EP4228636A1 - Compositions and methods for storage stable ophthalmic drugs - Google Patents

Compositions and methods for storage stable ophthalmic drugs

Info

Publication number
EP4228636A1
EP4228636A1 EP21880707.1A EP21880707A EP4228636A1 EP 4228636 A1 EP4228636 A1 EP 4228636A1 EP 21880707 A EP21880707 A EP 21880707A EP 4228636 A1 EP4228636 A1 EP 4228636A1
Authority
EP
European Patent Office
Prior art keywords
aceclidine
concentration
container
degrees celsius
viscosity
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21880707.1A
Other languages
German (de)
English (en)
French (fr)
Inventor
Gerald Horn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lenz Therapeutics Operations Inc
Original Assignee
Lenz Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US17/069,155 external-priority patent/US11273150B2/en
Application filed by Lenz Therapeutics Inc filed Critical Lenz Therapeutics Inc
Publication of EP4228636A1 publication Critical patent/EP4228636A1/en
Pending legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • ophthalmic drugs must be diluted just prior to instillation or if pre-formulated have a limited shelf life or require cold storage.
  • Current ophthalmic drugs that suffer from stability issues include aceclidine, latanoprost, latanoprost-timolol, chloramphenicol, azasite, cyclopentolate, proteins, peptides, amino acids and their derivatives.
  • Aceclidine has been shown effective for the treatment of glaucoma. Current aceclidine formulations require lyophilization of the aceclidine and mixing with a diluent just prior to instillation. 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;
  • T hus there is a need in the art for a method of stabilizing ophthalmic drugs such that an increase in shelflife is achieved.
  • 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 5 degrees Celsius.
  • 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.
  • 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 antileaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil, preferably biaxially-oriented polyethylene terephthalate.
  • 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, polytetrafluorethylene and aluminum foil, preferably biaxially-oriented polyethylene terephthalate.
  • 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 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.
  • the second container comprises a second closure, wherein the second closure provides an airtight seal.
  • the airtight seal is resealable.
  • the ophthalmic drug is aceclidine is at a concentration from about 0.25% to about 4.0% w/v aceclidine.
  • the methods of the present in vention 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.
  • 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 1 per second at 25 degrees Celsius.
  • compositions of the present invention has a viscosity from about 75 to about 1,000 centipoise at a shear rate of 0.
  • the present invention is directed to a method of stabilizing a composition comprising aceclidine, hydroxypropylmethyl 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.
  • the aceclidine 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
  • the antioxidant is at a concentration from about 0.10% to about 0.25% w/v.
  • 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 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 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 5 degrees Celsius.
  • 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.
  • 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.
  • the present invention is directed to a composition
  • a composition comprising from about 0.25% to about 4.0% w/v aceclidine 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, benzalkonim chloride, sodium ascorbate, sodium bisulfate, sodium metabisulfite, n-acetyl 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.
  • 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.
  • 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.
  • the present invention is further directed to a method of increasing the visual depth of field (i.e. depth of focus) secondary to pupil miosis, comprising administering to a subject in need thereof a pharmaceutically effecti ve amount of an ophthalmological composition of the present invention.
  • 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 ciliary body of the eye such that ciliary spasm, ciliary induced brow ache, and/or ciliary induced headache are substantially reduced or eliminated.
  • the present invention is further directed to a method of allowing binocular physiologic topical presbyopic correction.
  • the present invention is further directed to a method of eliminating the need for monocular limitation 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 mm 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.
  • DLK diffuse lamellar keratitis
  • the present invention is further directed at improving acuity relative to existing uncorrected refractive error.
  • 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 l onger require correction.
  • Patients with small to moderate degrees of hyperopia (farsightedness) may require no correction or reduced correction.
  • the present invention is directed to methods and ophthalmological compositions for improving eye sight.
  • the present invention is directed to methods and ophthalmological compositions for the treatment of presbyopia.
  • the present invention is directed to ophthalmological compositions comprising aceclidine.
  • the present invention is directed to methods of treating irregular astigmatism, keratoconic ectasia, and low myopia, or hyperopia, with or without astigmatism, comprising administering to a subject in need thereof an ophthalmological composition of the present invention.
  • the present invention is further directed to a method of stabilizing aceclidine comprising providing a first composition comprising about 1.75% w/v aceclidine and about 2.5% w/v mannitol in a first chamber and a second composition comprising about 0.01% w/v tropicamide, about 4.0% w/v polysorbate 80, about 1.25% w/v hydroxy propylmethyl 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.
  • 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.
  • 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.
  • 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.
  • Figure 3 is a graphical representation of the Efficacy Index for formulas #L33-#L94. Box color denotes a comfort level of good for white, fair for cross-hatched and poor for black.
  • Figure 4 is a graphical representation of percent stability of aceclidine cold storage compositions at 5 and 25 degrees Celsius over 30 months.
  • 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 and storing the composition in a container.: Definitions
  • 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.
  • stabilizing refers to any process which facilitates and/or enables an active agent to remain in solution.
  • stabilizing also refers to any means or process which inhibits and/or reduces the tendency of an active agent including a muscarinic agonist, including aceclidine, to degrade.
  • % w/v refers to the percent wei ght of the total composition.
  • the term “subject” refers but is not limited to a person or other anima]
  • 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.
  • 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.
  • cap or “closure” refers to any article capable of preventing the composition from exiting the container.
  • muscarinic receptor agonist encompasses agonists that activate muscarinic acetylcholine receptors (“muscarinic receptors”). Muscarinic receptors are divided into five subtypes named Ml -M5. Muscarinic agonists of the present invention include those muscarinic agonists that preferentially activate Ml and M3 receptors over M2, M4 and M5 receptors (“M1/M3 agonists”).
  • M1/M3 agonists include but are not limited to aceclidine, xanomeline, talsaclidine, sabcomeline, cevimeline, alvameline, arecoline, milameline, SDZ-210- 086, YM-796, RS-86, CDD-0102A (5-[3-ethyl-l,2,4-oxasdiazol-5-yl]-l,4,5,6- tetrahydropyrimidine hydrocholoride), N-arylurea-substituted 3-morpholine arecolines, VUO255-035 (N-[3-oxo-3-[4-(4-pyridinyl)-l-piperazinyl]propyl]-2,l,3-benzothiadiazole-4- sulfonamide), benzylquinolone carboxylic acid (BQCA), WAY-132983, AFB267B (NGX267), AC-42, AC-
  • a preferred M1/M3 agonist is aceclidine.
  • muscarinic agonist of the present invention include those muscarinic agonist that preferentially activate Ml and M3 over M2, M4, and M5; and even more preferably activate Ml over M3.
  • muscarinic agonist of the present invention include those muscarinic agonists that only activate Ml .
  • aceclidine encompasses its salts, esters, analogues, prodrugs and derivatives including, but not limited to, aceclidine as a racemic mixture, aceclidine (+) enantiomer, aceclidine (-) enantiomer, aceclidine analogues, including, but not limited to, highly Ml selective 1 ,2,5 thiadiazole substituted analogues like those disclosed in Ward. J.S.
  • a-2 adrenergic receptor agonists or “a-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.
  • 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.
  • 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.
  • brimonidine encompasses, without limitation, brimonidine salts and other derivatives, and specifically includes, but is not limited to, brimonidine tartrate, 5-bromo-6-(2- imidazolin-2 ⁇ ylamino)quinoxaline D-tartrate, and Alphagan®.
  • 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.
  • 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).
  • the term “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.
  • prodrugs refers to compounds, including, but not limited to, monomers and dimers of the compounds of the invention, which have cleavable groups and become, under physiological conditions, compounds which are pharmaceutically active in vivo.
  • 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.
  • 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.
  • cold chain refers to storage at temperatures from about 2 to about 8 °C from manufacture to immediately prior to administration.
  • the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids or bases.
  • 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 animal s 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. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • 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-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pahnitoate, pectinate, persulfate, 3 -phenylpropionate, picrate, pivalate, propionat
  • the basic nitrogen-containing groups can be quaternized 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 diamyl 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 oilsoluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates: long chain halides such as decyl, la
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, hyaluronic 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.
  • 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.
  • 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 on 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, methylammonium, dimethylammonium, trimethyl ammonium. tri ethylammonium, di ethylammonium, and ethylammonium among others,
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • esters as used herein is represented by the formula — OC(O)A ! or — C(O)OA‘, where A f can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, a heteroaryl group or other suitable substituent.
  • 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; b) fi Lling 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
  • 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.
  • 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.
  • 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 antileaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil, preferably biaxially-oriented polyethylene terephthalate.
  • 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, polytetrafluorethylene and aluminum foil, preferably biaxially-oriented polyethylene terephthalate.
  • 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 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.
  • the second container comprises a second closure, wherein the second closure provides an airtight seal.
  • the airtight seal is resealable.
  • the ophthalmic drug is aceclidine is at a concentration from about 0.25% to about 4.0% w/v aceclidine.
  • 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.
  • 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 1 per second at 25 degrees Celsius.
  • compositions of the present invention has a viscosity from about 75 to about 1,000 centipoise at a shear rate of 0.
  • the present invention is directed to a method of stabilizing a composition comprising aceclidine, hydroxypropylmethyl 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.
  • the aceclidine 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
  • the antioxidant is at a concentration from about 0.10% to about 0.25% w/v.
  • 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 centipoise 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 ni trogen ; 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 Celsisus and more preferably at about
  • the present invention is directed to a composition
  • a composition comprising from about 0.25% to about 4.0% w/v aceclidine 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, benzalkonim chloride, sodium ascorbate, sodium bisulfate, sodium metabisulfite, n-acetyl 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,
  • Ophthalmic drugs suitable for use in the present invention include, but are not limited to, aceclidine, latanoprost, latanoprost-timoiol, chloramphenicol, azasite, cyclopentolate, proteins, peptides, amino acids, salts thereof, derivatives thereof and combinations thereof
  • Surfactants suitable for use in the present invention include nonionic, ionic and amphoteric (zwitterionic) surfactants.
  • the surfactant used in the present invention are at a concentration above the critical micellar concentration for that surfactant.
  • Nonionic surfactants suitable for the present invention include cyclodextrins, polyoxyl alkyls, poloxamers, polysorbates or combinations thereof.
  • Preferred embodiments include Poloxamer 108, Poloxamer 188, Poloxamer 407, Polysorbate 20, Polysorbate 80, ionically charged (e.g. anionic) beta - cyclodextrins with or without a butyrated salt (Captisol®) 2- hydroxypropyl beta cyclodextrin (“HPpCD”), alpha cyclodextrins, gamma cyclodextrins, Polyoxyl 35 castor oil, and Polyoxyl 40 hydrogenated castor oil or combinations thereof.
  • ionically charged e.g. anionic beta - cyclodextrins with or without a butyrated salt (Captisol®) 2- hydroxypropyl beta cyclodextrin (“HPpCD”)
  • 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, hydroxypropyl- y- cyclodextrin, randomly methylated P-cyclodextrin, p-cyclodextrin sulfobutyl ether, y- cyclodextrin sulfobutyl ether or glucosyl- P- cyclodextrin, any cyclo
  • 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.
  • 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.
  • 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 lauryl sulfate, dioctyl sodium sulfosuccinate, sodium laureth sulfate, linear alkylbenzene sulfonate, sodium dodecyl sulfate, perfluorooctanesulfonate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearte, lignosulfonate, sodium lauryl sulfate, a olefin sulfonate, ammonium laureth sulfate and sodium ester lauryl sulfate.
  • Cationic surfactants suitable for use in the present invention include, but are not limited to benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetylpyridinium chloride, alkyl-dimethyl dichlorobenzene ammonium chloride, dequalinium chloride, phenamylinium chloride, cetyl trimethylammoniurn bromide, cetyl trimethylammoniurn chloride, cetrimonium bromide and cethexonium bromide.
  • 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 sultaines wherein the alkyl groups contain 8 to 24 carbon atoms such as coco or lauryl.
  • Surfactants may be used in the present invention at a concentration above their critical micellar concentration.
  • the critical micellar concentration for any particular surfactant may be calculated by a person of skill in the art.
  • 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 1) 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.
  • Ophthalrnological in situ gels which may be substituted for or added in addition to one or more surfactants include but are not l imited to gelatin, carbomers of various molecular weights including carbomer 934 P and 974 P, xanthan gums, alginic acid (alginate), guar gums, locust bean gum, chitosan, pectins and other gelling agents well known to experts in the art.
  • 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.
  • Viscosity agents suitable for the present invention include, but are not limited to gums such as guar gum, hydroxypropyl-guar (“hp-guar”), and xanthan gum, alginate, chitosan, gelrite, hyauluronic acid, dextran, Carbopol® (polyacrylic acid or carbomer) including Carbopol® 900 series including Carbopol® 940 (carbomer 940), Carbopol® 910 (carbomer 910) and Carbopol® 934 (carbomer 934), cellulose derivatives such as carboxymethyl cellulose (“CMC”), methylcellulose, methyl cellulose 4000, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyl propyl methyl cellulose 2906, carboxypropylmethyl cellulose, hydroxypropylethyl cellulose, and hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, poly
  • Viscosity agents may be used in the present invention at a concentration necessary 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.
  • compositions of the present invention has a viscosity from about 75 to about 1,000 centipoise at a shear rate of 0.
  • 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.
  • 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.
  • nonionic surfactant / viscosity combinations may result in phase separation over time with precipitate formation.
  • poiyoxyl 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 poiyoxyl nonionic surfactant, such as polysorbate 80 with either a cellulose derivative or noncellulose derivative viscosity agent may be substituted.
  • 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 poiyoxyl nonionic surfactant, such as polysorbate 80 with either a cellulose derivative or noncellulose derivative viscosity agent may be substituted.
  • the viscosity’ agent is carboxymethyl 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.
  • 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%.
  • compositions of the present invention may further comprise cryoprotectants, polyols, bulking agents, solubilizers, antioxidants, tonicity adjustors, preservatives, Cryoprotectants are compounds that either prevent freezing or prevent damage to compounds during freezing.
  • cryoprotectant or “cryoprotectants” include lyoprotectants.
  • Cryoprotectants 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-methyl-2,4-pentanediol, cellobiose, gelatin, polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), formamide, antifreeze protein 752 or a combination thereof.
  • PEG polyethylene glycol
  • DMSO dimethyl sulfoxide
  • polyol refers to compounds with multiple hydroxyl functional groups available for organic reactions such as monomeric polyols such as glycerin, pentaerythritol, ethylene glycol and sucrose.
  • polyols may refer to polymeric polyols including glycerin, pentaerythritol, ethylene glycol and sucrose reacted with propylene oxide or ethylene oxide
  • polyols are selected from the group consisting of mannitol, glycerol, erythritol, lactitol, xylitol, sorbitol, isosorbide, ethylene glycol, propylene glycol, maltitol, threitol, arabitol and ribitol.
  • the polyol is mannitol.
  • Sugars suitable for use in the present invention as cryoprotectants include, but are not limited to, glucose, sucrose, trehalose, lactose, maltose, fructose and dextran.
  • alcohols include, but are not limited to, methanol.
  • the present invention individually excludes each cryoprotectant from the definition of cryoprotectant.
  • 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.
  • lower alkanols include C1-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.
  • Bulking agents suitable for use in the present invention include, but are not limited to, saccharide, polyvinylpyrrolidone, cyclodextrin and trehalose.
  • Solubilizers suitable for use in the present invention include, but are not limited to, cyclic amide, gentisic acid and cyclodextrins.
  • antioxidants suitable for use in the present invention include, but are not limited to, bisulfite, ascorbic acid, disodium- or tetrasodium ethylenediaminetetraacetic acid, citrate, butylated hydroxy anisole (“BHA”), butylated hydroxytoluene (“BHT”), a sulfoxylate, propyl gallate, an amino acid containing a thio group, and a thiol.
  • 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% w/v, preferably about 0.01% w/v CaZDTPA which can be formulated by adding 0.0084% w/v Ca(OH)2 and 0.0032% w/v pentetic acid to theformulation and mixing slowly.
  • Ca2DTPA dicalcium diethylenetriamine pentaacetic acid
  • CaZDTPA dicalcium diethylenetriamine pentaacetic acid
  • Other antioxidants that can be used with the present invention include those well known to experts in the art such as ethylenediaminetetraacetic acid at a concentration from about 0.0001% to about 0.015% w/v.
  • a tonicity adjustor can be, without limitation, a salt such as sodium chloride (“NaCl”), potassium chloride, mannitol or glycerin, or another pharmaceutically or ophthalmologically acceptable tonicity adjustor.
  • a salt such as sodium chloride (“NaCl”), potassium chloride, mannitol or glycerin, or another pharmaceutically or ophthalmologically acceptable tonicity adjustor.
  • the tonicity' adjustor is 0.037% w/v NaCl
  • Preservatives that can be used with the present invention include, but are not limited to, benzalkonium chloride (“BAK”), sorbic acid, oxychloro complex, citric acid, chlorobutanol, thimerosal, phenylmercuric acetate, disodium ethylenediaminetetraacetic acid, phenylmercuric nitrate, perborate or benzyl alcohol.
  • the preservative is BAK, sorbic acid, oxychloro complex or a combination thereof.
  • B AK 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.
  • 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.
  • 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 mM concentration, and more preferably about 3 mM or 5 mM.
  • 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 7.0.
  • Acechcune One ophthalmic drug that may be stabilized by the methods of the present invention is aceclidine.
  • Aceclidine 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.
  • aceclidine Double-blind cross-over comparison of aceclidine and pilocarpine in open-angle glaucoma, BritJ Ophthal, Aug 1970, 54(8), 510-521 .
  • 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 of miosis 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 mm at the anterior iris plane and about 2.0 mm at the corneal surface.
  • 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 D or less creating a sum increase that may in some cases 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 miosis 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® corneal inlays, allowing binocular treatment without peak dimming.
  • 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-comeal pinholes created by the inlays.
  • Further pupil miosis provides a greater field of vision and transmission of more focused light, and in a discovered optimal pupil range of about 1.5 mm to 2.1 mm using formulation 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.
  • 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 pilocarpine and carbachol.
  • general muscarinic agonists such as pilocarpine and carbachol.
  • 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.
  • 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 hours in most cases, as the high ratio of accommodation to pupillary 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%.
  • 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 emmetropes 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.
  • 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.
  • 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.
  • 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 many cases improve distance vision as well.
  • aceclidine results in pupil miosis without excessive accommodation and attendant distance blur.
  • aceclidine alone may cause substantial redness and brow ache.
  • 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.
  • 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.
  • 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.
  • 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 penneation 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.
  • 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.
  • a selective a-2 adrenergic receptor agonist such as fadolmidine, brimonidine or guanfacine
  • a selective a-2 adrenergic receptor agonist such as fadolmidine, brimonidine or guanfacine
  • 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 100% of treated subjects within four weeks of use.
  • 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 miotic response.
  • the ratio of 1.40% aceclidine to about 0.040% tropicamide 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 mannitol, where 2.5% provides better effect than 4.0%.
  • cycloplegic agents such as tropicamide
  • cycloplegic agents have known pupil dilating effects at concentrations as low as 0.01% w/v (Griinberger J. et al., The pupillary response test as a method to differentiate various types of dementia. Neuropsychiatr, 2009, 23(1), 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.
  • concentrations of tropicamide discovered in the present invention apparently cause more relaxation of the ciliary muscle than the iris radial musculature.
  • 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.
  • 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).
  • 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 cycloplegic required to further eliminate mild, but potentially bothersome, ciliary side effects particularly in younger presbyopes and further modulate pupil miosis over aceclidine and a cryoprotectant combinations alone, reducing and in most cases eliminating any bothersome peak concentration dimming, as found in preferred embodiments of the present invention.
  • 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;
  • 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.
  • HPMC hydroxypropylmethyl cellulose
  • 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.
  • sodium chloride is added in a preferred embodiment.
  • sodium chloride may be substituted with boric acid, preferably at 0.35% or potassium borate, preferably at 0.47%;
  • 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 micromicaliar or nanomicellar range. 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.
  • 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%.
  • 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.
  • a minimal micelle diameter is achieved before significant multiple lamellae (layering) occurs.
  • nanomicelles of about 100 to 250 run along the surface are achieved surrounding the highly charged and hydrophilic aceclidine, facilitating its penetration through the very lipophilic epithelium;
  • BAK 0.02% to sorbate about 0.10%, EDTA about 0.10%, in a preferred composition of aceclidine 1.75%, mannitol 2.5%, tropicamide 0.0.1%, and citrate buffer (1 to 100 mM 3-5 mM preferred) is above the BAK critical micellar concentration.
  • BAK being a cationic surfactant
  • the concentration of such nonionic nucleophiles at a preferred pH in the preferred embodiment is relatively low, bu t 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/mannitol 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;
  • preferred embodiments of the present invention such as containing 1.25% hydroxypropyl 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 Liquigel® 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.
  • conventional high viscosity artificial tear formulations such as Celluvisc® at about 400 cps, which may blur vision for 10-20 minutes or Liquigel® at about 100 cps, which causes similar but slightly reduced blurring causes only about 60 seconds of blur dissipating rapidly with an influx of
  • General miotic agents such as pilocarpine, carbachol and phospholine diesterase, are capable of causing pupil miosis resulting in improved near vision of presbyopic patients.
  • these general miotic agents 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 coadministration of a cycloplegic agent with aceclidine surprisingly results in an attenuation of this reduction in distance vision.
  • 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-hydroxypropyl beta-cyc lodextrin (“HPpCD”), and, sulfobutyl ether derivative of p-cyclodextrin (Captisol ® ), 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® 35(Brij is a registered trademark of Uniqema Americas LLC); a viscosity enhancing agent, such as carboxymethyl cellulose (“CMC”); a tonicity adjustor, such as sodium chloride; a preservative, such as benzalkonium chloride and
  • an increase in the concentration of the nonionic surfactant may result in reduced redness.
  • increasing polysorbate from 0.10% to 0.50 - 1.0% results in reduced redness.
  • increasing CMC or Carbopol® 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.
  • compositions of the present invention comprising a viscosity agent may be from about 1 to about 10,000 cps prior to topical instillation in the eye.
  • the viscosity is lowered to a range from about 1 to about 25 cps at the high shear of blinking, and 50 cps to 200 cps at the low shear between blinks, allowing greater drop retention with less spillage and less nasolacrimal drainage and systemic absorption upon topical instillation.
  • the present invention is directed to an ophthalmological composition
  • an ophthalmological composition comprising aceclidine.
  • 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.
  • 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).
  • polarimetry demonstrated an exactly equal ratio of (+) and (- ) isomer for these concentrations. Altering this ratio could therefore alter this concentration range proportional to a change in ratio.
  • Acidic pH preferably less than 5.5, preferably less than 5.0 and most preferably at a pH of about 4.75;
  • 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%;
  • a cryoprotectant in a preferred embodiment a polyol, preferably Mannitol 2.5% - 4.0%:
  • the present invention is further directed to an ophthalmological composition
  • a muscarinic 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.
  • a viscosity enhancing agent or alternatively an in situ gelling agent.
  • 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).
  • Muscarinic 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% w/v still highly inductive of a-1 receptors and toxic for purposes of the present invention.
  • 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 dexmedetomidine, 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.
  • some degree of useful activity may occur at one or more orders of magnitude further reduction of concentration.
  • brimonidine, fadolmidine and guanfacine 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.
  • preventing or reducing redness for drugs that otherwise directly induce redness such as the acetylcholine agonist, aceclidine, 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.
  • each a-2 agonist has a preferred pH range depending on its lipophilicity and pKa value when added to the inventive compositions with aceclidine.
  • 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 7.0.
  • cyclodextrins and/or poly oxy 140 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 polyoxy 1 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.
  • Brimonidine is highly selective with moderate lipophilicity.
  • 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).
  • borate buffer 5 mM and BAK 0.007% 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.
  • 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.
  • 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.
  • the selective a-2 adrenergic receptor is selected from the group consisting of brimonidine, guanfacine, fadolmidine, dexmedetomidine, (+)-(S)-4-[l-(2,3- dimethyl-phenyl)-ethyl]-l,3”dihydro-imidazole-2-thione, l-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds. Analogues of these compounds that function as highly selecti ve a-2 agonists may also be used in compositions and methods of the present invention.
  • the selective a-2 agonist is selected from the group consisting of fadolmidine, guanfacine and brimonidine.
  • 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.
  • the salt is a tartrate salt.
  • 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 (“HC1”) salt.
  • HC1 hydrochloride
  • 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 HC1 salt.
  • 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 HC1 salt.
  • 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 6.0.
  • redness reduction is achieved at all pHs, and enhancement of aceclidine 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.
  • 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, aceclidine, 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.
  • Cycloplegic agents suitable for the present invention include, but are not limited to, atropine, Cyclogyl® (cyclopentolate hydrochloride), hyoscine, pirenzepine, tropicamide, atropine, 4-diphenylacetoxy-N-m.ethylpiperidine methobromide (4-DAMP), AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin (V esicare), tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium (Spriva), and otenzepad (a.k.a.
  • 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.
  • 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.
  • 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% w/v 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 (surprising due to its common use as a pupil dilating agent).
  • tropicamide did not reduce the mean degree of pupil miosis, the time of onset of pupil miosis or the subsequent visual benefits.
  • tropicamide blunted the peak miosis 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 found with its prior use.
  • tropicamide is useful to prevent transient constriction below 1.50 mm at 30 to 60 minutes following aceclidine in some embodiments and to reduce transient excessive and undesirable dimming of vision that may otherwise occur at peak onset of about 30 minutes.
  • an ophthalmological composition comprising 1.53% w/v aceclidine, 5% w/v HPpCD, 0,75% w/v CMC, 0.25% w/v NaCl , 0.01% w/v BAK and a phosphate buffer at pH 7.0; or 1 .45% w/v aceclidine; 5.5% w/v polyoxy] 40 stearate; 0.80% w/v CMC; 0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK and 5mM phosphate buffer at a pH 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.
  • 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).
  • FIG. 1 shows the effect of a miotic agent with or without a cycioplegic 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 (8b).
  • the carrier increases the beneficial effect of aceclidine resulting in better than 20.20 near vision.
  • lOd a similar increase in distance vision occurs.
  • lOe and 1 Of show the effects of adding 0.042% w/v tropicamide to the aceclidine in the carrier.
  • FIG. 1 shows that aceclidine is capable of temporarily correcting near vision in a presbyopic subject without affecting the baseline distance vision.
  • 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 poly oxy 140 stearate; 0.80% w/v CMC; 0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK; and 5mM 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).
  • 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% w/v and a viscosity agent at a concentration of about 0.75% to about 1.6% w/v, preferably about 1.25% to about 1.5% w/v.
  • 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.
  • 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.
  • 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 mM, wherein the pH is about 5.
  • 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 0.5% w/v;
  • NaCl at a concentration from about 0.10% to about 0.50% 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.
  • the ophthalmologies! 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 2.0% 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 mM, wherein the pH is about 5.25.
  • 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;
  • NaCl 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 0.015% w/v; wherein the pH is about 5,
  • 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;
  • NaCl 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.
  • 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;
  • BAK 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.
  • the ophthalmological cornposition 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.
  • the ophthalmological 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;
  • BzAK 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.
  • 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;
  • 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. wherein the pH is about 5.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.75%w/v; tropicamide at a concentration of about 0.015% w/v; mannitol at a concentration of about 2.5% w/v; polysorbate 80 at a concentration of about 0.75% w/v;
  • NaCI 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;
  • B AK 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.
  • 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% w/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 mM. wherein the pH is about 5.
  • 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;
  • 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.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.75% w/v; tropicamide at a concentration of about 0.040% w/v; poly oxy 1 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.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.55% w/v; tropicamide at a concentration of about 0.040% w/v; poly oxy 1 40 stearate at a concentration of about 5.0% w r /v; citric acid monohydrate at a concentration of about 0.1% w/v; mannitol at a concentration of about 4.0% w/v;
  • Carbopol® 940 at a concentration of 0.09% w/v; and optionally, acetate or phosphate buffer at a concentration of about 3.0 mM; wherein said composition has a pH of about 5.0.
  • the ophthalmological composition comprises: 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; optionally, phosphate buffer at a concentration of about 3.0 mM;
  • Carbopol® 940 at a concentration of about 0.85% w/v;
  • BAK at a concentration of about 0.01% w/v, wherein said composition has a pH of about 4.75.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.45% w/v; tropicamide at a concentration of about 0.042% w/v; poly oxy I 40 stearate at a concentration of about 5.5% w/v; citric acid monohydrate at a concentration of about 0.1% w/v; optionally, acetate buffer at a concentration of about 3.0 mM; and
  • Carbopol® 940 at a concentration of about 0.75% w/v, wherein said composition has a pH of about 4.75.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.45% w/v; tropicamide at a concentration of about 0.042% w/v; poly oxy 140 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 mM; and
  • Carbopol® 940 at a concentration of about 1.0% w/v, wherein said composition has a pH of about 4.75.
  • the ophthalmological composition comprises: about 1 .75% w/v aceclidine; about 2.5% w/v mannitol; about 2.75% w/v polysorbate 80; and about 1.25%; 1.0% - 1.80% w/v hydroxypropylmethyl cellulose (depending on its molecular weight).
  • 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% w/v polysorbate 80; and about 1.25%; 1.0% - 1.80% w/v hydroxypropylmethyl cellulose (depending on its molecular weight).
  • 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 mM phosphate buffer; about 0.50% w/v NaCl; and about 0.020% BAK or 0.15% sorbic acid as preservative, with a pH of about 5.0.
  • 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 hydroxypropyhnethyl cellulose (depending on its molecular weight);
  • 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 hydroxypropyhnethyl 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.
  • EDTA ethylenediaminetetraacetic acid
  • the ophthalmological composition comprises: about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 0.01% w/v tropicamide; about 0.1% w/v sodium citrate, anhydrous; about 0.02% w/v benzalkonium chloride; about 0.12% 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 5.0.
  • the ophthalmological composition comprises: about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 0.01% w/v tropicamide; about 0.1% w/v sodium citrate, anhydrous; about 0.02% w/v benzalkonium chloride; about 0.1% w/v sorbic acid; about 0.1% w/v EDTA; about 3.5% w/v polysorbate 80; and about 1.25%; 1.0% - 2.25% w/v hydroxypropylmethyl cellulose (depending on its molecular weight), wherein the pH is about 5.0.
  • the ophthalmological composition comprises: about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 0.01% w/v tropicamide; optionally, about 3mM phosphate buffer; about 0.02 % w/v benzalkonium chloride; about 0.1% w/v sorbic acid; about 0.1 % w/v citrate; about 3.5% w/v polysorbate 80; and about 1.25%; 0.25% - 2.25% w/v hydroxypropylmethyl cellulose (depending on its molecular weight); wherein the pH is about 5.0.
  • the ophthalmological composition comprises: aceclidine at a concentration of 1 .5% w/v, mannitol at a concentration of 2.5% w/v.
  • the ophthalmological composition comprises: aceclidine at a concentration of 1.55% w/v, mannitol at a concentration of 2.5% w/v.
  • the ophthalmological composition comprises: aceclidine at a concentration of 1.6% w/v, mannitol at a concentration of 2.5% w/v.
  • the ophthalmological composition comprises: aceclidine at a concentration of 1 .65% w/v, mannitol at a concentration of 2.5% w/v.
  • the ophthalmological composition comprises: aceclidine at a concentration of 1.7% w/v, mannitol at a concentration of 2.5% w/v.
  • the ophthalmological composition comprises: aceclidine at a concentration of 1.75% w/v, mannitol at a concentration of 2.5% w/v.
  • the ophthalmological composition comprises: aceclidine at a concentration of 1.80% w/v, mannitol at a concentration of 2,75% w/v and Carbopol® 940 at a concentration of 0.09% w/v.
  • 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.
  • the ophthalmological composition comprises: aceclidine at a concentration of 1.80% w/v, mannitol at a concentration of 2.5% w/v and Carbopol® 940 at a concentration of 0.9% w/v.
  • 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 mannitol, 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 0.077% w/w citrate, wherein the composition has a pH of about 5.0.
  • 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 mannitol, about 1.2% w/w hydroxypropylmethyl cellulose, about 0.1% w/w ethylenedi aminetetraacetic 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.
  • the present invention is directed to compositions for the treatment of presbyopia comprising about 1 .40% w/w aceclidine, about 2.0% w/wpolyoxyl stearate, about 2.5% w/w mannitol, 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.
  • Example 1 Effect of aceclidine on vision of subjects aged 47 to 67 years
  • 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% w/v HPpCD, 0.75% w/v CMC, 0.25% w/v NaCl and 0.01 % w/v BAK.
  • compositions administered to subjects 4 and 5 included 0.125% w/v tropicamide.
  • 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 2 Effect of concentration of concentration of aceclidine and tropicamide.
  • (C) indicates corrected vision
  • (m) indicates minutes
  • (hr) indicates hour
  • mm indicates millimeters
  • BD indicates baseline distance vision
  • BN indicates basetine near vision
  • BP indicates baseline pupil size
  • OD indicates right eye
  • OS indicates left eye and OU indicates both eyes.
  • '‘ Time’’ refers to durati on of the effect.
  • 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 #3) 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.
  • formula #7 To determine the effect of brimonidine on pupil miosis, formula #7, was administered. Administration of formula #7 resulted in only a slight decrease in pupil miosis to 1.70 mm with identical distance and near vision improvement to that of formula #5. A 2-3+ conjunctival injection was noted.
  • Example 3 Effect, of concentration of aceclidine, brimonidine, guanfacine, fadolmidine, tropic amide and aaaitives
  • Table 3 Effect of concentration of aceclidine, brimonidine, guanfacine, fadolmidine, tropicamide and additives.
  • AU percentages are w/v. Scores for nasal congestion, stinging initial, stinging, 3 min, redness initial, redness 15 min, whitening, pain and overall are out of 4. [0215] "pt” reflects size of print materials, 4 being equivalent to 20/20 vision and 3 to 20/15 vision.
  • Baseline vision was 20.20 both eyes for distance; 20.70 right eye unaided for near; 20.80 left eye for near (best @ 16”).
  • D/C stands for discontinued after eye washing due to intolerable stinging.
  • Aceciidine 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 aceciidine to 1.25% w/v 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 duration, and greater effect.
  • a decrease in the amount of aceclidine from 1.61 % to 1.53% w/v 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.
  • the 1.8 to 2.0 mm pupil created 41% more light than the 1.5 to 1.7 mm pupil.
  • 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 2.00 D seen with the 1.5-1.7 mm range.
  • 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.
  • Table 4 shows an unexpected result seen in formulas #13 and #17 where the increase of NaCl 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.
  • Formulas #15, #16 and #17 each result in an overall maximum rating of 5 by combining the benefits of: (1 ) reduced aceclidine concentrations to improve the amount of light produced without significantly affecting the near vision benefits seen in formulas #8 ⁇ #12; (2) increased NaCl 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.
  • 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 aceclidine.
  • Formula #20 is an excellent alternative for the minority of individuals that are low responders to formula #19.
  • Formula #21 is an excellent alternative for the minority of individuals that are low responders and get poor pupil response with Formula #20.
  • Colenbrander- Michelson 10% Lum 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+ 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 hrs 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.
  • 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 0.015% 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 6.0.
  • Example 1 Use of a preferred embodiment to prolong contact lens wear.
  • 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 6.0.
  • composition aceclidine at a concentration of about 1.40% ⁇ 1.80% w/v; and tropicamide at about 0.42% w/v; polyoxyl 40 stearate at about 5.5% w/v; mannitol 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 mM wherein said composition has a pH 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
  • 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% mannitol, 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.
  • 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 mM; wherein said composition has a pH of about 4.75.
  • Aceclidine alone causes incidence migraine-like severe ciliary spasm (brow ache) and myopic blur. These effects are inversely correlated 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 does not reduce the myopic effect of aceclidine.
  • the addition of 2.5% w/v mannitol however does reduce the myopic effect of aceclidine.
  • 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.
  • the addition of a nonionic surfactant increases both the quantitative measure of near vision improvement and the duration.
  • This effect is concentration sensitive
  • the non-ionic surfactant is at least 1%, preferably at least 2%, more preferably from about 1% to about 5%, and most preferably about 5%.
  • polysorbate 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.
  • 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.
  • a viscosity agent in a formulation with optimal ratios of aceclidine, tropicamide and a non-ionic surfactant dramatically improves duration.
  • 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.
  • a threshold above the critical micellar threshold greatly enhances penneation through the cornea by reducing micelle size from micrometers to nanometers. See Figure 2.
  • compositions containing little or no cycloplegic agent are sho wn in Table 8 below.
  • compositions containing little or no cycloplegic agent Compositions containing little or no cycloplegic agent
  • %* denotes amount can optionally vary from about 0.01% to about 1 % w/v.
  • # denotes formulation can include polysorbate 80 or not include polysorbate 80.
  • the efficacy index is demonstrated in Figure 3.
  • 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+ lines of improvement for 9 hours. [0254] As demonstrated by comparing the Reading vs.
  • Example 14 Use of a preferred embodiment optimizing tropicamide and hydroxypropyl methyl cellulose
  • 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 w'ere mild to nearly absent. Duration was excellent for each nonionic surfactant tested.
  • Example 16 Use of a compound containing optimizing nonionic surfactant and antioxidant additives and concentrations
  • HPMC 1.25% w/v high MW equaling viscosity of about 400 cps units
  • Comfort, 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 tor 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 1 1 .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.
  • Aceclidine cold chain storage compositions CS#l-5 and 11-20 were filled into vials each under a nitrogen overlay followed by a nitrogen purge of remaining headspace.
  • CS&6-10 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.
  • CS43-5 contaiing 0.10% sodium ascorbate, 0.10% sodium bisulfate or 0.10% sodium metabisulifite were stable for about 2 months at 25 degrees Celsisus and for about 26 months at 5 degrees Celsius.
  • Aceclidine formulations of the present invention were placed in containers that were subsequently placed in bi axially-oriented polyethylene terephthalate 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.
  • Mylar® was used as the source of biaxially-oriented polyethylene terephthalate. Mylar is a registered trademark of and available from DuPont Teijin Films US Limited.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (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)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (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)
EP21880707.1A 2020-10-13 2021-04-28 Compositions and methods for storage stable ophthalmic drugs Pending EP4228636A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17/069,155 US11273150B2 (en) 2018-10-10 2020-10-13 Compositions and methods for the treatment of presbyopia
PCT/US2021/029536 WO2022081204A1 (en) 2020-10-13 2021-04-28 Compositions and methods for storage stable ophthalmic drugs

Publications (1)

Publication Number Publication Date
EP4228636A1 true EP4228636A1 (en) 2023-08-23

Family

ID=81209258

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21880707.1A Pending EP4228636A1 (en) 2020-10-13 2021-04-28 Compositions and methods for storage stable ophthalmic drugs

Country Status (8)

Country Link
EP (1) EP4228636A1 (ko)
JP (1) JP2023544918A (ko)
KR (1) KR20230131822A (ko)
CN (1) CN116847841A (ko)
AU (1) AU2021361731A1 (ko)
CA (1) CA3195422A1 (ko)
MX (1) MX2023004298A (ko)
WO (1) WO2022081204A1 (ko)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101835473B (zh) * 2007-10-16 2012-12-05 太阳医药高级研发有限公司 一种含有拉坦前列腺素的眼药组合物
US20190038609A1 (en) * 2013-08-28 2019-02-07 Presbyopia Therapies, LLC Compositions and methods for the treatment of presbyopia
KR102598047B1 (ko) * 2015-06-18 2023-11-06 렌즈 테라퓨틱스 인코포레이티드 눈의 굴절 이상 치료 방법 및 저장 안정성 조성물
BR112021006618B1 (pt) * 2018-10-10 2022-09-27 Presbyopia Therapies, Inc Composições e métodos para o tratamento da presbiopia

Also Published As

Publication number Publication date
CA3195422A1 (en) 2022-04-21
JP2023544918A (ja) 2023-10-25
KR20230131822A (ko) 2023-09-14
WO2022081204A1 (en) 2022-04-21
CN116847841A (zh) 2023-10-03
AU2021361731A1 (en) 2023-05-25
MX2023004298A (es) 2023-08-09

Similar Documents

Publication Publication Date Title
US10836760B2 (en) Compositions and methods for the treatment of presbyopia
US10307408B2 (en) Contact lens compositions and methods for the treatment of presbyopia
US10052313B2 (en) Compositions and methods for the treatment of presbyopia
US20190038609A1 (en) Compositions and methods for the treatment of presbyopia
WO2017160548A1 (en) Compositions and methods for the treatment of presbyopia
US20230414494A1 (en) Compositions and methods for the treatment of presbyopia
US10959990B2 (en) Compositions and methods for the treatment of presbyopia
US20220233434A1 (en) Compositions and methods for the treatment of presbyopia
US20200188369A1 (en) Methods for the treatment of myopia
US10617763B2 (en) Compositions and methods for the treatment of presbyopia
US20190240152A1 (en) Contact lens compositions and methods for the treatment of presbyopia
US20230414587A1 (en) Compositions and methods for storage stable ophthalmic drugs
US20180235946A1 (en) Compositions and methods for the treatment of presbyopia
US11273150B2 (en) Compositions and methods for the treatment of presbyopia
WO2022081204A1 (en) Compositions and methods for storage stable ophthalmic drugs
US20230398064A1 (en) Compositions and methods for the treatment of presbyopia
US20230190739A1 (en) Compositions and methods for the treatment of presbyopia
US20230310392A1 (en) Compositions and methods for the treatment of eye conditions
WO2019135927A1 (en) Contact lens compositions and methods for the treatment of presbyopia
WO2023114347A9 (en) Compositions and methods for the treatment of eye conditions
BR122022017130B1 (pt) Composições e métodos para o tratamento da presbiopia

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20230510

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
RAP3 Party data changed (applicant data changed or rights of an application transferred)

Owner name: LENZ THERAPEUTICS OPERATIONS, INC.