[go: up one dir, main page]

WO2016205071A1 - Compositions et méthodes de traitement de la presbytie - Google Patents

Compositions et méthodes de traitement de la presbytie Download PDF

Info

Publication number
WO2016205071A1
WO2016205071A1 PCT/US2016/036694 US2016036694W WO2016205071A1 WO 2016205071 A1 WO2016205071 A1 WO 2016205071A1 US 2016036694 W US2016036694 W US 2016036694W WO 2016205071 A1 WO2016205071 A1 WO 2016205071A1
Authority
WO
WIPO (PCT)
Prior art keywords
concentration
composition
tropicamide
aceclidine
vision
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.)
Ceased
Application number
PCT/US2016/036694
Other languages
English (en)
Inventor
Gerald Horn
Lee NORDAN
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.)
Presbyopia Therapies Inc
Original Assignee
Presbyopia Therapies 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 US14/742,903 external-priority patent/US9320709B2/en
Priority claimed from US14/742,921 external-priority patent/US9314427B2/en
Priority claimed from US14/860,770 external-priority patent/US9968594B2/en
Priority claimed from US14/860,777 external-priority patent/US10064818B2/en
Application filed by Presbyopia Therapies Inc filed Critical Presbyopia Therapies Inc
Publication of WO2016205071A1 publication Critical patent/WO2016205071A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/06—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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61K47/40—Cyclodextrins; 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • Excellent unaided distance vision is also known as emmetropia.
  • the inability to focus on distant focal points is known as myopia and the inability to focus on near focal points is known as hyperopia.
  • "distance" vision is considered any focal point 1 meter or more from the eye and near vision is any focal point less than 1 meter from the eye.
  • the minimum focal length at which an object will come into focus is known as the "near point”.
  • Accommodation The change in focus from distance to the near point and any focal point in between is called accommodation.
  • presbyopia occurs because as a person ages the eye's accommodative ability which uses near reflex-pupil constriction, convergence of the eyes and particularly ciliary muscle contraction decreases. This reduction in accommodation results in an inadequate change in the normal thickening and increased curvature of the anterior surface of the lens that is necessary for the shift in focus from distant objects to near objects.
  • Important near focus tasks affected by presbyopia include viewing computer screens (21 inches) and reading print (16 inches).
  • Presbyopia is a normal and inevitable effect of ageing and is the first unmistakable sign for many in their forties that they are getting older.
  • Presbyopia carries with it a stigma resulting from the limitation in ability to quickly function at many tasks requiring focusing at both distant and near points, which once occurred almost immediately.
  • these tasks can be performed only by the use of eyeglasses, contact lenses or after undergoing invasive surgery.
  • One such optical modification, the monovision procedure can be executed with the use of glasses, contact lenses or even surgery.
  • the monovision procedure corrects one eye for near focus and the other eye for distance focus.
  • monovision correction is normally accompanied by loss of depth perception and distance vision particularly in dim light (e.g. night).
  • AcuFocus work by inlaying a pinhole on the cornea to increase the depth of focus.
  • a similar effect can be achieved with general miotic agents, such as pilocarpine (a nonselective muscarinic acetylcholine receptor agonist), carbachol (a non-selective muscarinic acetylcholine receptor agonist), and phospholine iodide (an acetylcholinesterase inhibitor).
  • pilocarpine a nonselective muscarinic acetylcholine receptor agonist
  • carbachol a non-selective muscarinic acetylcholine receptor agonist
  • phospholine iodide an acetylcholinesterase inhibitor
  • the induced accommodation may create up to 5 diopters or more of induced myopia resulting in induced myopia causing blurred distance vision generally and during shift of the focal point from distance to near.
  • any advantage of increased depth of focus from pinhole optics that might enhance both distance and near vision requires sufficiently great pupil constriction.
  • This pupil constriction requires higher concentrations of muscarinic agonists than the distance blur resulting from even modest concentrations will allow.
  • Miotic agents have been described in various patent and patent applications for the treatment of presbyopia.
  • US Patent Nos. 6,291,466 and 6,410,544 describe the use of pilocarpine to regulate the contraction of ciliary muscles to restore the eye to its resting state and potentially restore its accommodative abilities.
  • US Patent Application Publication No. 2010/0016395 describes the use of pilocarpine with the non-steroidal anti-inflammatory, diclofenac, to reduce brow ache from ciliary spasm, but does not prevent induced miosis and distance blur.
  • International PCT Application Publication WO/2013/041967 describes the use of pilocarpine with oxymetazoline or meloxicam to temporarily overcome ocular conditions such as presbyopia and possibly slightly decreases the degree of ciliary muscle contraction due to reduced pilocarpine levels in the ciliary body due to vasoconstriction of the ciliary vasculature.
  • ciliary induced miosis results in about 0.7 lines of distance vision loss, equating to an eye that is reduced to 20.27 distance vision. This reduction is about a 26% drop in distance acuity from the otherwise 20.20 best corrected vision.
  • US Patent No. 8,299,079 (HEK Development LLC) describes the use of direct acting general miotic agents such as pilocarpine, carbachol and phospholine iodide with brimonidine at a concentration from 0.05% to 3.0% w/v.
  • brimonidine concentrations at or above 0.05% w/v results in increased dryness and with regular use possible rebound hyperemia.
  • rebound redness occurs in 25% of patients using brimonidine 0.20% w/v (Alphagan ® , registered trademark of Allergan, Inc.) twice daily.
  • Further brimonidine only slightly reduces dilation of the pupil in scotopic conditions, does not enhance its constriction or affect ciliary induced myopia.
  • US Patent Application No. 2014/0113946 discloses means of treating presbyopia using pilocarpine and an alpha agonist, such as oxymetazoline.
  • pilocarpine 1.0% disclose a loss of 0.7 lines of average distance vision (26% reduction) and demonstrate pupil constriction greater than 2.0 millimeters ("mm") at all time points, ranging from 2.1 to 3.2 over a six hour period.
  • Oxymetazoline concentrations in preferred embodiments of 0.05% and 0.125% are both at or above concentrations known to be associated with rebound hyperemia (0.05%) and labeled for maximum daily use of three days (Visine L.R.*; Visine L.R. is a registered trademark of Johnson & Johnson Corp.).
  • an ophthalmological composition that will allow a person suffering from presbyopia to focus on near objects without significant side effects such as diminished distance vision, blurred vision, pain, and redness, impaired night driving or incapacitating dim light vision, induced nasal congestion, or risk of retinal detachment.
  • the present invention is directed to compositions and methods for the treatment of presbyopia.
  • the present invention is directed to compositions and methods for the treatment of presbyopia comprising a muscarinic agonist, wherein the muscarinic agonist preferentially activates Ml and M3 muscarinic acetylcholine receptors.
  • the muscarinic agonist is more highly selective for Ml than M3.
  • the present invention is directed to compositions and methods for the treatment of presbyopia comprising a muscarinic agonist that preferentially activates Ml and M3 muscarinic acetylcholine receptors.
  • the present invention is directed to compositions and methods for the treatment of presbyopia comprising a muscarinic agonist that activates only Ml muscarinic acetylcholine receptors.
  • the present invention is directed to compositions for the treatment of presbyopia comprising a muscarinic agonist, preferably selected from the group consisting of pilocarpine, aceclidine, talsaclidine, sabcomeline, cevimeline, WAY- 132983, AFB267B (NGX267), AC-42, AC-260584, 77-LH-28-1, and LY593039 or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof and a cycloplegic agent, preferably selected from pirenzepine, tropicamide, cyclopentolate hydrochloride, 4- diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin, tolterodine, oxybutynin, ipratropium, oxi
  • the present invention is directed to an ophthalmological composition of the present invention comprising a muscarinic agonist and a cycloplegic agent in a ratio greater than about 25: 1 , preferably greater than about 40: 1.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof and a cycloplegic agent, preferably selected from pirenzepine, tropicamide, cyclopentolate hydrochloride, 4- diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin, tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium, otenzepad and a combination thereof.
  • a cycloplegic agent preferably selected from pirenzepine, tropicamide, cyclopentolate hydrochloride, 4- diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), AF-DX 384, methoctra
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising pilocarpine at a concentration from about 0.5% to about 2.5% w/v, preferably about 1.5% w/v and a cycloplegic agent at a concentration from about 0.010% to about 0.1% w/v.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof and tropicamide.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising pilocarpine at a concentration from about 0.5% to about 2.5% w/v, preferably about 1.5% w/v and 0.95% w/v and tropicamide at a concentration from about 0.010% to about 0.1% w/v, preferably about 0.035% w/v and about 0.015% w/v.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof, tropicamide, a surfactant and a viscosity enhancer.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising:
  • pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof;
  • a surfactant selected from polyoxyl 40 stearate, a gamma cyclodextrin, sulfobutylether ⁇ - cyclodextrin, 2-hydroxypropyl cyclodextrin, sodium lauryl sulfate, sodium ester lauryl sulfate, a poloxamer, a polysorbate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, a polyoxyl alkyl, a cyclodextrin and combinations thereof; and
  • a viscosity enhancer selected from the group consisting of guar gum, hydroxypropyl-guar, xanthan gum, alginate, chitosan, gellan gum such as Gelrite ® ; Gelrite is a registered trademark of CP Kelco U.S. Inc., hyauluronic acid, dextran, and a carbomer.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof, tropicamide, polyoxyl 40 stearate and carfoomer 940.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising:
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising:
  • pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof;
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising pilocarpine at a concentration from about 0.5% to about 2.5% w/v, preferably about 1.75% w/v, about 1.5% w/v, about 1.25% w/v, about 1.0% w/v and 0.95% w/v and tropicamide at a concentration from about 0.010% to about 0.1% w/v, preferably about 0.012% w/v, about 0.42% w/v, about 0.0385% w/v, about 0.038% w/v, about 0.035% w/v, and for shorter acting embodiments about 0.012% to about 0.015% w/v, preferably 0.012% w/v and 0.015% w/v.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising:
  • pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof;
  • carbomer 940 an antioxidant selected from the group consisting of citrate, citric acid monohydrate, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid, dicalcium
  • a buffer selected from the group consisting of acetate buffer, citrate buffer, phosphate buffer and citrophosphate buffer.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof, tropicamide, polyoxyl 40 stearate, carbomer 940, citric acid monohydrate and acetate buffer.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof, tropicamide, polyoxyl 40 stearate, carbomer 940, citric acid monohydrate at a concentration from about 0.1% to about 0.2% w/v and acetate buffer at a concentration from about 1 millimolar to about S millimolar.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising:
  • pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof;
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising:
  • pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof;
  • tropicamide at a concentration selected from about 0.035% to 0.038% w/v, 0.035% w/v and 0.038% w/v;
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising:
  • pilocarpine or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof;
  • tropicamide at a concentration selected from about 0.035% to 0.038% w/v, 0.035% w/v and 0.038% w/v;
  • composition has a pH from about 4 to about 7 and more preferably a pH of about 5.
  • the present invention is directed to ophthalmological compositions for the treatment of presbyopia comprising:
  • the present invention is further directed to a method for treating presbyopia comprising administering to a patient in need thereof a pharmaceutically effective amount of a composition of the present invention.
  • the present invention is further directed to a method for treating presbyopia without reducing distance vision acuity comprising administering to a patient in need thereof a pharmaceutically effective amount of a composition of the present invention.
  • 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 myopic spherical equivalent fraction on distance vision acuity at various pupil sizes.
  • the present invention is directed to compositions and methods of treating presbyopia, irregular astigmatism, and/or refractive error, comprising administering to a patient in need thereof a pharmaceutical composition comprising a muscarinic agonist that preferentially activates Ml and M3 muscarinic acetylcholine receptors, preferably activate Ml more than M3 and most preferably aceclidine or its derivatives.
  • a pharmaceutical composition comprising a muscarinic agonist that preferentially activates Ml and M3 muscarinic acetylcholine receptors, preferably activate Ml more than M3 and most preferably aceclidine or its derivatives.
  • Pilocarpine and aceclidine have been surprisingly and unexpectedly discovered to provide enhanced presbyopic reversal with negligible side effects day or night (when viewing includes one or more direct or reflected light sources) using compositions of the present invention,
  • Aceclidine is traditionally used as a treatment for glaucoma.
  • aceclidine is used to treat glaucoma it is normally stored in a two-bottle system; one bottle containing the !yophiiized aceclidine and the second bottle containing the diluent necessary to reconstitute the lyophilized aceclidine before topical instillation.
  • aqueous aceclidine composition that is stable in combination with cold chain storage.
  • It is yet a further aspect of the present invention to provide a method of stabilizing aqueous aceclidine by combining effective excipients, pH ranges and temperature ranges.
  • compositions and methods of the present invention treat presbyopia by improving depth of focus in patients with presbyopia by administering an ophthalmoiogical composition to the eye that:
  • 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.
  • 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 with negligible increase in accommodative tone and with a reduction or ablation of the redness that is otherwise a hallmark of the use of miotic agents.
  • This pupil miosis with greatly diminished or absent accommodative tone is superior to the pinhole effect of the Kamra ® and Flexivue Microlens ® corneal inlays.
  • Pupil miosis is superior because the constriction of the actual pupil does not result in the attendant severe night vision disturbance caused by the light scattering borders of the pre-corneal pinholes created by the inlays.
  • Further pupil miosis provides a greater field of vision and transmission of more focused light.
  • the use of aceclidine has a minimal effect on the longitudinal ciliary muscle, thus reducing risk of retinal detachment when compared to the use of general muscarinic agonists such as carbachol.
  • the further inclusion of a cycloplegic agent resulted in only 0.04 mm of anterior chamber shallowing.
  • Aceclidine particularly as enhanced for the present invention also has greater magnitude, duration, and control of minimum pupil diameter.
  • Compositions of the present invention achieve these advantages while having negligible effects on accommodation, thus avoiding the distance blur typically seen in patients as a response to pilocarpine and/or carbachol induced miosis. Any effects on accommodation may be further reduced or totally eliminated in preferred embodiments with a cycloplegic agent.
  • Aceclidine is capable of producing the increased depth of focus by pupil miosis described in the present invention without the need of a selective a-2 adrenergic receptor agonist ("a-2 agonist").
  • compositions of the present invention thus making it possible to use an a-2 agonist at low concentrations to reduce eye redness.
  • administration to the eye almost exclusively affects pupil miosis rather than ciliary muscle contraction.
  • the administration of aceclidine results in pupil miosis without accommodation and attendant distance blur.
  • aceclidine may cause some redness and brow ache, and without formulation enhancement of the present invention may produce less than optimal pupil miosis or at extremely high concentration more than desired peak miosis with added dimming of vision in dim or absent lighting.
  • 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 enhancer. Similar benefit may be achieved using other permeation enhancers, particularly 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.
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising aceclidine.
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising aceclidine and a cyclopiegic agent.
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising aceclidine and a selective a-2 adrenergic receptor agonist.
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising aceclidine, a cyclopiegic agent and a selective a-2 adrenergic receptor agonist.
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising a general miotic agent and a cyclopiegic agent.
  • the present invention is directed to an ophthalmological composition of the present invention comprising:
  • a general miotic agent a muscarinic agonist or aceclidine
  • a cyclopiegic agent optionally a selective ct-2 adrenergic receptor agonist
  • a surfactant selected from the group consisting of an anionic surfactant, a nonionic surfactant, and a combination thereof.
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising:
  • aceclidine at a concentration from about 0.25% to about 2.0% w/v;
  • a cycloplegic agent at a concentration from about 0.010% to about 0.1% w/v, preferably selected from pirenzepine, tropicamide, cyclopentolate hydrochloride, 4-diphenylacetoxy-N- methylpiperidine methiodide (4-DAMP), AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin, tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium, otenzepad and a combination thereof and more preferably tropicamide;
  • a surfactant preferably selected from polyoxyl 40 stearate, a gamma cyclodextrin,
  • sulfobutylether ⁇ -cyclodextrin 2-hydroxypropyl cyclodextrin, sodium lauryl sulfate, sodium ester lauryl sulfate, a poloxamer, a polysorbate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, a polyoxyl alkyl, a cyclodextrin and combinations thereof and more preferably polyoxyl 40 stearate;
  • a tonicity adjuster preferably selected from mannitol, sodium chloride, potassium chloride, glycerin and combinations thereof and more preferably mannitol;
  • viscosity enhancer optionally a viscosity enhancer, preferably the viscosity enhancer is not a polysaccharide.
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising:
  • aceclidine at a concentration from about 0.25% to about 2.0% w/v;
  • a cycloplegic agent at a concentration from about 0.010% to about 0.1% w/v;
  • a viscosity enhancer selected from the group consisting of guar gum, hydroxypropyl-guar, xanthan gum, alginate, chitosan, Gelrite®, hyauluronic acid, dextran, and a carbomer, preferably carbomer 934 or carbomer 940 wherein the viscosity is from about 1 to about 5,000 centipoise ("cps") prior to topical installation and from about 1 to about 50 cps upon topical installation, preferably from about 1 to about 5,000 cps at from about 2 to about 8 °C and an antioxidant selected from citrate, citric acid monohydrate
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising:
  • aceclidine at a concentration from about 0.25% to about 2.0% w/v;
  • polyoxyl 40 stearate at a concentration from about 2.0% to about 10.0% w/v;
  • mannitol at a concentration from about 0.5% to about 6.0% w/v;
  • a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate buffer at a concentration of about 3 millimolar;
  • citric acid monohydrate at a concentration from about 0.1% to about 0.2% w/v;
  • a viscosity enhancer selected from carbomer 934 and carbomer 940 at a concentration from about 0.01% to about 1.0% w/v;
  • BAK benzalkonium chloride
  • pH of the composition is from about 4.75 to about 5.0 and wherein the viscosity of the composition is from about 1 to about 50 cps upon topical installation.
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising:
  • aceclidine at a concentration from about 0.25% to about 2.0% w/v;
  • polyoxyl 40 stearate at a concentration of about 4.0% w/v;
  • mannitol at a concentration from about 0.5% to about 6.0% w/v;
  • citric acid monohydrate at a concentration from about 0.1% to about 0.2% w/v;
  • carbomer 934 at a concentration from about 0.01% to about 1.0% w/v
  • a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate buffer at a concentration of about 3 millimolar,
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising:
  • aceclidine at a concentration from about 0.25% to about 2.0% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate buffer at a concentration of about 3 millimolar,
  • pH of the composition is about 5.0.
  • the present invention is directed to an ophthalmological composition for the treatment of presbyopia comprising:
  • aceclidine at a concentration from about 0.25% to about 2.0% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • mannitol at a concentration of about 0.5% to about 6% w/v;
  • citric acid monohydrate at a concentration from about 0.1% to about 0.2% w/v;
  • carbomer 940 at a concentration from about 0.01% to about 1.0% w/v
  • a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate buffer at a concentration of about 3 millimolar,
  • the pH of the composition is from about 4.75 to about 5.0 and the viscosity of the composition is from about 1 to about 5,000 cps at from about 2 to about 8 °C.
  • the aceclidine concentration is about 1.35% to about 1.75% w/v
  • the mannitol concentration is about 1.0% to 2.5% w/v
  • the carbomer 940 concentration is about 0.09% to 1.0% w/v (or equivalent viscosity using any other non- polysaccharide viscosity agent such as carbomer 934).
  • the present invention is further 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 for treating presbyopia comprising administering to a patient in need thereof a composition of the present invention.
  • the present invention is further directed to a method for treating presbyopia without inducing ciliary brow ache comprising administering to a patient in need thereof a
  • composition of the present invention is a pharmaceutically effective amount of a composition of the present invention.
  • the present invention is further directed to a method for enhancing near vision and distance vision without inducing ciliary brow ache comprising administering to a patient in need thereof a pharmaceutically effective amount of a composition of the present invention.
  • the present invention is further directed to a method for treating presbyopia via enhancing pinhole optics depth of focus comprising administering to a patient in need thereof a pharmaceutically effective amount of a composition of the present invention.
  • the present invention is further directed to a method for treating of treating presbyopia via enhancing pinhole optics distance depth of focus and pinhole optics near depth of focus comprising administering to a patient in need thereof a pharmaceutically effective amount of a composition of the present invention, wherein slight ciliary induced myopia occurs without reduction in distance vision.
  • the present invention is further directed to a method for inducing pupillary miosis focus comprising administering to a patient in need thereof a pharmaceutically effective amount of a composition of the present invention, wherein a substantial reduction in ciliary contraction occurs, an improvement in pinhole optics near depth of focus occurs, near vision and distance vision is improved and ciliary induced brow ache does not occur.
  • the present invention is further directed to a method for enhancing pinhole optics depth of focus and near vision depth of focus comprising administering to a patient in need thereof a pharmaceutically effective amount of a composition of the present invention, wherein ciliary muscle contraction induced miosis is reduced to a degree that does not reduce distance pinhole optics and wherein, optionally, slight additive accommodation occurs.
  • the present invention is further directed to a method for treating a refractive error of the eye comprising administering to a patient in need thereof a pharmaceutically acceptable amount of a composition of the present invention, wherein the size of the pupil is reduced to from about 1.5 to about 2.5 millimeters, preferably from about 1.7 to about 2.0 millimeters and wherein the refractive error is selected from the group consisting of corneal irregular astigmatism, an ectasia induced corneal irregularity, a pellucid induced corneal irregularity, a higher order aberration and a refractive surgery induced higher order aberration.
  • the present invention is further directed to a method of increasing the visual depth of field (i.e. depth of focus) comprising administering to a subject in need thereof a
  • 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 longer 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.
  • present invention is directed to ophthalmological compositions comprising aceclidine and a low-dose cycloplegic agent.
  • the present invention is directed to ophthalmological compositions comprising aceclidine, a low- dose cycloplegic agent and a combination of inactive ingredients that make effective and/or enhance aceclidine.
  • the present invention is further directed to a method for stabilizing the composition of claim 1 comprising maintaining the composition at a temperature from about 2 to about 8 °C.
  • the present invention is further directed to a method for stabilizing an aqueous aceclidine composition comprising the steps of:
  • a surfactant selected from polyoxyl 40 stearate, a gamma cyclodextrin, sulfobutylether ⁇ -cyclodextrin, 2-hydroxypropyI cyclodextrin, sodium lauryl sulfate, sodium ester lauryl sulfate, a poloxamer, a polysorbate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, a polyoxyl alkyl, a cyclodextrin and combinations thereof to the composition, preferably polyoxyl 40 stearate;
  • a tonicity adjustor selected from mannitol, sodium chloride, potassium chloride, glycerin and combinations thereof, preferably mannitol;
  • a viscosity enhancer selected from the group consisting of guar gum, hydroxypropyl-guar, xanthan gum, alginate, chitosan, Gelrite®, hyauluronic acid, dextran, a carbomer and combinations thereof to the composition, preferably carbomer 940,
  • the present invention is further directed to a method for stabilizing an aqueous aceclidine composition comprising the steps of:
  • composition maintaining the composition at a temperature from about 2 to about 8 °C.
  • 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.
  • cycloplegic agents such as tropicamide
  • 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.
  • This lack of impairment of the miotic response is an unexpected surprising discovery, as particular cycloplegic agents, such as tropicamide, have known pupil dilating effects at concentrations as low as 0.01% w/v (GrOnberger 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.
  • 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. In fact, iris mydriasis is discovered to be suppressed by the addition of tropicamide to
  • compositions containing concentrations of aceclidine used in the present invention with instead a more consistent level of miosis for the duration of the miotic effect.
  • 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).
  • General miotic agents such as pilocarpine, carbachol and phospholine diesterase, are capable of causing pupil miosis resulting in improved near vision of presbyopic patients.
  • 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-cyclodextrin ("HPPCD"), and or sulfobutyl ether derivative of ⁇ -cyclodextrin (Captisol*), polyoxyl 40 stearate or poloxamer 407; a viscosity enhancing agent, such as carboxymethyl cellulose ("CMC"); a tonicity adjustor, such as sodium chloride; a preservative, such as benzalkonium chloride and a pH from about 5.0 to about 8.0.
  • a nonionic surfactant such as cyclodextrin alpha, beta, or gamma chains, preferably 2-hydroxypropyl beta-cyclodextrin (“HPPCD”), and or sulfobutyl
  • an increase in the concentration of the viscosity agent and the electrolyte may result in reduced redness.
  • increasing CMC from 0.50% to 0.75% w/v (preferably 0.80% w/v) and sodium chloride from 0.25% to 0.50% w/v results in reduced redness.
  • compositions of the present invention comprising a viscosity enhancer may be from about 1 to about 5,000 cps prior to topical instillation in the eye.
  • the viscosity is lowered to a range from about 1 to about 50 cps upon topical instillation, preferably from about 15 to about 35 cps.
  • 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 a muscarinic agonist, including aceclidine or pilocarpine, to degrade.
  • % w/v refers to the percent weight of the total composition.
  • muscarinic receptor agonist encompasses agonists that activate muscarinic acetylcholine receptors ("muscarinic receptors"). Muscarinic receptors are divided into five subtypes named M1-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 pilocarpine, 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]- 1,4,5,6- tetrahydropyrimidine hydrocholoride), N-arylurea-substituted 3-morpholine arecolines,
  • VUO255-035 N-[3-oxo-3-[4-(4-pyridinyl)-l -piperazinyl]propyl]-2, 1 ,3-benzothiadiazole-4- sulfonamide), benzylquinolone carboxylic acid (BQCA), WAY-132983, AFB267B (NGX267), AC-42, AC-260584, chloropyrazines including but not limited to L-687, 306, L-689-660, 77-LH- 28-1, LY593039, and any quiniclidine ring with one or more carbon substitutions particularly that include an ester, sulfur, or 5 or 6 carbon ring structure including with substituted nitrogen(s) and or oxygen(s), or any pharmaceutically acceptable salts, esters, analogues, prodrugs or derivatives thereof.
  • a preferred 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 agonist 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. et al., 1,2,5-Thiadiazole analogues of aceclidine as potent ml muscarinic agonists, J Med Chem, 1998, Jan. 29, 41(3), 379-392 and aceclidine prodrugs including but not limited to carbamate esters.
  • pilocarpine encompasses its salts, esters, analogues, prodrugs, derivatives and pilocarpine analogues.
  • 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 ⁇ x-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.
  • low concentrations or “low-dose” 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 affect 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.
  • 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 animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Phamtaceutical 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, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate
  • 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 oil- soluble 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 decy
  • 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, trimethylammonium,
  • 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(0)A' or— €(0) ⁇ ', where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, a heteroaryl group or other suitable substituent.
  • 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 1.25% to about 1.85% w/v, and most preferably from about 1.35% to about 1.65% 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).
  • concentrations 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.
  • 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.
  • 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).
  • Nonionic surfactants suitable for the present invention include cyclodextrins, polyoxyl alkyls, poloxamers or combinations thereof, and may include in addition combinations with other nonionic surfactants such as polysorbates.
  • Preferred embodiments include polyoxyl 40 stearate and optionally Poloxamer 188, Poloxamer 407, Polysorbate 20, Polysorbate 80, ionically charged (e.g.
  • 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.
  • Captisol ® 2- hydroxypropyl beta cyclodextrin
  • HPPCD 2- hydroxypropyl beta cyclodextrin
  • alpha cyclodextrins alpha cyclodextrins
  • gamma cyclodextrins gamma cyclodextrins
  • Polyoxyl 35 castor oil and Polyoxyl 40 hydrogenated castor oil or combinations thereof.
  • 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- ⁇ - cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, randomly methylated ⁇ -cyclodextrin, ⁇ -cyclodextrin sulfobutyl ether, ⁇ - cyclodextrin sulfobutyl ether or glucosyl- ⁇ - cyclodextrin, any combination of amer analogue or derivative, polysorbate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, any polysorbate an
  • an anionic surfactant such as sodium lauryl sulfate and or sodium ester Iauryl sulfate may be preferred.
  • Ophthalmologic ⁇ in situ gels which may be substituted for or added in addition to one or more nonionic surfactants include but are not limited 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.
  • nonionic surfactant is polyoxyl 40 stearate at a
  • polyoxyl 40 stearate is found to enhance the redness reduction effect preferentially over aqueous solutions and other nonionic surfactants such as poloxamer 407, particularly in the presence of an a-2 agonist.
  • Viscosity enhancers suitable for the present invention include, but are not limited to, guar gum, hydroxypropyl-guar ("hp-guar”), 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), carboxymethyl cellulose (“CMC”), methylcellulose, methyl cellulose 4000, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyl propyl methyl cellulose 2906, carboxypropylmethyl cellulose, hydroxyethyl cellulose, or hydroxyethyl cellulose, hyaluronic acid, dextran, polyethylene glycol,
  • the viscosity enhancer 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 enhancer is Carbopol* 940 (carbomer 940) at a concentration from about 0.5% to about 6.0% 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.
  • polyoxyl 40 stearate, and cellulose derivatives, particularly hydroxypropyl methyl cellulose use of a nonpolysaccharide derivative for viscosity
  • polyacrylic acid derivatives such as polyacrylic acid derivatives (carbomers, carbomer 934 or 940 in preferred embodiments) may prevent such separation.
  • Acidic pH preferably less than 5.5, preferably less than 5.0 and most preferably at a pH of about 4.75;
  • Viscosity enhancer preferably at 25C viscosity of about 15-50 cps, and more preferably
  • the selective a-2 agonist 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. Further, 0.10% to 0.5% w/v is still too high and even 0.070% to 0.10% w/v is associated with a higher than preferred incidence of rebound hyperemia
  • 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 polyoxyl 40 stearate as a nonionic surfactant component or as the sole nonionic surfactant, result in a greater whitening effect when the a-2 agonist is included in the composition rather than poloxamer 407.
  • the a-2 agonist may optionally be applied separately or in certain preferred embodiments with formulations of the present invention that do not include an a-2 agonist, such as those formulas with polyoxyl 40 stearate 5.5% w/v as the non-ionic surfactant, although the a-2 agonist is not required except for occasional sensitive subjects. Fadolmidine represents the a-2 agonist with highest hydrophilicity and therefore high surface retention for the present invention.
  • Guanfacine is also highly selective and hydrophilic.
  • 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]- 1 ,3-dihydro-imidazole-2-thione, 1 -[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds. Analogues of these compounds that function as highly selective 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 ("HCl") salt.
  • 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 further comprising a cycloplegic agent.
  • a cycloplegic agent 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-methylpiperidine methobromide (4-DAMP), AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin (Vesicare ® ; Vesicare is a registered trademark of Astellas Pharma Inc.), tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium (Spriva), and otenzepad (a.k.a.
  • the cycloplegic agent is tropicamide at a concentration from about 0.01% to about 0,10% w/v, more preferably from about 0.025% to about 0.080% w/v and still more preferably from about 0.04% to about 0.06% 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.S0 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 polyoxyl 40 stearate; 0.80% w/v CMC; 0.037% w/vNaCl; 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.
  • This additional pupil size modulation with a cycloplegic agent allows aceclidine or pilocarpine concentrations sufficient for prolonged effect while blunting the attendant peak excessive constriction that is undesirable as well as any uncomfortable brow ache.
  • tropicamide achieves this blunting effect without causing mydriasis.
  • 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 cycloplegic 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.
  • lOe and lOf 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. Similar results can be achieved with a different miotic agent, pilocarpine, with the addition of a cycloplegic agent such as tropicamide. A proper drug carrier can also have a beneficial effect.
  • the present invention is further directed to an ophthalmological composition further comprising a tonicity adjuster and a preservative.
  • a tonicity adjuster can be, without limitation, a salt such as sodium chloride (“Nad”), potassium chloride, mannitol or glycerin, or another pharmaceutically or ophthalmologically acceptable tonicity adjuster.
  • a salt such as sodium chloride (“Nad”), potassium chloride, mannitol or glycerin, or another pharmaceutically or ophthalmologically acceptable tonicity adjuster.
  • the tonicity adjuster is 0.037% w/v NaCl,
  • Preservatives that can be used with the present invention include, but are not limited to, benzalkonium chloride ("BAK”), chlorobutanol, thimerosal, phenylmercuric acetate, disodium emylenediaminetetraacetic acid, phenylmercuric nitrate, perborate or benzyl alcohol.
  • the preservative is BAK at a concentration of about 0.001% to about 1.0% w/v, more preferably at a concentration of about 0.007% w/v.
  • 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.
  • the preservative is a combination of BAK, sorbate and borate.
  • buffers and means for adjusting pH can be used to prepare ophthalmological compositions of the invention.
  • buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers.
  • 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 5 mM.
  • the pH is from about 4.0 to about 8.0, more preferably from about S.O to about 7.0, even more preferably from about 5.0 to about 6.5 and most preferred from about 5.0 to about 6.0.
  • the present invention is further directed to an ophthalmological composition further comprising an antioxidant.
  • Antioxidants that can be used with the present invention include but are not limited to 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 Ca2DTPA which can be formulated by adding 0.0084% w/v Ca(OH)2 and 0.0032% w/v pentetic acid to the formulation and mixing slowly. Further combinations of antioxidants can be used. Other antioxidants that can be used with the present invention include those well known to experts in the art such as
  • ethylenediaminetetraacetic acid at a concentration from about 0.0001% to about 0.015% w/v.
  • topical formulations of the present invention particularly one of the preferred embodiments comprising aceclidine 1.35% to 1.55% w/v; 5.5% w/v polyoxyl 40 stearate; 0.80% w/v CMC; 0.037% w/v 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).
  • the ophthalmological composition comprises:
  • pilocarpine at a concentration of about 1.0% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • carbomer 940 at a concentration of about 0.5% w/v;
  • citric acid monohydrate at a concentration of about 0.1% w/v;
  • composition has a pH of about 5.
  • the ophthalmological composition comprises:
  • pilocarpine at a concentration of about 0.95% w/v;
  • polyoxyl 40 stearate at a concentration of about 3.85% w/v;
  • carbomer 940 at a concentration of about 0.50% w/v;
  • citric acid monohydrate at a concentration of about 0.1% w/v;
  • composition has a pH of about 5.
  • the ophthalmological composition comprises: pilocarpine at a concentration of about 1.50% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • carbomer 940 at a concentration of about 0.385% w/v or about 0.85% w/v; citric acid monohydrate at a concentration of about 0.1% w/v; and
  • composition has a pH of about 5.
  • the ophthalmological composition comprises: pilocarpine at a concentration of about 1.50% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • carbomer 940 at a concentration of about 0.385% w/v or about 0.85% w/v; citric acid monohydrate at a concentration of about 0.1% w/v; and
  • composition has a pH of about 5.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.75% w/v;
  • polyoxyl 40 stearate at a concentration of about 4.5% w/v;
  • mannitol at a concentration of about 2.5% w/v;
  • composition has a pH of about 4.75.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.55% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • citric acid monohydrate at a concentration of about 0.1 % w/v;
  • mannitol at a concentration of about 4.0% w/v;
  • acetate buffer at a concentration of about 3.0 mM; wherein said composition has a pH of about 4.75.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.50% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • mannitol at a concentration of about 2.5% w/v;
  • composition has a pH of about 4.75.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.45% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • mannitol at a concentration of about 4.0% w/v;
  • citric acid monohydrate at a concentration of about 0.1% w/v;
  • composition has a pH of about 4.75.
  • the ophthalmological composition comprises: aceclidine at a concentration of about 1.45% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • mannitol at a concentration of about 4.0% w/v;
  • citric acid monohydrate at a concentration of about 0.1% w/v;
  • composition has a pH of about 4.75.
  • 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 1.48% w/v
  • mannitol at a concentration of 4.0% w/v
  • the ophthalmological composition comprises:
  • aceclidine at a concentration of 1.48% w/v
  • mannitol at a concentration of 4.0% w/v
  • the ophthalmological composition comprises:
  • aceclidine at a concentration of 1.48% w/v
  • mannitol at a concentration of 2.5% w/v
  • 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 baseline near vision
  • BP indicates baseline pupil size
  • OD indicates right eye
  • OS indicates left eye and OU indicates both eyes.
  • Time refers to duration 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% vv/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, tropicamide and additives Effect of concentration of aceclidine, biimonidine, guanfacine, fadolmidine, tropicamide and additives.
  • 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.
  • Aceclidine at a concentration of 1.55% w/v was able to reduce the size of the pupil to about 1.63 mm 30 minutes after topical instillation resulting in corrected near and distance vision to 20.20 or better for at least 6 hours, with noticeable affect lasting about 7.5 hours as seen in Table 3.
  • Lowering of the concentration of aceclidine to 1.25% w/v 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.
  • AB 11 T did not include glycerin, poloxamer 188, or polyoxyl 40 stearate, which resulted in substantial stinging and discontinuation of the experiment with eye flush irrigation immediately after topical instillation.
  • Substitution of guanfacine 0.037% w/v in AB12T for brimonidine resulted in minimal initial redness with prolonged redness reduction and some degree of whitening, and appeared to provide overall the best cosmesis though requiring slightly higher aceclidine concentration for optimal effect.
  • AB4T and AB6T were repeated both monocularly and binocularly. Substantial improvement in depth perception, near point acuity to 3 pt (20.15), and near point distance (8", 20.20) was noted when both eyes were treated vs. monocular treatment. Monocular treatment resulted in worsening of vision with both eyes open versus testing only the treated eye.
  • Example 4 Effect of concentration of aceclidine, brimonidine, tropicamide, and additives Table 4: Effect of concentration of aceclidine, brimonidine, tropicamide, and additives.
  • 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.
  • Captisol ® (sulfobutylether ⁇ -cyclodextrin) was substituted with similar findings.
  • a viscosity enhancer preferably CMC 0.80% w/v or an amount of Carbopol ® 934 or 940 sufficient to achieve a viscosity of from about S to about 35 cps upon topical instillation, such as Carbopol® 940 at a concentration from about 0.09% to about 1.0% w/v;
  • a phosphate, citrate, citrophosphate, or acetate buffer from about 3 to about 10 mM
  • pH is from about 4.75 to about 6.0.
  • Wetting very high, the eye maintaining sensation of improved wetting for most of a 24 hour period after a single topical instillation.
  • Example 7 Use of a preferred embodiment to prolong contact lens wear.
  • a viscosity enhancer 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;
  • a phosphate, citrate, citrophosphate, or acetate buffer from about 3 to about 10 mM
  • pH is from about 4.75 to about 6.0.
  • compositions (Formulas #25 and #26).
  • CAPB cocamidopropyl betaine
  • Replacing polyoxyl 40 stearate with Captisol* (sulfobutylether ⁇ -cyclodextrin) and adding mannitol achieves similar results in redness reduction as the addition of CAPB to polyoxyl 40 stearate but without the attendant ache resulting in the highest overall rating among aceclidine compositions (Formula #32).
  • Captisol* 1 sulfobutylether ⁇ -cyclodextrin
  • aceclidine at a concentration of about 1.40%- 1.80% 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;
  • a preservative such as BAK at a concentration of about 0.2% w/v; optionally citrate at a concentration of about 0.1%;
  • acetate or phosphate buffer at 2-100 mM, more preferably 3-5 raM
  • composition has a pH of about 4.50 to about 5.0; and preferably, about 4.75 to about 5.0; and
  • 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.
  • aceclidine at a concentration of about 1.50% 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
  • composition has a pH of about 4.75.
  • First container or chamber [0193] First container or chamber:
  • aceclidine at a concentration of about 1.50% w/v lyophilized with mannitol as a cryoprecipitate at a concentration of about 2.5% w/v;
  • Second container or chamber [0194] Second container or chamber:
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • citrate at a concentration of about 0.1% w/v;
  • BAK as a preservative at a concentration of about 0.02% w/v.
  • VA visual acuity
  • BAK may also be at 0.02%
  • aceclidine at a concentration of about 1.48% w/v;
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • mannitol at a concentration of about 2.5% w/v;
  • Carbopol* 940 (carbomer 940) at a concentration of about 0.09% w/v;
  • citrate at a concentration of about 0.2% w/v;
  • acetate or phosphate buffer at a concentration of about 3.0 mM
  • preservative such as BAK at a concentration of about 0.02% w/v;
  • composition has a pH of about 4.75.
  • aceclidine at a concentration of about 1.48% w/v;
  • polyoxyl stearate at a concentration of about 4.0% w/v;
  • mannitol at a concentration of about 4.0% w/v;
  • Carbopol ® 940 (carbomer 940) at a concentration of about 0.09% w/v;
  • citrate at a concentration of about 0.2% w/v;
  • acetate buffer at a concentration of about 3.0 mM
  • preservative such as BAK at a concentration of about 0.02% w/v;
  • composition has a pH of about 4.75.
  • BAK 0.02% w/v or a combination of BAK, sorbate and borate
  • citrate 0.1% w/v
  • acetate, citrate, citrophosphate or phosphate buffer at 3 to 10 mM
  • Aceclidine can be packaged in a convenient dual chamber unit dose pack allowing complete mixing prior to installation.
  • An assembly comprising two chambers of a unit-dose container are separated by an impermeable thin membrane, or thick membrane with thin central region.
  • Aceclidine is lyophilized with mannitol as a cryoprecipitate and placed within the base of the unit dose container and sealed at its end creating a lyophilized chamber (first chamber).
  • the lyophilized chamber is vacuum sealed and/or purged of air with nitrogen gas both before and while being sealed.
  • An ophthalmologically effective diluent formulation as listed above is placed at the apex of the unit dose and sealed at its end creating a diluent chamber
  • the user may then simply pinch the diluent chamber firmly, creating a break in the impermeable membrane between the lyophilized chamber and diluent chamber and releasing the lyophilized aceclidine into the diluent chamber with premixing resulting in a suspension or a solubilized solution prior to subject topical instillation.
  • the assembly may be optionally designed to effect an automatic compression of the diluent chamber causing the impermeable membrane to rupture and deliver the drug into the diluent chamber.
  • An example of such an automatic compression may occur by placing the unit dose packs in a rack assembly where an upper plastic planar assembly is designed with a smaller opening than the diameter of the unit dose pack at its apex (i.e. the diluent chamber), wherein pulling a tab of the unit dose may then squeeze the upper chamber and effect its internal rupture and mixing of the lyophilized tyrosine kinase inhibitor and ophthalmologically effective diluent.
  • the puncturing of the impermeable membrane is effected by the turning of a screw cap thus mixing the lyophilized aceclidine with the preferred diluent.
  • m indicates meters
  • mm indicates millimeters
  • cm indicates centimeters
  • h indicates hour
  • OD indicates right eye
  • OS indicates left eye
  • OU indicates both eyes.
  • LogMAR is a visual acuity chart specialized for research settings. LogMAR values approximate to Snellen Chart values as follows: 1.00 (20/200), 0.90 (20.160), 0.80 (20.125), 0.70 (20.100), 0.60 (20.80), 0.50, (20.63), 0.40 (20.50), 0.30 (20.40), 0.20 (20.32), 0.10 (20.25), 0.00 (20.20), - 0.10 (20.16), -0.20 (20.13), -0.30 (20.10). * indicates failure of the Neuroptix pupillometer. Results
  • pilocarpine at a concentration of about 1.25% w/v
  • polyoxyl 40 stearate at a concentration of about 5.5% w/v
  • carbomer 940 at a concentration of about 0.50% w/v
  • citric acid monohydrate at a concentration of about 0.10% w/v
  • a subject with a best corrected 20.15 acuity eye was subject to refractive correction from 0.0 diopters ("D") to the myopic targets indicated (-0.5 D to -6 D). At all diopters tested the subject was topically administered a combination of aceclidine and tropicamide to adjust pupil size.
  • pinhole optics substantially correct refractive error at or about 2.0 mm or less;
  • the improvement is degraded by about 1 line of vision or more once
  • the present invention demonstrates that pupil sizes ranging from about 1.7 - 2.1 mm result in substantial near vision improvement with no demonstrable accommodation;
  • the additive benefit of 0.50 D of accommodative tone might further enhance near vision improvement without deleterious effect on distance.
  • Formula #34 and Formula #35 were each instilled at separate times in the eye of a subject, which had 20.20 distance vision acuity and 20.40 near vision acuity and a pupil size of 5 millimeters. Distance and near vision were checked using Jaeger near charts and Snellen distance acuity charts at the times indicated in Table 11. Pupil size was measured using an Orbscan ® IIz with no room illumination or adjustment for measured pupil size and compared with a Marco video caliper adjusted scale.
  • Formula #35 constricted the pupil to 1.9 mm after 1 hour and maintained constriction to 2 mm and 2.1 mm at 4 and 6 hours, respectively. Instillation of Formula #35 resulted in improvement of distance vision to 20.15 for 5 hours, which returned to 20.20 at 7 hours. Further, instillation of Formula #35 resulted in improvement of near vision to 20.20 at 4 hours, 20.25 at 7 hours and 20.30 at 8 hours post instillation. Pupil miosis occurred 20 minutes after instillation and resulted in only slight ciliary sensation and redness and no discomfort beyond a medium discomfort for 15 seconds following instillation. See Table 11.
  • BA ciliary sensation: 0.5 slight sharp well tolerated sensation, 1.0 discomfort, 2.0 - 4.0 definite pain to intolerable
  • Formula #35 is an improvement over the use of a formula containing 1% pilocarpine and 0.12% oxymetazoline as described in U.S. Patent Application Publication No. 2014/0113946 ("Allergan Formula"). Specifically, the Allergan Formula resulted in near vision correction of 3.5 lines up to 4 hours after instillation and 2.1 lines of correction at 6 hours post instillation. Instillation of Formula #35 resulted in comparable, yet longer lasting, near vision correction with 3 lines of correction up to 4 hours after instillation and 2 lines of correction at more than 7 hours post instillation.
  • instillation of Formula #35 resulted in an unexpected and marked improvement in distance vision over the Allergen Formula. Specifically, instillation of the Allergan Formula resulted in a deterioration in distance vision of -0.65 lines (26% reduction) for up to 4 hours; whereas instillation of Formula #35 resulted in an improvement of distance vision of 0.7 lines (26% increase) for more than 5 hours.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions et des méthodes de traitement de la presbytie. Dans un mode de réalisation préféré de l'invention, la correction de la presbytie s'effectue sans réduction de l'acuité de la vision de loin. Les compositions selon l'invention contiennent de préférence un agoniste muscarinique et un agent cycloplégique.
PCT/US2016/036694 2015-06-18 2016-06-09 Compositions et méthodes de traitement de la presbytie Ceased WO2016205071A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US14/742,903 US9320709B2 (en) 2013-08-28 2015-06-18 Storage stable compositions and methods for the treatment of refractive errors of the eye
US14/742,921 US9314427B2 (en) 2013-08-28 2015-06-18 Compositions and methods for the improvement of distance vision and the treatment of refractive errors of the eye
US14/742,903 2015-06-18
US14/742,921 2015-06-18
US14/860,777 2015-09-22
US14/860,770 US9968594B2 (en) 2013-08-28 2015-09-22 Compositions and methods for the treatment of presbyopia
US14/860,777 US10064818B2 (en) 2013-08-28 2015-09-22 Compositions and methods for the treatment of presbyopia
US14/860,770 2015-09-22

Publications (1)

Publication Number Publication Date
WO2016205071A1 true WO2016205071A1 (fr) 2016-12-22

Family

ID=57545731

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/036694 Ceased WO2016205071A1 (fr) 2015-06-18 2016-06-09 Compositions et méthodes de traitement de la presbytie

Country Status (1)

Country Link
WO (1) WO2016205071A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12128036B2 (en) 2018-10-10 2024-10-29 Lenz Therapeutics Operations, Inc. Compositions and methods for storage stable ophthalmic drugs
US12180206B2 (en) 2021-11-17 2024-12-31 Lenz Therapeutics Operations, Inc. Aceclidine derivatives, compositions thereof and methods of use thereof
EP4288049A4 (fr) * 2021-02-04 2025-01-01 Sydnexis, Inc. Compositions ophtalmiques pour la presbytie
US12414942B1 (en) 2024-03-15 2025-09-16 Lenz Therapeutics Operations, Inc. Compositions, methods, and systems for treating presbyopia

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120028910A1 (en) * 2007-10-08 2012-02-02 Jean-Philippe Combal Storage-stable aqueous ophthalmic formulations
US20120315265A1 (en) * 2011-06-13 2012-12-13 Chang Gung University Hydrogel-forming polymer, and preparation process and uses thereof
US20140221446A1 (en) * 2013-02-01 2014-08-07 Ocularis Pharma, Llc Methods and compositions for daily ophthalmic administration of phentolamine to improve visual performance
US20150065511A1 (en) * 2013-08-28 2015-03-05 Presbyopia Therapies, LLC Compositions and Methods for the Treatment of Presbyopia
US20160008278A1 (en) * 2013-08-28 2016-01-14 Presbyopia Therapies, LLC Compositions and Methods for the Treatment of Presbyopia

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120028910A1 (en) * 2007-10-08 2012-02-02 Jean-Philippe Combal Storage-stable aqueous ophthalmic formulations
US20120315265A1 (en) * 2011-06-13 2012-12-13 Chang Gung University Hydrogel-forming polymer, and preparation process and uses thereof
US20140221446A1 (en) * 2013-02-01 2014-08-07 Ocularis Pharma, Llc Methods and compositions for daily ophthalmic administration of phentolamine to improve visual performance
US20150065511A1 (en) * 2013-08-28 2015-03-05 Presbyopia Therapies, LLC Compositions and Methods for the Treatment of Presbyopia
US20160008278A1 (en) * 2013-08-28 2016-01-14 Presbyopia Therapies, LLC Compositions and Methods for the Treatment of Presbyopia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Lubrizol Pharmaceutical Bulletin 21", 31 May 2011 (2011-05-31), pages 4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12128036B2 (en) 2018-10-10 2024-10-29 Lenz Therapeutics Operations, Inc. Compositions and methods for storage stable ophthalmic drugs
EP4288049A4 (fr) * 2021-02-04 2025-01-01 Sydnexis, Inc. Compositions ophtalmiques pour la presbytie
US12180206B2 (en) 2021-11-17 2024-12-31 Lenz Therapeutics Operations, Inc. Aceclidine derivatives, compositions thereof and methods of use thereof
US12414942B1 (en) 2024-03-15 2025-09-16 Lenz Therapeutics Operations, Inc. Compositions, methods, and systems for treating presbyopia

Similar Documents

Publication Publication Date Title
AU2019200623B2 (en) Compositions and methods for the treatment of presbyopia
US10064818B2 (en) Compositions and methods for the treatment of presbyopia
AU2016280616B2 (en) Compositions for the improvement of distance vision and the treatment of refractive errors of the eye
US9320709B2 (en) Storage stable compositions and methods for the treatment of refractive errors of the eye
US9314427B2 (en) Compositions and methods for the improvement of distance vision and the treatment of refractive errors of the eye
US9968594B2 (en) Compositions and methods for the treatment of presbyopia
WO2020076769A1 (fr) Compositions et procédés pour le traitement de la presbytie
EP3429584A1 (fr) Compositions et méthodes de traitement de la presbytie
WO2016205071A1 (fr) Compositions et méthodes de traitement de la presbytie
WO2019135927A1 (fr) Compositions et procédés pour le traitement de la presbytie
HK40111435A (en) Storage stable compositions and methods for the treatment of refractive errors of the eye
HK40014460A (en) Aceclidine for use in the treatment of presbyopia
HK40014460B (en) Aceclidine for use in the treatment of presbyopia

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16812175

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16812175

Country of ref document: EP

Kind code of ref document: A1