% 1.75%
Mannitol 2.50% 2.50% 2,50% 2.50% 2.50% 2.50% 2.50%
............ . ..........
Polysorbate 80 4.00% .. 4.00% 4,00% 4,00% 4.00% 4.00% 4.00%
HPMC
1 1.25% 1.25% . 1,25% 1,25% 1.25% 0.75% 1.10%
1,10%
Sodium Citrate 0.10% 0.10% 0.10% 0.10% 0.10%
0.10% = 0.10%
BAK_ 0.02% 0.02% 0.02% 1 0.02% 0.02% 0.02%
Sorbie Acid 0.12% 0.12% 0.10% 0,12%
0,12% 0,12% 1 0.12% 0_12%
Disodium Edetate 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%
Dihydrate ............................................... -....................................
.5 1 Sodium =
0.10% .. -.. ...=-...... .....
Ascorbate L..._ _________________ : Sodium 0.10%
bisulfate Sodium - - - - 0.10%
' metabisulfite .................... ., ........
, pH 1 5.0 6.0 6.0 6.5 6.5 7.0 5.0 6.0 . .
.
N2 fill/purge 7- Yes Yes Yes Yes Yes I
No No I No Table 11. Cold Chain Storage Compositions (cont'd) Composition CS#9 1 CS#10 CS#11 CS#12 CS#13 CS#14 FCSit15 .CS#16 .
Aceelidine 4.00% 0.50% 2.50% 3.00% 4.00% 4.00% 4.00i'70 4.00% .
Mannitol ;- - ..- - - - ----. Polysorbate 80 ' - - - .-- - -' HPMC - --- - 0.75% 1.25% 1.25% 1.25% 1.25%
. __ . __________________________________________ Sodium Citrate ¨ - _I - - .. 0.10% - -B AK - - - - - ..
- .. ----t _____________________________________________ L ,, ,. .. .
r¨Suibie Acid . - - - ... .. ... ...
Disodium ! , Edetate - - -.= - - - --, Dihydrate . . =
Sodium - .:.
Aseorbate .. i . .
Sodium :
- - - - -0.10% -bisulfate . .
Sodium , _ _ - ... -. _ .. 0.10%
metabisulfite =
pH 5.0 7.0 6.0 6.0 6.0 6.0 6.0 6.0 ____________________________________________ 1 -________________________________ , N2 fill/purge No No Yes Yes Yes 1 1.-- Yes Yes Yes ____________________ . t Table 11. Cold Chain Storage Compositions (cont'd) Composition CS#17 CS#18 C S#19 CS#20 .Aceclidine 4.00% 4.00% 4.00% 4.00%
Mannitol 2.50% 2.50% 2.50% 2.50%
. .
Polysorbate 80 4.00% 4.00% 4.00% 4.00%
HPMC L25% L25% 1.25% 115%
Sodium Citrate 0.10% 0.25%
BAK 0.02%
0.02% 0.02% 0.02%
Sorbic Acid 0.12% 0.12% 0.12%
0.12%
Disodium Edetate Dihydrate Sodium Ascorbate Sodium 0.10%
bisulfate Sodium 0.10%
metabisuffite pH 6.0 6.0 6.0 6.0 N2 fill/purge Yes Yes Yes-7 Yes Methodc [02691 Aceclicline cold chain storage compositions CS#1-5 and 11-20 were filled into vials each under a nitrogen overlay followed by a nitrogen purge of remaining headspace.
CS46-10 were filled into vials each under ambient air and headspace. 1 vial of each composition was stored at 25 degrees Celsius and the other was stored at 5 degrees Celsius.
Results Table 12, Aceclidine Cold Chain Storage Composition Stability Composition CS#9 C#10 CS#11 CS412 C'.S#13 CS414 õ
25 Celsius 90% 4 5 , Stability weeks) == _______________________ ;= =
Celsius !
90% 7 12 12.5 15 18 Stability (months) =
==
=
Table 12. Aceclidine Cold Chain Storage Composition Stability (cont'd) r...Composition C S415 CS#16 J CS#17 CS#18 (S19 CS#20 25 Celsius 90% Stability . (weeks) ! 5 Celsius 90% Stability 18 13 = 20 20 20 22 (months) ____________________________ I.=
[0270] As seen in Figure 4, CS#3-5 contaiing 0.10% sodium ascorbate, 0.10%
sodium bisulfate or 0,10% sodium metabi,sulifite were stable for about 2 months at 25 degrees Celsisus and for about 26 months at 5 degrees Celsius, [0271] As seen in Table 12, filling vials under a nitrogen overlay and nitrogen purge of the headspace resulted in a cold storage stability increase of 4-5 months, The addition of I-IPMC
further increased stability another 3 months; sodium citrate, sodium bisulate or sodium metabistilifite another 3 months; and the further addition of sorbic acid and BAK another 2 months further increased the length of stability. CS#20 increased stability up to 22 months.
Example 18. Stability in Mylar lined Pouches [0272] .Aceclidine formulations of the present invention were placed in containers that were subsequently placed in biaxially-oriented polyethylene tereplithalate lined pouches at -20, 5 and 25 C for up to 3 months. Aceclidine total related substances was recorded at 1, 2, 3 and 6 months. Results of this study can be seen in Table 13, below.
[0273] Mylar was used as the source of biaxially-oriented polyethylene terephtbalate. Mylar is a registered trademark of and available from DuPont Teijin Films US Limited, Table 13, Aceclidine Total Related Substances after Storage C-onclitions Initial RestitTOne Month Resuit'ITwo Month Reseitrktee Month .Result Si.* Month Result (Total / I
i lin tithed 5C ---I, 0.55% ________ , 1-=
0.51% z: 0.09%
0.444.S Z O. 014%
. i., - õ¨ ¨
= õ
Un.ouc ed (2 =C
. ......................................................................... Z
= . _ _, ert 5C' .. i 0 S4% .. i .: : :
1 0 11S% i 0 .4-i%
z= , ,,, , f ....v.,. , i....., ... ......, , Pouched 250 0A1% 0.S1*
i ... -- /.-i . Pouched 20C'- t 0'I$% i :: : :i!::::,::: ,i,,,,,: ,,:, : ,::,', Z.
i:.: :: ::::.::::: :: .::::::.: :: ..:.: t.. 02% Z OM%
stkAti%
Pouched SC,:- -$ i3 ei,m.. 1:: . .:i::::
:::::.:.::;:;:; .i::;:;: ::.:i::. - ..., .------L.::¨....--: ::.:::.:...:.: ::
,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Pouched-(25C) 1 .:t'% i':: .
..
102741 As seen in Table 13, the use of a Mylar lined pouches helped maintain aceclidine potency by reducing degradation rate. Specifically, compare Unpouched at room temperature (25 C) total % change of 4.46% to the -0.05% and 0.041% total % change of Pouched at room temperature (25 C).
Example 19. Aceclidine Potency following Storage [0275] Aceclidine formulations of the present invention were placed in containers that were subsequently placed in biaxially-oriented polyethylene terephthalate lined pouches at -20, 5 and 25 C for up to 3 months. Aceclidine potency was recorded at 1, 2, 3 and 6 months. Results of this study can be seen in Table 14, below.
Table 14. Aceclidine Potency after Storage 1 ..............................................
1 f 1 1 __________ ,--3 Percent Change , (Between initial and PTP.le initial Rewit One klenth Result Two Month Result Three Month Resulti Six Month Result I $ix Month Reuslt* , I Unpouched (5C) i 99.3% t ¨
i 1020% It-10.W, .. VAL 5%
....
itinpouched (25c) .94..10%101 9%
i.' . 98.2% 97.7%
= M: , Pouched (5C) X' 0% 1,:i'il.*:
):::.....:::::..:::!1:i.....:.1::6i!I 99.7% 10a e% 1.1%
Pouched (25C) __ 9$.4% ......,,i,iNiO:MiUM4 97.5% 94.9%
Pouched (-25C) .. 98.5% !:::.:.::::::......: ..: . ..,:,:,:,i:i::
101.4% 1011% IS%
Pouched (5C) 99,60% 99.6% r.H..i..'' .: .. . : . .. q 10?..3'A . . .102.2% 26% :
. ¨
i Pouched (25C) 103.0% ,., 99.0%
96.0% I .. 3.5%
, ................ ,.. . . .
3.---, .....
[0276] As seen in Table 14, the use of 5 degrees Celsius storage helped maintain aceclidine potency. Specifically, compare Unpouched at room temperature (25 C) total %
change of -2.0%
potency to the 0.8% change of Unpouched in cold storage (5 C) for the initial result of 99.70%
and compare Unpouched at room temperature (25 C) total % change of 3.6%
potency to the 2.6% change of linpouched in cold storage (5 C) for the initial result of 99.60%.

Claims (24)

  1. WHAT IS CLAIMED IS:
    I. A inethod of stabilizing an ophthalmic drug comprising the following steps:
    a) adding a surfactant and a viscosity enhancer to the ophthahnic drug to create a composition wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 eentipoise or more at shear rate of 1 per second at 25 degrees Celsius;
    b) tilling the composition from step a) into a container; and c) storing the container at a temperature from about 2 degrees Celsius to about 25 degrees Celsius.
  2. 2. The method of claim I, wherein the ophthalmic drug is selected from the group consisting of aceelidine, latanoprost and cOmbinations thereof,
  3. 3. The method of claim 1 , wherein the ophthahnie drug is aceelidine.
  4. 4. The. method of claim I, wherein the surfactant is selected from the.
    group consisting of polysorbates, poloxamers, polyoxyl alkyls, cyclodextrins, anunonium lauryl sulfate, dioctyl sodium sulfosuceinate, sodium laureth sulfate, linear alkylbenzene sulfonate, sodium dodecyl sulfate, perfluorootanesulfonate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pared/
    sulfate, sodium stearate, lignosulfonate, sodium lauryl sulfate, a olefin sulforiate, ammonium laureth sulfate, sodium ester lauryl sulfate, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetylpyridinium chloride, alkyl-dimethyl dichlorobenzene ammonium chloride, dequalinium chlorid.e, phenamylinium chloride, cetyl trimethylammonium bromide, cetyl trimethylammonium chloride, cetrimonium bromide, cethexonium bromide, alkyl-amphoacetates, alkenyl-amphoaeetates, alkyl-amphodiacetates, alkenyl-arnphodiacetates, alkylamphopropionates, alkylamphodipropionates, alkyl amphohydroxypropyl sultaines and combinations thereof.
  5. 5. The rnethod of claim 1, wherein the viscosity enhancer is selected from the group consisting of gums, cellulose derivatives, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, gellan, carrageenan, alginic acid, earboxyvinyl polymer and combinations thereof.
  6. 6. The method of claim 1, wherein the viscosity at shear rate of 1 per second at 25 degrees Celsius is about 150 eentipoise or more.
  7. 7. The method of claim 6, wherein the viscosity at shear rate of 1 per second at 25 degrees Celsius is about 300 centipoise or more.
  8. 8. The method of claim I., wherein the container is stored at a temperature from about 2 to about 8 degrees Celsius.
  9. 9. The rnethod of claim 8, wherein the container is stored at a temperature of about 5 degrees Celsius.
  10. 10. The method of claim 1, wherein the composition is filled into the container under an inert gas overlay.
  11. 11. The method of claim 1, wherein the filling step creates a headspace in the container and the headspaee is purged with an inert gas.
  12. 12, The method of claim I, wherein the container comprises a closure and a vessel wherein a portion of the closure and a portion of the vessel are sealed with an anti-leaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetralluorethylene and aluminum foil.
  13. 13. The method of claim I, wherein the container is disposed in a second container that is formed with or lined with an anti-leaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil.
  14. 14. A container comprising an ophthalmic drug prepared by the process comprising the. steps of:
    a) providing a container;
    b) filling the container with a composition comprising an ophthalmic drug, a surfactant and a viscosity enhancer, preferably under an inert gas overlay, preferably nitrogen, wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 centipoise or more at shear rate of 1 per second at 25 degrees Celsius;
    c) capping the container; and d) storing the container at a temperature from about 2 to about 25 degrees Celsius.
  15. 15. The container of claim 14, wherein the ophthalmic drug is selected from the group consisting of aceclidine, latanoprost and combinations thereof.
  16. 16. The container of claim 1.4, wherein the ophthalrnic drug is aceclidine.
  17. 17. The container of claim 14, wherein the surfactant is selected from the group consisting of polysorbates, poloxamers, polyoxyl alkyls, cyclodextrins, ammonium lauryl sulfate, dioctyi sodium sulfosuccinatc, sodium laureth sulfate, linear alkylbenzene suifonate, sodium dodecyl sulfate, perfhtorooctanesulfbnate, sodium lauryi sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, lignosulfonate, sodium lauryl sulfate, a olefin sultbnate, ammonium laureth sulfate, sodium ester lauryl sulfate, ben2-alkonium chloride, benzethonium chloride, methylbenzethonium chloride, eetylpyridinium chloride, alkyl-dimethy1 dichlorobenzene ammonium chloride, dequalinium chloride, phenamylinium chloride, cetyl trimethylarnmonium bromide, cetyl trimethylammonium chloride, cetrimonium bromide, eethexonium bromide, alkyl-arnphoacetates, alkeny l-amphoacetates, alkyl-amphodiaeetates, alkenyl-amphodiacetates, alkylanaThopropionates, alkylamphodipropionates, alkyl amphohydroxypropyi suhaines and combinations thereof.
  18. 18, The container' of claim 14, wherein the viscosity enhancer is selected from the group consisting of gums, cellulose derivatives, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, gellan, carrageenan, alginic acid, carboxyvinyl polymer and combinations thereof
  19. 19. The container of claim 14, wherein the viscosity at shear rate of 1 per second at 25 degrees Celsius is of about 150 centipoise or more.
  20. 20. The container of claim 19, wherein the viscosity at shear rate of 1 per second at 25 degrees Celsius is of about 300 eentipoise or more.
  21. 21. The contain.er of claim 14, wherein the container is stored at a temperature from about 2 to about 8 degrees Celsius.
  22. 22. The container of claim 21, wherein the container is stored at a temperature of about 5 degrees Celsius.
  23. 23. The container of claim 14, wherein after step b) and prior to step c) a headspace created during the filling step is purged with an inert gas.
  24. 24. The container of claim 14, wherein the inert gas is nitrogen
CA3195422A 2020-10-13 2021-04-28 Compositions and methods for storage stable ophthalmic drugs Pending CA3195422A1 (en)

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CA2702478C (en) * 2007-10-16 2014-12-09 Sun Pharma Advanced Research Company Limited Ophthalmic composition
US20190038609A1 (en) * 2013-08-28 2019-02-07 Presbyopia Therapies, LLC Compositions and methods for the treatment of presbyopia
CA2987783A1 (en) * 2015-06-18 2016-12-22 Presbyopia Therapies, LLC Storage stable compositions and methods for the treatment of refractive errors of the eye
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