EP3853317A2 - Larmes artificielles, lentilles de contact et compositions de véhicule pour médicament et leurs procédés d'utilisation - Google Patents

Larmes artificielles, lentilles de contact et compositions de véhicule pour médicament et leurs procédés d'utilisation

Info

Publication number
EP3853317A2
EP3853317A2 EP19863887.6A EP19863887A EP3853317A2 EP 3853317 A2 EP3853317 A2 EP 3853317A2 EP 19863887 A EP19863887 A EP 19863887A EP 3853317 A2 EP3853317 A2 EP 3853317A2
Authority
EP
European Patent Office
Prior art keywords
composition
poloxamer
compositions
millimolar
tear
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19863887.6A
Other languages
German (de)
English (en)
Other versions
EP3853317A4 (fr
Inventor
Gerald Horn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ps Therapy Inc
Original Assignee
Ps Therapy Ltd
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 US16/137,738 external-priority patent/US20190021990A1/en
Priority claimed from US16/372,582 external-priority patent/US20190224136A1/en
Priority claimed from US16/372,625 external-priority patent/US11583496B2/en
Priority claimed from US16/372,596 external-priority patent/US20190225917A1/en
Priority claimed from US16/412,943 external-priority patent/US20190262290A1/en
Application filed by Ps Therapy Ltd filed Critical Ps Therapy Ltd
Publication of EP3853317A2 publication Critical patent/EP3853317A2/fr
Publication of EP3853317A4 publication Critical patent/EP3853317A4/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • 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
    • A61K47/26—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
    • A61K47/36—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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the invention is directed to mild dry eye artificial tear compositions, moderate dry eye artificial tear compositions, severe dry eye artificial tear compositions, extreme dry eye artificial tear compositions; contact lens multi-purpose storage solution compositions, contact lens wear treatment compositions, contact lens saline enhanced blister pack storage compositions, and topical drug vehicle platform compositions for ophthalmological and dermatological use.
  • compositions comprise one or more nonionic surfactants, and two or more excipients selected from non-Newtonian viscosity enhancer(s), polyols, and electrolyte; or hypotonic electrolyte/sodium chloride concentrations; and optionally an ophthalmological antibiotic, steroid, nonsteroidal, immunosuppressant, glaucoma, or other drug for topical delivery onto or into the eye.
  • the invention is further directed to methods of treating a spectrum of ocular surface disease epitheliopathies including but not limited to dry eye in a human or mammal.
  • the invention is further directed to contact lenses, punctum plugs, pellets or any other device used to deliver drugs to the surface of the eye, coated or infused with compositions of the invention.
  • the eye produces tears that are spread across the eye while blinking.
  • the unique components of tears combined with the blinking process create a tear film that is made up of a mucous layer, an aqueous layer and a lipid layer.
  • This tear film undergoes significant forces that can compromise the integrity of the film including: 1) evaporation, 2) spreading along the ocular surface, which is driven by high shear blinks, 3) draining, which is aided by blink powered lacrimal pumping and 4) low shear flow along the lid tear menisci.
  • the film is continually replenished with new tear film components upon each blink, which is triggered by tear breakup and corneal surface nerve excitation.
  • tears have critical components derived from the blood plasma that are filtered to nourish the ocular surface, reduce infection risk and promote healing of ocular surface tissues.
  • a healthy tear film is necessary for optimal vision just as an unhealthy tear film results in degradation of visual quality and or acuity.
  • There are several events that can cause a reduction in the quantity or quality of tears including intra- or extraocular surgery affecting the ocular surface, dry eye syndrome, dry eye following eye surgery, ocular surface abnormalities from medication and or preservative toxicity, and contact lens solution and or contact lens use.
  • the tear film is the single most important optical surface. Disturbances that affect the quality and duration of that film on the cornea can dramatically alter quality of vision. These disturbances include reduced volume as measured by Schirmer’s test, reduced tear breakup time and reduced tear prism (i.e. the measure of the meniscus along the lower lid where tears flow).
  • the true measures of a healthy tear film the thickness and or volume of each layer, the composition within each layer, and the resulting flow properties and stabilization of the tear film are not easily measured. Tear abnormalities manifest as a large range of tear deficiencies from composition abnormalities of one or more of the mucous, aqueous and lipid layers to volume abnormalities including reduction in the thickness and or volume of one or more of these layers and combinations thereof.
  • Dry eye is a generic term for any abnormality in tear layer thickness or tear layer composition. Dry eye is a common affliction that is caused by the failure of the eye to produce either an adequate amount or maintain a proper balance of tear components in the mucous, aqueous or lipid layers. In either instance, the tear film that normally covers the eye becomes unstable (i.e. no longer covers the entire eye evenly and for a sufficient period.) A sufficient period is typically about eight seconds. Tear film instability causes tears to bead up leaving surface coverage dry spots while failing to remove irritants. These dry spots and irritants cause many of the conditions associated with dry eye such as burning, stinging, itching and tired eyes.
  • Dry eye symptoms can be exacerbated by activities that extend the time between eye blinks such as prolonged computer use and reading. Even mild tear film degradation can reduce the tear break up time (“TBUT”) leading to excessive blinking. Blinking may achieve brief moments of complete even tear film coverage where vision is optimized. However, this relief is sporadic and short-lived and the tear film may become degraded altogether making even frequent blinking ineffective.
  • TBUT tear break up time
  • Dry eye often occurs following any incisional or ablative procedure that cuts corneal nerves, by reducing the neurologic trigger for tear secretion, or disrupting the external surface creating abnormal spreading and elevated dry spots (dellen).
  • Procedures include: corneal or scleral eye surgery including but not limited to cataract incisions; corneal transplant surgery; glaucoma surgery filtering blebs; and any incisional or ablative corneal surgery. Dry eye following eye surgery can lead to increased pain to the patient, increased infection risk, reduced vision and increased sensitivity to topical medications and preservatives. This increased sensitivity may exacerbate ocular surface disease, have similar symptomatology to dry eye, and result in prolonged epithelial healing times.
  • Celluvisc ® Celluvisc is a registered trademark of Allergan, Inc.
  • CMC carboxymethyl cellulose
  • cps centipoise
  • Refresh Liquigel ® Refresh Liquigel is a registered trademark of Allergan, Inc.
  • These high viscosity artificial tear compositions are long lasting but cause significantly blurred vision lasting up to 10 minutes or longer.
  • the third generation promotes slower lacrimal duct drainage and greater retention on the eye by providing non-Newtonian flow properties. However, the third generation has only moderate tear layer stabilization and retention. The third generation also decreases the duration of blur and stabilizes the tear film. However, third generation formulations are oilier and their unnatural,‘moisture-lacking’ sensation makes them less popular than many products on the market today from the second generation. Further, the third generation has very little demonstrated therapeutic clinical differentiation from the second generation.
  • a fourth generation was developed consisting of lipid-based oil - in - water (“O/W”) emulsions. The O/W emulsions of the fourth generation reduces tear film evaporation, stabilizes the lipid layer and prolongs duration.
  • O/W lipid-based oil - in - water
  • formulations require the addition of nonionic or cationic surfactants for stabilization.
  • these formulations do not promote increased spreading, provide any useful adjunctive aqueous layer stabilizers across the eye, or retard high shear blink lacrimal pumping leading to minimally enhanced retention.
  • These formulations may be limited by the low concentrations of surfactants in conventional artificial tears due to their known toxicity at 1.0% or greater. Additionally, as with the third generation, the fourth-generation artificial tear has minimal therapeutic detectable clinical benefit and a synthetic and less comfortable quality.
  • Biofilms reduce the efficacy of antimicrobial solutions and increase the rate of attachment of microbes.
  • the most dangerous of these microbes include spores of Acanthamoeba spp. and filaments of Fusarium fungi. Attachment of these pathogenic microbes may result in severe and difficult to treat keratitis that may cause partial or even complete vision loss from ensuing infections.
  • Many contact lenses incorporate antimicrobial compounds within the contact lens to counteract such infestations. However, these efforts are not always effective and long wear times increase the risk of pathogenic infections.
  • Ophthalmic drug efficacy is severely limited by non-compliance. Compliance is adversely affected by the reduced comfort, irritation, and transient quality of vision loss, which lasts minutes to tens of minutes, that is common to many drugs. In particular, these adverse effects are caused by suspensions commonly used for highly lipophilic drugs or the requirement of very high topical concentrations for highly hydrophilic drugs.
  • Gelling agents have been used with some success in increasing drug residence time and improving drug solubility. By definition such agents are instilled as liquid and then almost immediately triggered to a gel phase, where drug residence time is increased and drug release time extended.
  • Timoptic XE® gel (gellan gum; Timoptic XE is a registered trademark of Merck & Co, Inc.), AzaSite® (Azasite is a registered trademark of Insite Vision, Inc.) (polycarbophil, poloxamer), and Besivance® (Besivance is a registered trademark of Bausch & Lomb, Inc.), (polycarbophil, poloxamer), 0.3% alginate Keltrol®) (Keltrol is a registered trademark of CP Kelco U.S., Inc.) are examples of such agents, where polycarbophil-poloxamer gels are commercially known as Durasite® (Durasite is a registered trademark of Insite Vision, Inc.).
  • Gelling agents experience a phase transition to a highly viscous state, typically achieving 500-1000 cps or more after their transition. Ionic, pH, and thermal triggers are typically used. However, the high shear force of each blink breaks up such phase modified films into discrete particles easily drained into the nasolacrimal duct to the nasal turbinates where residual drug may readily enter systemic circulation.
  • Many gelling agents combine poloxamers of various molecular weights with viscosity enhancers or other gelling agents to create the desired phase transition from liquid on instillation to gel. Typically for those formulations using poloxamer without a second gelling agent, poloxamer concentrations of 15% or greater are needed to achieve gel -transition temperatures at body temperature (37° C.).
  • Patel Int. J. of Pharm. Chem. Sci., Vol. 1, October-December 2012, describes the use of poloxamer and a viscosity enhancing agent— a low molecular weight, low viscosity hydroxypropylmethyl cellulose (HPMC E50LV) 1.5% with brimonidine, and demonstrates on testing concentrations of poloxamer with the HPMC from 1% to 19%, no clinically useful gelling capacity in vitro below 15%. Given the dilution of tear film, this typically requires about 21% poloxamer to achieve phase transition to gel on ophthalmic instillation. For example, Qian (Drug Dev.
  • This composition should reduce discomfort, reduce debris and particulate accumulation and increase wear time while being comfortable to the wearer. Particularly, this composition should reduce the formation of biofilm and attachment of Acanthamoeba spores and Fusarium filaments.
  • the present invention is directed to artificial tear compositions comprising surprising and unexpected combinations whereby one or more nonionic surfactants and at least one excipient selected from a viscosity enhancer, a polyol and an electrolyte confer the desired properties of enhanced therapeutic tear enhancement.
  • the present invention is directed to artificial tear compositions comprising a means for inducing tears and a means for sequestering tears.
  • the means for inducing tears is selected from a pH from about 5 to about 6, a terpenoid and an osmolarity of from about 270 to about 550 milliosmoles.
  • the means for sequestering tears comprises from about 1.5% to about 5.9% w/v total volume of one or more nonionic surfactants and one or more viscosity enhancers, wherein the one or more viscosity enhancers provides a viscosity of from about 50 to about 10,000 centipoise at 0 shear to 1 second.
  • the one or more nonionic surfactants are selected from the group consisting of poloxamers, polysorbates, cyclodextrins (alpha, beta or gamma), alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls.
  • the one or more viscosity enhancers are selected from the group consisting of cellulose derivatives, carbomers, gums, dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycols, propylene glycol, chitosans, and hyaluronates and hyaluronic acids, more preferably the cellulose derivatives are selected from the group consisting of carboxymethyl cellulose (“CMC”) high molecular weight blend, CMC low molecular weight blend, CMC moderate molecular weight blend, methylcellulose, methyl cellulose 4000, hydroxy methyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (“HPMC”) high molecular weight blend, hydroxylpropylmethyl cellulose 2906, carboxypropylmethyl cellulose (CPMC) high molecular weight blend, hydroxyethyl cellulose, hydroxymethyl cellulose and combinations thereof.
  • CMC carboxymethyl cellulose
  • CMC carboxymethyl cellulose
  • CMC
  • the artificial tear compositions of the present invention further comprise a polyol, preferably selected from the group consisting of mannitol, xylitol, sorbitol, isosorbide, erythritol, glycerol, maltitol and a combination thereof.
  • the artificial tear compositions of the present invention further comprise one or more electrolytes, preferably selected from the group consisting of magnesium ions, sodium chloride, potassium chloride and a combination thereof.
  • the artificial tear compositions of the present invention do not contain magnesium ions including magnesium chloride.
  • the artificial tear compositions of the present invention further comprise one or more lipids, preferably omega 3 fatty acids.
  • the present invention is directed to artificial tear compositions comprising one or more nonionic surfactants and a polyol.
  • the present invention is directed to artificial tear compositions comprising one or more nonionic surfactants and an electrolyte.
  • the present invention is directed to artificial tear compositions comprising one or more nonionic surfactants, a polyol and an electrolyte.
  • the present invention is directed to artificial tear compositions comprising one or more nonionic surfactants, a viscosity enhancer and a polyol.
  • the present invention is directed to artificial tear compositions comprising one or more nonionic surfactants, a viscosity enhancer and an electrolyte.
  • the present invention is directed to artificial tear compositions comprising one or more nonionic surfactants, a viscosity enhancer, a polyol and an electrolyte.
  • the present invention is directed to artificial tear compositions comprising one or more nonionic surfactants, preferably at a concentration from about 1.25% to about 10.0% w/v, one or more viscosity enhancers and a means of inducing tearing including via nociception, preferably selected from the group consisting of a pH below 6.0; an osmolarity of about 250 mosm less, an osmolarity of 350 mosm or more; an osmolarity of 400 mosm or more; an osmolarity of 450 mosm or more; from about 0.05 to about 4.0 mM menthol and a combination thereof, preferably resulting in induced tearing and prolonged sequestration.
  • the present invention is directed to artificial tear compositions comprising from about 1.5% to about 5.9% w/v total concentration of one or more nonionic surfactants, one or more viscosity enhancers, a means of inducing tearing selected from the group consisting of a pH below 6.0; an osmolarity of 350 mosm or more; menthol, and a combination thereof.
  • the present invention is directed to artificial tear compositions comprising from about 1.5% to about 5.9% w/v total concentration of one or more nonionic surfactants and one or more excipient selected from the group consisting of a viscosity enhancer, a polyol and an electrolyte.
  • the present invention is directed to artificial tear compositions comprising:
  • nonionic surfactants selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls at a total concentration from about 1.25% to about 7.0% w/v, preferably selected from the group consisting of about 0.01% to about 4.0% w/v of a polysorbate, from about 0.01% to about 3.0% w/v of one or more poloxamers, from about 0.01% to about 1.0% w/v of a polyoxyl and from about 0.01% to about 5.0% w/v hydroxypropyl-gamma-cyclodextrin;
  • a viscosity enhancer selected from the group consisting of cellulose derivatives, carbomers, gums, dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycol, propylene glycol, chitosans, hyaluronates, hyaluronic acids and combinations thereof; from about 0.01% to about 3.0% w/v of an electrolyte selected from the group consisting of sodium chloride, potassium chloride, magnesium ions and combinations thereof, preferably the electrolyte is selected from about 0.01% to about 0.90% w/v magnesium ions, from about 0.10% to about 2.0% w/v sodium chloride, from about 0.1% to about 0.5% w/v potassium chloride and combinations thereof;
  • a polyol preferably the polyol is 0.25% to about 2.5% w/v of mannitol or from 0.5% to about 2.5% w/v glycerol;
  • a means of inducing tearing selected from the group consisting of a pH below 6.0; an osmolarity of 350 mosm or more; menthol, and a combination thereof; and
  • the concentration of the viscosity enhancer provides a composition with a viscosity from about 0.1 to about 1,000 centipoise (cps), and preferably, wherein a low shear viscosity is from about 1 to about 1000 cps and a final high shear viscosity is about 30 cps or less.
  • cps centipoise
  • the present invention is directed to artificial tear compositions comprising:
  • nonionic surfactants selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls at a total concentration from about 1.25% to about 7.0% w/v
  • the one or more nonionic surfactants are selected from the group consisting of from about 0.01% to about 4.0% w/v of a polysorbate, from about 0.01% to about 3.0% w/v of one or more poloxamers, from about 0.01% to about 1.0% w/v of a polyoxyl and optionally, from about 0.01% to about 5.0% w/v hydroxypropyl-gamma-cyclodextrin; optionally, from about 0.1% to about 0.75% w/v sodium chloride;
  • a polyol optionally, from about 0.1% to about 4% w/v of a polyol, preferably the polyol is mannitol or glycerol at a concentration from about 1.0% to about 2.5% w/v;
  • a viscosity agent selected from the group consisting of cellulose derivatives, carbomers, gums, dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycol, propylene glycol, chitosans, hyaluronates, hyaluronic acids and combinations thereof, preferably wherein the composition has a viscosity from about 1 to about 1,000 centipoise; and
  • magnesium ions optionally, from about 0.01% to about 0.90% w/v magnesium ions.
  • the present invention is directed to artificial tear compositions comprising:
  • nonionic surfactants selected from the group consisting of polysorbates, poloxamers, polyoxyl castor oils, cyclodextrins and combinations thereof;
  • a viscosity enhancer selected from the group consisting of carboxymethyl cellulose and carbomer 940;
  • a polyethylene glycol having a molecular weight from about 400 to about 20,000 Daltons preferably selected from polyethylene glycol 400, polyethylene glycol 6000, polyethylene glycol 10000, polyethylene glycol 20000 and a combination thereof; from about 0.1% to about 2.0% w/v sodium chloride; and
  • w/v denotes weight by total volume of the composition and wherein the composition has a pH from about 5.0 to about 7.4, preferably from about 5.0 to about 6.0.
  • the present invention is further directed to methods of treating dry eye comprising administering a composition of the present invention to a subject in need thereof.
  • the present invention is further directed to methods of treating ocular surface defects, deficiencies and disease selected from the group consisting of superficial punctate keratitis, epithelial abrasions, post-surgical ocular surface abnormality such as post glaucoma shunt, post cataract, post refractive surgery, dry eye syndrome, keratoconjunctivitis sicca, dry eye following incisional or ablative surgery such as corneal/glaucoma surgery, cataract incisions, corneal transplant, glaucoma surgery filtering blebs, ocular surface abnormalities caused by medication, preservatives, contact lens solution and contact lens use or methods of treating endophthalmitis.
  • post-surgical ocular surface abnormality such as post glaucoma shunt, post cataract, post refractive surgery, dry eye syndrome, keratoconjunctivitis sicca, dry eye following incisional or ablative surgery such as corneal/glaucoma surgery, cataract incisions, corneal transplant, glaucoma surgery
  • the present invention is further directed to methods of treating eye pain comprising administering a composition of the present invention to a subject in need thereof.
  • the present invention is further directed to methods of enhancing wound healing following corneal surgery comprising administering a composition of the present invention to a subject in need thereof.
  • the present invention is further directed to methods of treating Meibomian gland dysfunction comprising administering a composition of the present invention to a subject in need thereof.
  • the present invention is further directed to an artificial tear composition
  • an artificial tear composition comprising one or more nonionic surfactants, one or more viscosity enhancers, a polyol, one or more electrolytes and menthol.
  • the one or more nonionic surfactants are polysorbate 80, poloxamer 407, poloxamer 188 and polyoxyl castor oil.
  • the one or more viscosity enhancers are selected from cellulose derivatives.
  • the polyol is mannitol.
  • the one or more electrolytes are magnesium chloride and sodium chloride.
  • the one or more nonionic surfactants are polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma- cyclodextrin.
  • the artificial tear compositions of the present invention further comprise a polyethylene glycol.
  • the polyethylene glycol is polyethylene glycol
  • the artificial tear compositions of the present invention further comprise ascorbic acid or d-alpha tocopherol.
  • the cellulose derivative is at a concentration that provides a viscosity equivalent to hydroxypropylmethyl cellulose at a concentration from about 0.01% to about 2.5% w/v, more preferably from about 0.01% to about 1.5% w/v or high molecular weight carboxymethyl cellulose at a concentration from about 0.01% to about 1.5% w/v, wherein “high molecular weight” is at 3,500 cps or more.
  • the menthol is at a concentration from about 0.01 to about 4.0 millimolar, more preferably from about 0.01 to about 0.50 millimolar and even more preferably from about 0.01 to about 0.40 millimolar.
  • the present invention is further directed to an artificial tear composition
  • an artificial tear composition comprising from about 0.5% to about 1.5% w/v polysorbate 80, preferably, from about 1.00% to about 1.50% w/v polysorbate 80, from about 0.5% to about 1.5% w/v poloxamer 407, preferably from about 0.7% to about 1.00% w/v poloxamer 407, from about 0.20% to about 1.00% w/v poloxamer 188, from about 0.01% to about 0.50% w/v polyoxyl castor oil, preferably from about 0.01% to about 0.30% w/v polyoxyl castor oil, from about 0.1% to about 2.0% w/v carboxymethyl cellulose, preferably from about 0.1% to about 1.5% w/v carboxymethyl cellulose and from about 0.01 to about 0.50 millimolar menthol, preferably from about 0.01 to about 0.40 millimolar menthol and optionally, from about 0.1% about 1.5% w/v polyethylene glycol 400
  • the artificial tear compositions of the present invention further comprise from about 0.1% to about 0.15% w/v sorbate, preferably from about 0.11% to about 0.12% w/v sorbate.
  • the artificial tear compositions of the present invention further comprise greater than 0.1% w/v sorbate, preferably from 0.11% to about 10.0% w/v.
  • the artificial tear compositions of the present invention further comprise from about 0.25% to about 5.5% w/v hydroxypropyl-gamma- cyclodextrin, preferably from about 1.5% to about 2.0% w/v.
  • the artificial tear compositions of the present invention further comprise from about 1 to about 200 international units of d-alpha tocopherol, preferably from about 30 to about 50 international units.
  • the artificial tear compositions of the present invention have a pH from about 5.7 to about 8.0, preferably from about 5.7 to about 6.5.
  • the present invention is further directed to an artificial tear composition
  • an artificial tear composition comprising from about 0.5% to about 1.5% w/v polysorbate 80, preferably, from about 1.00% to about 1.50% w/v polysorbate 80, from about 0.5% to about 1.5% w/v poloxamer 407, preferably from about 0.7% to about 1.00% w/v poloxamer 407, from about 0.20% to about 1.00% w/v poloxamer 188, from about 0.01% to about 0.50% w/v polyoxyl castor oil, preferably from about 0.01% to about 0.30% w/v polyoxyl castor oil, from about 0.1% to about 2.0% w/v hydroxypropylmethyl cellulose, preferably from about 0.1% to about 1.2% w/v hydroxypropylmethyl cellulose, from about 0.1% about 1.5% w/v polyethylene glycol 400, preferably about 0.50% w/v polyethylene glycol 400, from about 0.5% to about 1.5% mannito
  • An artificial tear composition comprising about 3.5% w/v polysorbate 80, a viscosity enhancer selected from about 0.8% to about 1.2% hydroxypropylmethyl cellulose and from about 1% to about 1.4% w/v carboxymethyl cellulose, about 0.75% w/v polyethylene glycol 400, from about 0.5% to about 0.75% w/v mannitol, from about 0.6% to about 1.25% w/v sodium chloride, from about 0.1 to about 3.0 millimolar menthol and from about 0.1% to about 0.12% w/v sorbate, wherein the composition has a pH from about 6 to about 6.5.
  • An artificial tear composition comprising about 1% w/v polysorbate 80, about 1% w/v poloxamer 407, about 0.2% w/v poloxamer 188, about 0.25% w/v polyoxyl castor oil, about 1.5% w/v hydroxypropyl gamma cyclodextrin, a viscosity enhancer selected from about 0.8% to about 1.2% hydroxypropylmethyl cellulose and from about 1% to about 1.4% w/v carboxymethyl cellulose, about 0.75% w/v polyethylene glycol 400, from about 0.5% to about 0.75% w/v mannitol, from about 0.6% to about 0.7% w/v sodium chloride, from about 0.1 to about 3.0 millimolar menthol, wherein the composition has a pH from about 6 to about 6.5.
  • all artificial tear compositions of the present invention are capable of being used as contact lens compositions.
  • the present invention is further directed to a contact lens storage composition
  • a contact lens storage composition comprising:
  • nonionic surfactants selected from the group consisting of polysorbates, polyoxyls, cyclodextrins, poloxamers, alkyl aryl polyethers and polyoxyethyleneglycol alkyl ethers at a total concentration from about 1.5% to about 5.9% w/v;
  • a viscosity agent optionally, a viscosity agent.
  • the present invention is further directed to a punctum plug or a pellet coated or infused with one or more nonionic surfactants at a total concentration from about 1.25% to about 7.0% w/v, preferably the one or more nonionic surfactants are selected from poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, and polyoxyls.
  • the present invention is further directed to a method of enhancing contact lens wear time comprising administering a composition of the present invention to a subject in need thereof.
  • the present invention is further directed to a method of reducing Acanthamoeba spp. cyst count on contact lenses comprising administering a composition of the present invention to a subject in need thereof.
  • the present invention is further directed to a method of treating dry eye comprising applying the artificial tear composition of the present invention to a surface of a contact lens, optionally the application is overnight storage or immediately prior to instillation of the contact into the eye of the subject in need thereof, and inserting the contact lens into an eye of a subject in need thereof and optionally administering the composition of the present invention to the eye of the subject prior to inserting the contact lens.
  • the present invention is further directed to a method of reducing contact lens deposits comprising applying the contact lens compositions of the present invention to a contact lens surface and optionally to an eye to which the contact lens is inserted.
  • all artificial tear compositions of the present invention are capable of being used as drug vehicles.
  • the present invention is directed to an ophthalmological drug composition
  • an ophthalmological drug composition comprising a means to sequester tears and an ophthalmological drug, preferably selected from the group consisting of trehalose, cyclosporine (cyclosporine is the active ingredient in Restasis® available from and a registered trademark of Allergan, Inc.
  • lifitegrast is the active ingredient in Xiidra® available from and a registered trademark of SARcode Bioscience Inc.
  • diquafosol is the active ingredient in Diquas® available from and a registered trademark of Santen Pharmaceutical Co., Ltd
  • a C-terminal 25 amino acid fragment of lacritin known as Lacripep® available from and a registered trademark of TearSolutions, LLC
  • lacritin KPI-121
  • KPI-121 is the active ingredient in InveltysTM available from Kala Pharmaceuticals
  • tivanisiran is the active ingredient in Sylentis® available from and a registered trademark of Sylentis, S.A.U.
  • omega 3 fatty acids an antibiotic, a steroid anti-inflammatory, a nonsteroidal anti-inflammatory, a glaucoma drug, a prostaglandin, a mus
  • the present invention is further directed to an ophthalmological drug vehicle composition
  • an ophthalmological drug vehicle composition comprising an ophthalmological drug and one or more nonionic surfactants and at least one excipient selected from a viscosity enhancer, a polyol and an electrolyte
  • the ophthalmological drug is selected from the group consisting of diquafosol, cyclosporine, a prostaglandin, an antibiotic, a muscarinic receptor agonist, a non steroidal anti-inflammatory, a steroidal anti-inflammatory, GLC.
  • acetylsalicylic acid, salicylic acid and a combination thereof are examples of acetylsalicylic acid, salicylic acid and a combination thereof.
  • compositions of the present invention are capable of solubilizing or encapsulating an ophthalmological drug and providing a prolonged exposure to the surface of the eye. This prolong exposure may allow the drug to be both longer acting and increase the penetration of the drug into the eye.
  • Ophthalmological drugs suitable for use in the present invention include, but are not limited to, diquafosol, cyclosporine, a prostaglandin, an antibiotic, a non-steroidal anti-inflammatory, a steroidal anti-inflammatory or a combination thereof.
  • the present invention is directed to an ophthalmological drug delivery means, preferably selected from the group consisting of contact lenses, punctum plugs and pellets, coated or infused with the compositions of the present invention.
  • ophthalmological drug compositions of the present invention include standard dropper bottles, multi-dose preservative free bottles and unit dose delivery.
  • the present invention is further directed to methods of increasing drug residency time on the surface of the eye comprising the steps of: suspending or dissolving an ophthalmological drug in a composition of the present invention to create an ophthalmological drug composition; and
  • the active agent for the treatment of dry eye achieves greater efficacy via residence time and permeation; and greater efficacy via vehicle sequestration of induced tearing.
  • the present invention is further directed to methods of reducing ocular infections comprising instilling the composition of the present invention into the eye of a subject in need thereof.
  • the present invention is further directed to methods of treating dry age-related macular degeneration, wet age-related macular degeneration or diabetes comprising administering to a subject in need thereof an ophthalmological drug vehicle of the present invention.
  • the present invention is further directed to a topical drug vehicle composition
  • a topical drug vehicle composition comprising a topical drug and one or more nonionic surfactants and at least one excipient selected from a viscosity enhancer, a polyol and an electrolyte, preferably the ophthalmological drug is selected from the group consisting of cyclosporine, a prostaglandin, an antibiotic, a non-steroidal anti-inflammatory, a steroidal anti-inflammatory, GLC and a combination thereof.
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising lidocaine or a salt thereof and magnesium chloride.
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising lidocaine or a salt thereof, magnesium chloride, a nonionic surfactant, a polyethylene glycol, mannitol, a viscosity enhancer and sodium chloride.
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising:
  • magnesium chloride from about 0.05% to about 0.2% w/v magnesium chloride.
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising:
  • the present invention is directed to a method of inducing local anesthesia in an eye of a patient comprising topically applying compositions of the present invention to the eye of the patient.
  • the patent or application file contains at least one drawing executed in color.
  • Figure 2 Graph of Moisture-LockTM effect values over time for various % w/v nonionic surfactant concentrations.
  • Figure 3 Tear breakup (percent vs. time) following inserting a contact lens into the eye that was stored in saline/Refresh® CL.
  • Figure 4 Tear breakup (percent vs. time) following inserting a contact lens into the eye that was stored in Composition Y of the present invention.
  • Figure 9 Average micelle size of Composition #C 12, panel A, and Restasis®, panel B.
  • the present invention is directed to the surprising discovery that artificial tears can be formulated to cover a sufficient surface area of the eye to create an evaporative tear shield that can stabilize the aqueous and lipid layers of the tear film without the addition of lipids.
  • Particularly surprising is the discovery that total concentration of nonionic surfactants may be increased in the presence of the compositions of the present invention to well above 1.0% w/v, which has been demonstrated as toxic in prior art ophthalmological preparations.
  • compositions of the present invention with total nonionic surfactant concentrations up to 7.0% w/v may be routinely instilled in the eye without toxicity.
  • compositions of the present invention surprisingly cause an evaporative tear shield to form and can be formulated to induce natural tearing that is maintained under this evaporative tear shield.
  • the discovery of such compositions is novel because present artificial tears that include lipids do not create an evaporative tear shield and leave an oily, unnatural feeling.
  • the artificial tear compositions of the present invention stabilize the lipid layer of the tear film as well as stabilize and spread the aqueous layer. Components of all three layers of the tear film are critical to successful tear function.
  • the shape of the nano-micelles formed by the artificial tear compositions of the present invention provides an improved barrier to evaporation by covering a substantial portion of the surface of the eye. These nano-micelles may be from about 12 to about 20 nanometers in diameter, from about 12 to about 14 nanometers in diameter, from about 15 to about 20 nanometers in diameter or about 19 nanometers in diameter.
  • the presence of the nano-micelle layer consists of a nonpolar and a polar surface.
  • This dual surface allows compositions of the present invention to not only stabilizes the natural lipid and aqueous layers of the tear film, but also create an evaporative barrier.
  • the nano-micelle layer finds its preferred lowest energy level when against any hydrophobic surface by spreading along that interface. Hydrophobic surfaces of the eye include both the original tear lipid layer and the air- tear interface. Perhaps most important is the effect provided by these specific interactions.
  • the 1) nonpolar seal, 2) polar and nonpolar stabilization of lipid and aqueous layers, 3) improved spreadability per blink, and 4) greater tear film prism provided by the compositions of the present invention create what is called the Moisture-LockTM effect.
  • the Moisture-LockTM effect can be quantified somewhat with tear volume analysis via Schirmer’s strip measurement or phenol thread. However, these tests are notoriously difficult to use accurately due to the many environmental variables including reflex tearing that can compromise these measurements.
  • the viscosity of the composition and additional excipients play an important role in the present invention for a range of conditions that require these variables to be customized.
  • analyzing the Moisture-LockTM effect with these variables fixed produces a well-defined range where the Moisture-LockTM effect occurs. See Example 1 below.
  • the Moisture-LockTM effect results from any natural secretion of tear components and particularly aqueous components being sealed under the nano-micelle layer created by compositions of the present invention. Such sequestration creates prolonged contact of critical aqueous factors resulting in great therapeutic and comfort benefits, much like found with blood serum eye drop application. It has been discovered that a mild to extreme degree of the Moisture- LockTM effect may be triggered by creating even slight tearing, such as by adjusting pH or osmolarity, which then becomes amplified by the tear sequestration property of the present invention.
  • Meibomian ducts are responsible for secreting components of the natural tear that reduce tear evaporation. This clinical condition, known as Meibomian gland dysfunction, plagues not only many dry eye patients, but is a common affliction of glaucoma patients and others that must continually use eye drops.
  • Artificial tear compositions of the present invention also, stimulate secretion of the aqueous component of the natural tear.
  • the evaporative shield created then prevents evaporation of this natural aqueous layer in what is felt by the patient as the Moisture-LockTM effect.
  • the net effect of the stimulation of the natural tear in combination with the ability to sequester it, may provide greater additional exposure of the eyes to natural tear elements than that provided by prescription medications such as Restasis® and Xiidra® (Restasis is a registered trademark of Allergan, Inc. and Xiidra is a registered trademark of SARcode Bioscience Inc.).
  • compositions of the present invention provide an extensive shield that seals in natural tear production via the discovered means of tear sequestration. Even the slightest trigger of natural tearing, which may be induced by pH adjustment, osmolarity adjustment, or addition of components such as menthol, may create an amplified benefit of the present invention by exposing the eye to greater volumes of natural tears. This tear volume exposure is greater than that provided by Restasis® or Xiidra®, which increase tear volume by natural tear secretion only. Further, these topical medications are prescription in nature and extremely costly at as much as $300 per month. However, the present invention discovers novel means of combining generally regarded as safe ingredients to formulate an artificial tear composition with truly surprising and unexpected results over these prior art formulations.
  • the present artificial tear compositions further seal in natural tears for prolonged contact and wetting of the surface of the eye exposing the eye to growth factors, lysozymes, and other tear constituents that help heal and protect the eye.
  • the protective shield provided by the present artificial tear compositions decrease tear wetting angle with formation of large tightly packed nano-micellar structures sealing the entire surface area and providing the unexpected result of a Moisture-LockTM effect. This effect has not been possible with any previous generation of artificial tear.
  • the Moisture-LockTM effect is equivalent to triggering natural tear synthesis for prolonged periods of time and possibly more substantial than plugging the punctal duct.
  • compositions of the present invention nominally trigger, sequester, and restrict tear drainage in the eye with only zero to tens of seconds of visual blur even for the most extreme viscosities, which are only necessary for the most extreme therapeutic needs. This is in stark contrast to prior art formulations, which for example at 400 centipoise requires ten or more minutes of visual blur to stabilize.
  • the present invention is directed to artificial tear compositions comprising one or more nonionic surfactants and an electrolyte such that the compositions achieve desired fluid flow and non-Newtonian (nonlinear vs. lid shear) viscosity properties that are dramatically affected by electrolyte concentration and optimized by electrolyte concentrations that are preferably hypo-osmolar.
  • the present invention is further directed to an artificial tear composition capable of increasing duration of the artificial tear composition on the eye and stabilizing the natural aqueous and lipid layers.
  • the composition further increases duration of exposure of the eye to the stabilized natural aqueous layer including growth factors, antimicrobial factors, and other proteins and nutritional elements.
  • tear breakup time is an antiquated means to quantify tear function and has less clinical relevance than the actual amount and duration of exposure of the corneal epithelium to the nutritional rich aqueous layer.
  • the leading market dominating formulations (Allergan® Refresh® product line) demonstrate the most refreshing sensation of added moisture rather than a synthetic oily feeling.
  • a‘Moisture-LockTM Index’ described in Example 1 below better correlates with extent and duration of this important sensation for an artificial tear to be most tolerated and desired.
  • the present invention is further directed to a method of treating dry eye comprising administering a composition of the present invention to an eye of a subject in need thereof, wherein administration provides sequestration of a tear layer under a nonionic surfactant layer and preferably, wherein the nonionic surfactant layer allows the retention of the aqueous layer via the hydrophobic outer layer aligning with the hydrophobic lipid layer or air.
  • This layer is impervious to water permeation and provides a hydrophilic opposing surface. This opposing surface stabilizes the aqueous layer, and results in the aqueous constituents of normal and induced tears, as well as the therapeutic constituents of the present invention such as the polyol and the electrolytes to maintain prolonged contact with the eye.
  • a further advantage of the present invention is the surprising discovery that addition of viscosity enhancers, particularly cellulose derivatives, carbomers, gums, dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycol, propylene glycol, chitosans, and hyaluronates and hyaluronic acids, provides a low shear non-Newtonian high viscosity between blinks and high shear low viscosity during blinks.
  • the low shear viscosity between blinks helps spread the present artificial tear compositions over the eye and the high shear viscosity during blinks prevents the break up and drainage of the evaporative shield.
  • viscosity agents of the present invention provides a viscosity of 300 - 400 centipoise (“cps”) on instillation, yet within 60 seconds no longer result in visual blur. Further, these viscosity agents provide a differential of about 70 cps between blinks (low shear conditions) and below 30 cps, preferably below 20 cps, during each blink (high shear conditions.) This is about ten times quicker than the vision recovery of similarly viscous conventional drops such as Refresh Celluvisc®.
  • a still further discovery of the present invention is inclusion of a polyol and electrolytes that may protect the surface of the eye and facilitate healing. These additional excipients may also reduce effects of preservative toxicity from other prescribed drops such as antibiotics, steroids, nonsteroidals and or glaucoma drops.
  • concentrations of polyols above about 0.5% w/v and, particularly, above about 1.25% w/v are preferred.
  • compositions of the present invention include:
  • compositions that has high viscosity on instillation that quickly equilibrates to normal tear viscosity and then fluctuates between normal and high viscosities between and during blinks, respectively, by adding particular viscosity agents thus reducing vision blur and prolonging the duration of the composition on the eye; and iv) provision of additional benefits including possible improvement in nerve regeneration and epithelial healing by adding a polyol and magnesium ions in the form of salts.
  • nonionic surfactants Prior to the present invention, nonionic surfactants were used at very low concentrations in artificial tears or as storage/soaking solutions for contact lenses. It was thought that the use of nonionic surfactants at the concentration ranges of the present invention was too toxic for topical application.
  • OTC over-the-counter
  • OTC tear formulations have the disadvantage of: 1) minimal nonionic surfactant stabilization of the natural lipid layer, 2) minimal reduction of wetting angle to enhance spreading of the aqueous layer, 3) insufficient nonionic surfactant for the discovered advantages of improved nano-micelle geometries and 4) required surface area coverage for evaporative shield protection.
  • compositions of the present invention create a“welling of tears” for prolonged periods of time, reflected in creation of a large tear prism thickness along the lower lid margins.
  • a“welling of tears” for prolonged periods of time, reflected in creation of a large tear prism thickness along the lower lid margins.
  • the sensation is further enhanced in most compositions of the present invention by the nonlinear (non-Newtonian) viscosity with increased interblink thickness and very low wetting angle, so that tears tend not to cross the hydrophobic air interface or run down the cheeks despite the larger tear prism along the lid margins.
  • the disclosed invention results in a novel sensation for an hour or longer.
  • This novel sensation is the feeling of trapped tears, resulting from the lining of both lids flooding with moisture to the extent of an overflow onto the lid margin for as long as 60 minutes.
  • This phenomenon herein hereafter referred to as the Moisture- LockTM effect, is measured by the Moisture-LockTM index.
  • the total nonionic surfactant concentration range creates a micellar layer that becomes sufficiently packed to dramatically cover the ocular surface and spread at an extremely low wetting angle acting like a lipid and aqueous stabilizer. This layer also spreads along the air or lipid hydrophobic interface aligning the nonpolar ends to create a robust non- evaporative surface.
  • CMC critical micellar concentration
  • CMT concentration micelle trigger
  • this CMT is surprisingly discovered to occur in a range which is about 15 to 600 times above each of the CMCs of the nonionic surfactant(s) resulting in the discovered non- evaporative shield and the resultant Moisture-LockTM effect.
  • This effect is maintained to a peak within this range and at an upper concentration limit (“CUL”) begins to have surface toxicity as well as reduced effect.
  • This reduced effect is possibly a result of a change in the geometric configuration of the micellar layer(s).
  • micellar layer at or above the CMT provides a concentration range with the CUL as its upper limit within which a coating / shield effect results with two or more of several observed novel properties:
  • tear breakup time is determined by tear chemistry driven beading vs. time and is a difficult variable to measure accurately because it is influenced by irritation and other factors
  • ii) providing extremely low surface tension for most immediate coverage of the corneal surface and any dellen (i.e. irregular topography along the corneal epithelium that creates dry spots);
  • a coating that once placed on a contact lens before insertion provides a long-lasting coating effect that reduces deposits on the contact lens surface and enhances vision on instillation and facilitates improved comfort when instilled during wear, particularly at least 16 hours after instillation of the contact, thus reducing epitheliopathy, with minimal tear dispersion surprisingly discovered for at least 24 seconds compared to a normal tear breakup at 8 seconds;
  • x) a cumulative effect from the combination of two or more of noted features above that improves comfort and health of the corneal surface, allowing growth factors from tears to provide prolonged beneficial protection and healing benefits for a variety of external surface related physiologic stresses and disease states.
  • nonionic surfactants available for ophthalmic use including, but not limited to, polysorbate 20, 60, and 80; tyloxapol, poloxamer 188 and 407; polyoxyl 30 and 40 castor oil; cyclodextrins including hydroxypropyl-gamma-cyclodextrin, gamma cyclodextrin, Brij® 35, 78, 98, and 700 (polyoxyethyleneglycol alkyl ethers; Brij is a registered trademark of Uniqema Americas LLC); Span®20, 40 , 60, and 80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, and sorbitan monooleate; Span is a registered trademark of Uniqema Americas Inc.), or combinations thereof in the concentration range of about 1.5% to about 5.5% w/v and where the critical micellar threshold range
  • polyoxyls and particularly polyoxyl castor oils may preferentially solubilize Meibomian gland secretions.
  • compositions of the present invention especially results in longer lasting tear sequestration.
  • a further surprising discovery of the present invention is the prolonged Moisture-
  • LockTM effect of even mild hyperosmolarity such as provided by increasing concentrations of the electrolyte to about 0.20% w/v or above.
  • sodium chloride is preferred for this purpose. It is believed the very gentle but slight irritation created by a hyperosmolar tear triggers an initial increase in tearing, which becomes“locked” under the micellar layer. This tear secretion is then further sealed by non-Newtonian flow properties providing valuable inotropic growth factors and other nutrients and physiologic components to the surface of the eye. These non- Newtonian flow properties provide sealing by limiting lacrimal drainage via increased viscosity at the low shear between blinks while improving visual acuity by the low viscosity triggered at the high shear during a blink.
  • a polyol, particularly mannitol, and or magnesium ions, and particularly the combination provide protection of the corneal surface from epitheliopathy, including but not limited to the effects of preservatives and or antioxidants.
  • Variations in the a) concentration, particularly of viscosity agent(s), b) epithelial protective excipients such as polyols such as mannitol and c) addition of electrolytes particularly magnesium ions and NaCl provide a means to titrate duration of wetting effect (i.e. Moisture- LockTM effect), degree of initial blur (i.e. from about 0 to 15 seconds), and a range of other effects including protective and therapeutic effects.
  • This variability of compositions of the present invention allow treatment of a range of conditions.
  • MMD meibomian gland dysfunction
  • lid massage and oil expression techniques such as a cotton ball roll along the lid margins.
  • these conditions may also benefit from the robust nonionic surfactant surface layer created in the CMT range for the total nonionic surfactant concentration (i.e. from about 1.5% to about 5.9% w/v, more preferably from about 2.5% to about 4.0% w/v).
  • nonionic surfactants such as polyoxyls, preferably polyoxyl castor oils, and most preferably polyoxyl 30 or 40 castor oil at a concentration from about 0.001% to about 2.0% w/v, and more preferably from about 0.010% to about 1.0% w/v may further enhance such formulations for treatment of MGD. It is additionally discovered that addition of a polyethylene glycol enhances the stability of the composition.
  • the present invention combines a high degree of mucoadhesiveness and temperature sensitive alteration in rheological properties between and during blink. These rheological properties allow for physiologic blinking without blur, and after equilibration, within about 15 to 60 seconds depending on the embodiment selected, creates a thin tear film of about 5- 10 pm. It has been surprising that the present invention: a) creates prolonged wetting and hydration typically of about one hour or longer; b) creates minimal blur on instillation of tens of seconds, typically 30 seconds or less (See Table 2 above);
  • Excipients of the present invention that may reduce epithelial toxicity include one or more of polyols and electrolytes, where it is surprisingly discovered that the combination of nonionic surfactants of the present invention is further enhanced by from about 0.10% to about 0.90% w/v NaCl, more preferably from about 0.20 to about 02.00% w/v, and most preferably from about 0.25% to about 2.00% w/v. Normal isotonic solutions would typically require 2.00% w/v NaCl.
  • a second electrolyte in preferred embodiments is magnesium ions.
  • the source of magnesium ions is MgCh.
  • the MgCb is at a concentration from about 0.01% to about 0.25% w/v, more preferably from about 0.05% to about 0.15% w/v, and most preferably from about 0.07% to about 0.125% w/v.
  • the polyol is preferably mannitol and more preferably mannitol is at a concentration from about 0.25% to about 4.0% w/v, even more preferably from about 0.75% to about 4.0% w/v, and more preferably from about 1.5% to about 4.0% w/v.
  • these excipients enhance epithelial healing, recovery of injured neuronal components, reduce pain, promote quicker epithelial surface smoothing and health, and reduce or eliminate superficial punctate keratopathy.
  • Superficial punctate keratopathy is a common ocular surface abnormality from exposure to irritants. These irritants are particularly preservatives found in most eye drops including antibiotics, steroids, nonsteroidals, and glaucoma drugs. Accounting for toxicity after cataract surgery due to these irritants and for those on medications for chronic eye diseases, such as glaucoma, the compositions of the present invention may considerably alleviate associated symptoms.
  • the present invention benefits from a total surfactant concentration of at least 1.0% w/v, preferably from about 1.0% to about 10% w/v, more preferably from about 1.0% to about 5.9% w/v, even more preferably from about 1.5% to about 5.9% w/v, even more preferably from about 2.5% to about 5.5% w/v, and most preferably from about 3.0% to about 5.0% w/v, where the nonionic surfactant or nonionic surfactants each have a critical micellar concentration (the concentration at which micelle formation occurs and surface tension is no longer reduced) in the range of 10 3 to 10 4 M.
  • the nonionic surfactant may consist of one or more of cyclodextrins (where hydroxy propyl gamma cyclodextrin, gamma cyclodextrin, and beta cyclodextrin are most preferred); polyoxyl sorbates, including all Tween ® sorbates (polysorbates; Tween is a registered trademark of Uniqema Americas, LLC), including Tween ® 80, 60, 40, or 20; other polyoxyls (most preferred being polyoxyl castor oils and polyoxyl stearates); alkyl aryl polyethers (most preferred being tyloxapols); alkyl ethers including all Brij ® alkyl ethers (most preferred being Brij ® 35, 78, 98, and 700; Span® 20, 40 , 60, and 80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, and sorbitan monooleate)
  • the non-Newtonian viscosity component is increasingly important proportional to the clinical need for treatment of a dry eye or dry eye related condition.
  • the non-Newtonian viscosity component is especially important in the absence of an inserted device including contact lenses and punctum plugs.
  • the non-Newtonian viscosity component provides reduced tear drainage between blinks when the viscosity is at more than about 30 cps, preferably from about 35 to about 50 cps, and most preferably from about 70 to about 400 cps between blinks; and during each blink less than about 30 cps, preferably less than about 25 cps, and most preferably about 20 cps or less.
  • the nonlinear shear viscosity ratio is from about 5: 1 to about 10: 1 interblink to blink viscosity.
  • the combination of nonionic surfactant in the preferred range and viscosity agents at low creates a surprising equilibration of vision at high viscosity and improved flow properties.
  • Figure 4 for Composition #64 from Table 3 below, has an initial 400 cps formulation and visually equilibrates in 50 seconds to excellent vision.
  • Viscosity agents for preferred embodiments of the present invention including, but not limited to, cellulose derivatives such as HPMC, HPC, HPEC and CMC; Carbopol® compounds such as Carbopol® 90 and 940; hyaluronates; and gums such as guar and locust gums.
  • compositions of the present invention results in a substantial adherence of the composition to the contact lens surface reducing deposits.
  • the dramatically reduced bioburden associated with reduced contact lens deposits following application of preferred embodiments of the present invention as described in Example 5 and shown in Figure 6B, is a surprising and unexpected finding that substantially reduces the risk of serious bacterial and or fungal keratitis in contact lens wearers.
  • Such application prior to lens wear, with or without additional drops during wear prevents deposits via long-term coating and or dissolves deposits upon application either prior to insertion or during wear. This reduction in deposits is likely to reduce the bio-burden of bacteria and or fungi.
  • compositions of the present invention can be applied to a contact lens surface.
  • the application to a contact lens creates a robust sealing layer allowing dry eye, contact lens intolerant patients to achieve a therapeutic contact lens effect and treatment modality simply with coverage of the lens in packaging or upon instillation.
  • novel means of tear sequestration provided by compositions of the present invention can be applied to the surface of a punctum plug or pellets.
  • compositions of the present invention with a total concentration of one or more nonionic surfactants from about 1.5% to about 5.9% w/v, preferably about 2.5% to about 3.5% w/v, and most preferably about 3.0% w/v to a contact lens prior to inserting in the eye results in dramatic reduction in tear break up time (“TBUT”) and tear dispersion over both saline and other commercially available contact lens comfort topical formulations. See Examples 8-11 below.
  • TBUT tear break up time
  • the contact lens industry has failed to find an answer to the problem of loss of contact lens tolerance coinciding with the duration of wear throughout the day or cumulative time worn. Specifically, prior to the compositions of the present invention, no additive(s) have been found to be both safe and effective.
  • the resulting product is polished to create as smooth a surface as possible to aid in vision correction.
  • no currently manufactured contact lenses have a completely smooth surface.
  • the nano-micelles formed by the compositions of the present invention penetrate and adhere to contact lenses and improve the vision correcting power of the lens by about 1 line on the Snellen Chart. Not wishing to be held to a particular theory, this vision improvement is likely due to the fact that the nano- micelles of the present invention bind water and hold it to the surface of the lens creating a much smoother lens surface providing both improved light transmission and reduced deposits. Additionally, the dilution of the compositions of the present invention in over-the-counter contact lens solutions does not reduce the ability of the nano-micelles to smooth the lens.
  • Preferred embodiments also increase epithelial safety, which is an advantage of the present invention both topically and for application as a composition for contact lens storage and shelf life in blister packs.
  • viscosity agents including cellulose derivatives, carbomers, gums, dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycol, propylene glycol, chitosans, and hyaluronates, hyaluronic acids and combinations thereof, further reduce the slight epithelial toxicity of nonionic surfactants that otherwise increases with concentration.
  • polyols such as mannitol further reduce epithelial toxicity.
  • Preferred embodiments of the present invention for use as a contact lens storage composition or as a topical drop while using contact lenses contain a viscosity agent that result in a viscosity at low shear of 5 to 25 cps, and a polyol such as mannitol at a preferred concentration from about 0.50% to about 2.5% w/v.
  • a further advantage of the present invention is the surprising discovery that when used as a contact lens storage composition the composition can be reactivated to provide all the original benefits of the composition simply by adding preservative free 0.09% saline solution.
  • a further surprising discovery of the present invention is that ophthalmological drugs added to the present invention increase duration of the drugs on the surface of the eye, increase permeation across the cornea, and reduce systemic absorption, creating an ideal platform vehicle for drug delivery while reducing dry eye symptoms and irritation that might otherwise occur for many such active agents such as non-steroidals, antibiotics, and glaucoma drugs.
  • This drug vehicle may be particularly useful for enhancing the therapeutic duration and benefits of cyclosporine-A currently found in Restasis®.
  • These compositions may be capable of formulating up to 0.09% and from about 0.05% to about 0.09% cyclosporine-A without the need to create an emulsion.
  • the cyclosporine-A drug vehicles of the present invention may not contain emulsifiers.
  • the cyclosporine-A drug vehicle of the present invention provides from about 12 to about 20 nanometer diameter nano-micelles. Further, the cyclosporine-A drug vehicle of the present invention delivers suffusion of tears for up to 60 minutes.
  • a further surprising discovery of the present invention is the suppression of preservative toxicity effect resulting from one or more of preservatives in the presence of the present invention, particularly therapeutic excipients such as a polyol and or magnesium ions.
  • This discovery is surprising in light of the long-held tenet that tear formulation preservatives cause epithelial toxicity, and is potentially of great importance as many chronic use ophthalmic drugs, such as for glaucoma, or inflammation are compromised by the accrued effect of induced epithelial toxicity often limiting their duration of use.
  • a further surprising discovery of the present invention is the sustained release of a drug.
  • the peak concentration of the drug can be increased about 50% in duration, (e.g. from 2 to 4 hours).
  • compositions of the present invention may be used in anesthetic gels, as an anti-adhesion for prevention of scarring, in implantable devices, in time- release impregnated bandages, in parenterals, in inhalers, in sprays, in topical lotions, in topical gels, in topical liquids, in anti-aging skin products such as day and night product and under eye products, in sunscreens, in body wash, in therapeutic shampoos, in antiperspirant, for stretch marks, in shaving creams, as a blade glide coating, in OTC lidocaine compositions, in OTC cortisone compositions, in Ben-Gay® like products including Ben-Gay®, for treating acne, in collagen-based products, in retinal-based products, for treating dry skin, for treating dermatitis, psoriasis, for reducing or eliminating scars or port wine stains, for enhancing hair growth, as a non-irritating hair dye and for facial wasting disease.
  • the ophthalmological compositions of the present invention could be used for prevention, treatment and minimization or eradication of aging and other imperfections in the skin.
  • the administration and use of a nanomicellar nonionic surfactant composition with a physiologically based pH, as disclosed herein has the benefit of providing a cleansing, mildly exfoliating and reparative moisturizing effect on facial tissue.
  • the effect can deliver, based on a proscribed treatment regimen, visible improvement in the areas of managing fine to moderate wrinkling, lightening and size reduction of sun, age and/ or liver spots on the skin.
  • the long-term moisturizing effect that penetrates the top skin layers can also provide long term hydration for the skin which maintains skin tone and texture. Further contemplated are eliminating of common blemishes, reducing skin thickness (supporting use on scar removal over time), improving dry skin as well as elasticity and collagen. Further contemplated as a use for the compositions of the present invention is maintenance of normal pore size as well as the increase in hydration, which can also increase the tightness of the facial skin, thus improving the overall smoothness.
  • compositions of the present invention may comprise droplets, and these droplets may comprise an aqueous phase, at least one oil, a mix of four or more nonionic surfactants, at a specific concentration range, in a topically applied lotion or other compatible and pharmaceutically accepted forms.
  • this base composition may be used as the sole treatment method for the skin.
  • the highly compatible base formula can be combined with any of the known active drug substances, such as Botox®, retinoids, and any other proven topical treatment.
  • the specific nonionic nanoparticles enhance permeation into the top layers of the skin, which enhances efficacy.
  • the least irritating cleanser will contain non ionic/silicone-based surfactants combined with moisturizers, as they will cause the least disruption to the moisture skin barrier and the normal skin flora. While this describes cleanser qualities, these same benefits, plus some new findings, indicate that use after cleansing provides benefit to a patient’s skin conditions and, when used as directed, can effectively manage a host of dermatologic conditions that would otherwise negatively affect self-esteem and social acceptance. It is a discovery of the present invention that most issues surrounding aging skin can be effectively managed by the nonionic surfactant alone or when combined with a specific active drug treatment used on the skin.
  • 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.
  • % w/v refers to the percent weight of the total composition.
  • the term“subject” refers but is not limited to a person or other animal.
  • polyol refers to compounds with multiple hydroxyl functional groups available for organic reactions such as monomeric polyols such as glycerin, pentaerythritol, ethylene glycol and sucrose. Further, polyols may refer to polymeric polyols including glycerin, pentaerythritol, ethylene glycol and sucrose reacted with propylene oxide or ethylene oxide.
  • the phrase“means for inducing tears” includes any means by which production of natural tears may be induced in the subject to which the compositions of the present invention are applied.
  • tears may be induced by modifying the pH of the composition to a range from about 5.0 to about 6.0, modifying the osmolarity of the composition to a range from about 350 to about 550 milliosmoles and or including a terpenoid, such as menthol.
  • the phrase“means for sequestering tears” includes any means by which natural tears induced by the compositions of the invention and the artificial tears compositions of the invention may be sequestered on the eye.
  • a combination of particular concentrations and types of nonionic surfactants and particular concentrations and types of viscosity enhancers are used as the means for sequestering tears.
  • Nonionic surfactants that can be used in accordance with the present invention include, but are not limited to, poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls.
  • Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)).
  • Polysorbates are oily liquids derived from ethoxylated sorbitan esterified with fatty acids.
  • Cyclodextrins are composed of 5 or more a-D-glucopyranoside units linked together at position 1 and 4.
  • Polyoxyls are a mixture of mono- and diesters of stearate and polyoxyethylene diols. Preferred embodiments include but are not limited to poloxamers-poloxamer 188 and poloxamer 407; polysorbates-polysorbate 20, polysorbate 60, polysorbate 80, tyloxapol, Brij® 35, Brij® 78, Brij® 98 and Brij® 700, Span® 20, Span® 40, Span® 60, Span® 80; cyclodextrins-2-HP- cyclodextrin, ionically charged (e.g.
  • beta - cyclodextrins with or without a butyrated salt (Captisol ® ; (sulfobutylether b-cyclodextrin, Captisol is a registered trademark of Cydex Pharmaceuticals), hydroxypropyl-gamma-cyclodextrin, gamma cyclodextrin; and polyoxyls- polyoxyl 40 stearate, polyoxyl 30 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil; or combinations thereof.
  • Captisol ® (sulfobutylether b-cyclodextrin, Captisol is a registered trademark of Cydex Pharmaceuticals)
  • hydroxypropyl-gamma-cyclodextrin gamma cyclodextrin
  • polyoxyls- polyoxyl 40 stearate polyoxyl 30 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil
  • Total nonionic surfactant concentrations of the present invention are from about 1.0% to about 7.0% w/v, preferably, 1.5% to about 7.0% w/v, preferably from about 1.5% to about 6.0% w/v, more preferably from about 1.5% to about 5.9% w/v, more preferably from about 1.5% to about 5.5% w/v, more preferably above about 2.0% w/v and less than 6.0% w/v, from about 2% to about 4% w/v, more preferably from about 2.5% to less than about 5.9% w/v, more preferably from about 2.5% to about 5.5% w/v, more preferably from about 2.5% to about 3.5% w/v, more preferably from about 2.8% to about 5.9% w/v, more preferably from about 3% to about 5% w/v, more preferably from about 3% to about 3.5% w/v.
  • the one or more nonionic surfactants include a poloxamer such as poloxamer 188 and or poloxamer 407, a polyoxyl such as a polyoxyl castor oil including polyoxyl 35 castor oil or polyoxyl 40 hydrogenated castor oil, a cyclodextrin, such as hydroxypropyl-gamma-cyclodextrin and tyloxapol.
  • a poloxamer such as poloxamer 188 and or poloxamer 407
  • a polyoxyl such as a polyoxyl castor oil including polyoxyl 35 castor oil or polyoxyl 40 hydrogenated castor oil
  • a cyclodextrin such as hydroxypropyl-gamma-cyclodextrin and tyloxapol.
  • the one or more nonionic surfactants include from about 0.01% to about 3.5% w/v polysorbate 20, preferably, from about 0.2% to about 3.5% w/v, preferably, about 0.1%, 0.2%, 0.7%, 1%, 3% and 3.5% w/v.
  • the one or more nonionic surfactants include from about 0.01% to about 3.5% w/v poloxamer 407, preferably, from about 0.2% to about 3.5% w/v, preferably, about 0.1%, 0.2%, 0.7%, 1%, 3% and 3.5% w/v.
  • the one or more nonionic surfactants include from about 0.01% to about 3% w/v poloxamer 188, preferably, from about 0.1% w/v to about 1% w/v, preferably about 0.01%, 0.1%, 0.14%, 0.2%, 0.4%, 0.5% and 0.75% w/v.
  • the one or more nonionic surfactants include from about 0.001% to about 2.0% w/v polyoxyl castor oil, preferably, from about 0.005% to about 0.25% w/v, preferably, from about 0.01% w/v to about 1% w/v, preferably, from about 0.01% to about 0.1% w/v, preferably, from about 0.15% to about 0.25% w/v, preferably about 0.001%, 0.01%, 0.1%, 0.15%, 0.18%, 0.25%, 0.5% and 1% w/v.
  • the one or more nonionic surfactants include from about 0.01% to about 5% w/v hydroxypropyl-gamma-cyclodextrin, preferably from about 0.5% to about 5% w/v, preferably, from about 1.5% to about 3.0% w/v, preferably, about 0.25%, 0.5%, 0.7%, 0.75%, 1%, 1.05%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4% and 5% w/v.
  • the addition of 0.005% to 4.0% w/v tyloxapol or from about 1.75% to about 3.00% w/v sorbitol may be added in combination or as a replacement for the one or more nonionic surfactants such that the total surfactant concentration does not exceed 7% w/v;
  • the one or more nonionic surfactants may include polyoxyl 35 castor oil at an amount from about 0.25% to about 5.00% w/v; preferably from about 0.15% to about 0.25% w/v.
  • Viscosity enhancers that can be used in accordance with the present invention are non-Newtonian viscosity enhancers, which include, but are not limited to cellulose derivatives, carbomers (Carbopol®), gums, and hyaluronic acids (hyaluronates), dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycol, propylene glycol and chitosans; where for cellulose derivatives particularly preferred are one or more of carboxymethyl cellulose (“CMC”) high molecular weight blend, CMC low molecular weight blend, CMC moderate molecular weight blend, sodium CMC, methylcellulose, methyl cellulose 4000, hydroxymethyl cellulose, hydroxypropyl cellulose (“HPC”), hydroxypropylmethyl cellulose high molecular weight blend (“HPMC”), hydroxyl propyl methyl cellulose 2906, carboxypropylmethyl cellulose high molecular weight blend (“CPMC”), hydroxyethyl cellulose, or
  • viscosity enhancers of this type can be seen in Figure 7, which demonstrates the during blink and between blink difference in viscosity.
  • This viscosity can be modified to target specific clinical treatments.
  • Specific viscosities and viscosity enhancers may achieve an intrablink (high shear rate) viscosity of about 30 cps or less, more preferably about 25 cps or less, and most preferably about 20 cps or less.
  • Specific clinical treatments may use the following interblink (low shear rate) viscosities:
  • contact lens use about 1 to about 5 cps;
  • the viscosity enhancing excipient is selected from the group consisting of sodium CMC, CMC low molecular weight blend, CMC moderate molecular weight blend, CPMC, HPC, HPMC and carbomer 940 or a combination thereof.
  • the amount of CMC from about 0.01% to about 1.75% w/v including 0.05% w/v, 0.10% w/v, 0.20% w/v, 0.25% w/v, 0.3% w/v, 0.4% w/v, 0.5% w/v, 0.55% w/v, 0.62% w/v, 0.65% w/v, 0.75% w/v, 1.0% w/v, 1.25% w/v, 1.35% w/v, 1.38% w/v, 1.40% w/v and 1.45% w/v.
  • the amount of sodium CMC from about
  • the amount of HPC is from about 0.10% to about 1.75% w/v including 1.0% w/v, 1.25% w/v, 1.40% w/v, 1.50% w/v or 1.75% w/v.
  • the amount of HPMC is based on the molecular weight of Methocell® (Dow-Corning) from about 0.10% to about 1.75% w/v, preferably from about 0.1% to about 1.5% w/v, from about 0.5% to about 1.25% w/v, from about 0.65% to about 1.0% w/v, from about 1% to about 1.35% w/v, from about 1.25% to about 1.35% w/v, from about 1.35% to about 1.5% w/v, from about 1.35% to about 1.45% w/v, preferably about 0.10% w/v, 0.20% w/v, 0.25% w/v, 0.3% w/v, 0.4% w/v, 0.5% w/v, 0.55% w/v, 0.62% w/v, 0.65% w/v, 0.75% w/v, 0.85% w/v, 1.0% w/v, 1.25% w/v, 1.3%
  • the amount of carbomer 940 is from about 0.01% to about 2.0% w/v, preferably from about 0.8% to about 1.3% w/v and more preferably at about 0.01%, 0.8% 0.9%, 1.1%, 1.2% or 1.3% w/v.
  • polyvinyl alcohol may be used as a viscosity enhancer in compositions of the present invention.
  • PVA is at a concentration from about 0.1% about 0.5% w/v.
  • the present invention further comprises glycerin in an amount from about 0.05% to about 2.0%w/v; preferably from about 0.1% to about 0.4% w/v.
  • Polyols suitable for use in the present invention include, but are not limited to, mannitol, glycerol, erythritol, lactitol, xylitol, sorbitol, isosorbide, and maltitol.
  • the polyol is mannitol.
  • the polyol is at a concentration from about 0.1% to about 4% w/v, from about 0.25% to about 5.5% w/v, from about 0.25% to about 4.0% w/v, from about 0.25% to about 2.5% w/v, from about 1% to about 4% w/v, from about 1% to about 2.5% w/v, from about 1.5% to about 3.0% w/v, from about 1.5% to about 2.5% w/v, from about 2% to about 2.5% w/v and about 1% and 2.5% w/v.
  • Electrolytes suitable for use in the present invention include, but are not limited to, magnesium ions, sodium chloride (“NaCl”), potassium chloride (“KC1”) and a combination thereof.
  • the magnesium ions are derived from magnesium chloride.
  • the total electrolyte concentration is at a concentration from about 0.01% to about 2.0% w/v.
  • the magnesium ions are at a concentration from about 0.01% to about 0.90% w/v as MgCb, preferably about 0.05% to about 0.15% w/v and from about 0.075% to about 0.125% w/v
  • the NaCl is at a concentration from about 0.01% to about 2.0% w/v, preferably, from about 0.1% to about 2.0% w/v from about 0.2% to about 2.0% w/v, from about 0.25% to about 2.0% w/v, and more preferably about 0.01%, 0.07%, 0.2%, 0.25%, 0.3%, 0.35%, 0.37%, 0.4%, 0.5%, 0.62%, 0.7%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, and 2.0% w/v
  • the KC1 is at a concentration from about 0.1% to about 0.5% w/v.
  • artificial tear compositions of the present invention do not contain magnesium ions, including magnesium chloride.
  • Preservatives suitable for use in the present invention include, but are not limited to, benzalkonium chloride (“BAK”), sorbate, methylparaben, polypropylparaben, chlorobutanol, thimerosal, phenylmercuric acetate, perborate, phenylmercuric nitrate and combinations thereof.
  • the preservative is BAK, sorbate or a combination thereof.
  • the preservative is at a concentration from about 0.005% to about 0.15% w/v.
  • BAK is at a concentration from about 0.005% to about 0.02% w/v
  • sorbate is at a concentration from about 0.015% to about 0.15% w/v.
  • Antioxidants suitable for use in the present invention include, but are not limited to, citrate. EDTA, sodium metabi sulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene and a combination thereof.
  • the preservative is at a concentration from about 0.05% to about 0.2% w/v.
  • a terpenoid may be used in compositions of the present invention.
  • a terpenoid includes, but is not limited to, citral, WS-12, icilin and menthol.
  • menthol may be used in compositions of the present invention.
  • menthol is at a concentration from about 0.01 to about 4.00 mM, from about 0.01 to about 2.5 mM, from about 0.01 to about 2.0 mM, from about 0.025 to about 0.07 mM, from about 0.07 to about 0.3 mM, from about 0.07 to about 0.1 mM, from about 0.1 to about 0.40 mM, from about 0.1 to about 0.2 mM, from about 0.15 to about 0.25 mM, from about 0.02 to about 1.5 mM, from about 0.25 to about 2.0 mM and about 0.01, 0.07, 0.1, 0.14, 0.15, 0.2, 0.27, 0.30, 0.32, 0.34, 0.36, 0.37, 0.38, 0.40, 0.42, 0.44, 0.46, 0.48, 0.5, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 1.0, 1.2, 1.5, 1.75, 2.0 or 4.0
  • Buffers and pH adjustors that can be used in accordance with the present invention include, but are not limited to, acetate buffers, carbonate buffers, citrate buffers, phosphate buffers and borate buffers.
  • the buffers and pH adjustors are at a concentration from about 1 to about 100 millimolar, more preferably from about 3 to about 10 millimolar and most preferably about 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 millimolar It is understood that various acids or bases can be used to adjust the pH of the composition as needed.
  • pH adjusting agents include, but are not limited to, sodium hydroxide and hydrochloric acid. Surprisingly, pH has not been found to alter comfort in the artificial tears compositions. pH of the compositions can be from 4.0 to 8.0, more preferably from about 5.0 to about 8.0 and from about 5.0 to about 6.0, and less than 6.0.
  • the present invention discovers a narrow therapeutic range of non-ionic surfactant(s) concentration(s) in a preferred embodiment requiring either a non-Newtonian viscosity excipient(s), electrolytes or other excipients that provide improved epithelial protection and healing such that with regular use or even on a single instillation both comfort and efficacy are improved.
  • the ingredients and concentrations of the compositions represented herein are the best-known embodiments but are not intended to be all inclusive.
  • the present invention is directed to artificial tear compositions comprising a means for inducing tears and a means for sequestering tears.
  • the means for inducing tears is selected from a pH from about 5 to about 6, a terpenoid and an osmolarity of from about 270 to about 550 milliosmoles, preferably from about 350 to about 350 milliosmoles.
  • the means for sequestering tears comprises from about 1.5% to about 5.9% w/v total volume of one or more nonionic surfactants and one or more viscosity enhancers, wherein the one or more viscosity enhancers provides a viscosity of from about 50 to about 10,000 centipoise at 0 shear to 1 second.
  • the one or more nonionic surfactants are selected from the group consisting of polysorbates, poloxamers, polyoxyl castor oils, cyclodextrins and combinations thereof.
  • the one or more viscosity enhancers are selected from the group consisting of cellulose derivatives, carbomers, gums, and hyaluronic acids, dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycols, propylene glycol, chitosans and combinations thereof, even more preferably the one or more viscosity enhancers are selected from the group consisting of cellulose derivatives, carbomers, polyvinyl alcohol, polyethylene glycols and combinations thereof.
  • the artificial tear compositions of the present invention further comprise a polyol, preferably selected from the group consisting of mannitol, xylitol, sorbitol, isosorbide, erythritol, glycerol, maltitol and a combination thereof.
  • a polyol preferably selected from the group consisting of mannitol, xylitol, sorbitol, isosorbide, erythritol, glycerol, maltitol and a combination thereof.
  • the artificial tear compositions of the present invention further comprise one or more electrolytes, preferably selected from the group consisting of magnesium ions, sodium chloride, potassium chloride and a combination thereof.
  • the present invention is further directed to an artificial tear composition comprising:
  • nonionic surfactants selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls at a total concentration from about 1.5% to about 6.0% w/v; preferably the one or more nonionic surfactants are selected from the group consisting of from about 0.01% to about 4.0% w/v of a polysorbate, from about 0.01% to about 3.5% w/v of a poloxamer, from about 0.01% to about 2.0% w/v of a polyoxyl and from about 0.01% to about 5.0% w/v hydroxypropyl-gamma-cyclodextrin;
  • viscosity enhancers selected from the group consisting of cellulose derivatives, carbomers, gums, dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycol, propylene glycol, chitosans, and hyaluronates and hyaluronic acids;
  • the one or more electrolytes selected from the group consisting of sodium chloride, potassium chloride and magnesium ions, preferably, the one or more electrolytes is selected from about 0.01% to about 0.25% w/v magnesium ions, from about 0.10% to about 2.0% w/v sodium chloride and from about 0.1% to about 0.5% w/v potassium chloride;
  • a polyol optionally, from about 0.1% to about 4% w/v of a polyol, preferably the polyol is selected from 0.25% to about 4.0% w/v of mannitol or glycerol;
  • polyethylene glycol selected from the group consisting of polyethylene glycol 400, polyethylene glycol 6000, polyethylene glycol 10000, polyethylene glycol 20000 and a combination thereof;
  • a citrate buffer or a phosphate buffer wherein the concentration of the viscosity enhancers provides a composition with a viscosity from about 0.1 to about 1,000 centipoise (cps), preferably wherein a low shear viscosity is from 1 to 1000 cps and a final high shear viscosity is 30 cps or less.
  • the present invention is further directed to an artificial tear composition comprising:
  • nonionic surfactants selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma- cyclodextrin at a total concentration from about 0.1% to about 1.0% w/v or from 1.0% to about 5.9% w/v, wherein the upper range provides greater tear moisture retention and therapeutic efficacy for more severe dry eye;
  • mannitol optionally, from about 0.25% to about 4.0% w/v mannitol, preferably from about 0.75% to about 2.5% w/v;
  • polyethylene glycol 400 or polyethylene glycol 20000 optionally, from about 0.1% to about 0.75% w/v polyethylene glycol 400 or polyethylene glycol 20000;
  • menthol preferably from about 0.1 to about 1.75 millimolar, more preferably from about 1.0 to about 1.75 millimolar;
  • sorbate preferably at 0.1% or 0.12% w/v
  • composition has a pH from about 5.0 to about 7.0.
  • the present invention is directed to artificial tear compositions comprising: from about 2.0% to about 4.0% w/v of one or more nonionic surfactants selected from the group consisting of polysorbates, poloxamers, polyoxyl castor oils and combinations thereof;
  • a viscosity enhancer selected from the group consisting of carboxymethyl cellulose and carbomer 940;
  • a polyethylene glycol having a molecular weight from about 400 to about 20,000 Daltons preferably selected from polyethylene glycol 400, polyethylene glycol 6000, polyethylene glycol 10000, polyethylene glycol 20000 and a combination thereof;
  • w/v denotes weight by total volume of the composition and wherein the composition has a pH from about 5.0 to about 7.4, preferably from about 5.0 to about 6.0.
  • polyoxyl castor oils have from at least 30 moles of ethylene oxide, preferably from about 30 to about 40 moles of ethylene oxide.
  • artificial tear compositions of the present invention further comprising from about 0.25 to about 4.00 millimolar menthol.
  • artificial tear compositions of the present invention further comprising about 0.1% w/v magnesium chloride.
  • artificial tear compositions of the present invention further comprising an excipient selected from the group consisting of about 0.1% w/v ethylenediaminetetraacetic acid, 0.5% w/v polyvinyl alcohol and a combination thereof.
  • the present invention is directed to artificial tear compositions comprising:
  • a surfactant selected from the group consisting of about 3.50% w/v poloxamer 407 or about 0.25% w/v poloxamer 407 and 1.75% w/v sorbitol;
  • the present invention is further directed to an artificial tear composition comprising:
  • composition has a pH of about 7.0 and wherein the total nonionic surfactant concentration is from about 1.5% to about 5.0% w/v.
  • the present invention is further directed to an artificial tear composition comprising:
  • nonionic surfactants selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma- cyclodextrin at a total concentration from about 1.5% to about 5.9% w/v;
  • composition has a pH from about 5.0 to about 7.0.
  • the present invention is further directed to an artificial tear composition comprising:
  • nonionic surfactants selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma- cyclodextrin at a total concentration from about 1.5% to about 5.9% w/v;
  • composition has a pH from about 5.0 to about 7.0.
  • the present invention is further directed to an artificial tear composition
  • an artificial tear composition comprising: two or more nonionic surfactants selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma- cyclodextrin at a total concentration from about 1.5% to about 5.9% w/v;
  • composition has a pH from about 5.5 to about 7.0.
  • the present invention is further directed to an artificial tear composition comprising:
  • nonionic surfactants selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma- cyclodextrin at a total concentration from about 1.5% to about 5.9% w/v;
  • composition optionally, about 0.1% w/v sorbate, wherein optionally, the composition has a pH from about 5.5 to about 7.0.
  • the present invention is further directed to an artificial tear composition comprising:
  • nonionic surfactants selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma- cyclodextrin at a total concentration from about 1.0% to about 5.9% w/v;
  • composition has a pH from about 5.5 to about 7.0.
  • the present invention is further directed to an artificial tear composition comprising:
  • nonionic surfactants selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma- cyclodextrin at a total concentration from about 1.5% to about 5.9% w/v, wherein one of the two or more nonionic surfactants is from about 0.25% to about 1.0% w/v polyoxyl castor oil;
  • composition has a pH from about 5.0 to about 7.0.
  • the present invention is further directed to an artificial tear composition comprising:
  • the present invention is further directed to an artificial tear composition for severe dry eye comprising:
  • the present invention is further directed to an artificial tear composition for severe dry eye comprising:
  • the present invention is further directed to an artificial tear composition comprising:
  • millimolar menthol from about 0.07 to about 0.50 millimolar menthol, preferably 0.07, 0.10, 0.14 0.20 or 0.40 millimolar menthol;
  • composition has a pH of about 7.0.
  • present invention is further directed to an artificial tear composition comprising:
  • hydroxypropylmethyl cellulose preferably 0.70%, 0.75% or 0.80% w/v;
  • composition has a pH of about 7.0.
  • the present invention is further directed to an artificial tear composition comprising:
  • the present invention is further directed to an artificial tear composition
  • an artificial tear composition comprising: about 2.0% w/v polysorbate 80;
  • the present invention is further directed to an artificial tear composition comprising:
  • a buffer at a concentration from about 1 mM to about 100 mM, wherein the composition has a pH from about 5.5 to about 8.0 and wherein the viscosity is less than or equal to 500 centipoise.
  • the present invention is further directed to an artificial tear composition
  • composition has a pH from about 6.0.
  • An artificial tear composition comprising about 0.70% w/v polysorbate 80, about
  • 0.7% w/v poloxamer 407 about 0.14% w/v poloxamer 188, about 0.18% w/v polyoxyl castor oil, about 1.05% w/v hydroxypropyl-gamma-cyclodextrin, about 0.04% w/v sodium carboxymethyl cellulose, about 0.70% w/v polyethylene glycol 400, about 0.53% w/v mannitol, about 0.07% w/v magnesium chloride, about 0.55% w/v sodium chloride, about 0.12% w/v potassium sorbate and 3 mM phosphate buffer, wherein the composition has a pH of about 7.
  • An artificial tear composition comprising about 1.00% w/v polysorbate 80, about
  • An artificial tear composition comprising about 1.00% w/v polysorbate 80, about
  • An artificial tear composition comprising about 3.5% w/v polysorbate 80, a viscosity enhancer selected from about 0.8% to about 1.2% hydroxypropylmethyl cellulose and from about 1% to about 1.4% w/v carboxymethyl cellulose, about 0.75% w/v polyethylene glycol 400, from about 0.5% to about 0.75% w/v mannitol, from about 0.6% to about 1.25% w/v sodium chloride, from about 0.1 to about 3.0 millimolar menthol, preferably from about 0.1 to about 0.15 millimolar or from about 2.5 to about 3.0 millimolar, and from about 0.1% to about 0.12% w/v sorbate, optionally, about 0.25% w/v polyoxyl castor oil, optionally, from about 0.5% to about 1.5% w/v hydroxypropyl gamma cyclodextrin and optionally, about 4 millimolar citrate buffer, wherein the composition has a pH from about 6 to about 6.5
  • An artificial tear composition comprising about 1% w/v polysorbate 80, about 1% w/v poloxamer 407, about 0.2% w/v poloxamer 188, about 0.25% w/v polyoxyl castor oil, about 1.5% w/v hydroxypropyl gamma cyclodextrin, a viscosity enhancer selected from about 0.8% to about 1.2% hydroxypropylmethyl cellulose and from about 1% to about 1.4% w/v carboxymethyl cellulose, about 0.75% w/v polyethylene glycol 400, from about 0.5% to about 0.75% w/v mannitol, from about 0.6% to about 0.7% w/v sodium chloride and from about 0.1 to about 3.0 millimolar menthol, preferably from about 0.1 to about 0.2 millimolar or from about 2.0 to about 3.0 millimolar, and optionally, about 0.1% w/v ethylenediaminetetraacetic acid, optionally, about 0.1% w/v
  • AQusTM CL-Tears may represent compositions with the following ingredients and concentrations:
  • AQusTM CL-Tears may also represent compositions with the following ingredients and concentrations:
  • AQusTM CL-Tears may also represent compositions may represent composition of
  • NaCl may be at a concentration from 0.1% to 0.75%, preferably from 0.2% to 0.5%
  • % HPMC equivalent denotes an amount of CMC necessary to result in a final viscosity equivalent to the final viscosity achieved if the given % w/v of HPMC were used.
  • AQusTM Tears Plus may represent compositions of Table 4.
  • NaCl may be at a concentration from 0.1% to 0.75%, preferably from 0.2% to 0.5%
  • % HPMC equivalent denotes an amount of CMC necessary to result in a final viscosity equivalent to the final viscosity achieved if the given % w/v of HPMC were used
  • AQusTM Tears Advanced may represent compositions of Table 5.
  • NaCl may be at a concentration from 0.1% to 0.75%, preferably from 0.2% to 0.5%
  • % HPMC equivalent denotes an amount of CMC necessary to result in a final viscosity equivalent to the final viscosity achieved if the given % w/v of HPMC were used
  • AQusTM Tears Advanced Plus or AQusTM Tears Extreme may represent compositions of Table 6.
  • NaCl may be at a concentration from 0.1% to 0.75%, preferably from 0.2% to 0.5%
  • % HPMC equivalent denotes an amount of CMC necessary to result in a final viscosity equivalent to the final viscosity achieved if the given % w/v of HPMC were used.
  • AQusTM Tears MGD may represent compositions of Table 7.
  • NaCl may be at a concentration from 0.1% to 0.75%, preferably from 0.2% to 0.5%
  • % HPMC equivalent denotes an amount of CMC necessary to result in a final viscosity equivalent to the final viscosity achieved if the given % w/v of HPMC were used.
  • artificial tear compositions of the present invention do not contain polyacrylates such as Pemulen® (Pemulen was a registered trademark of B.F. Goodrich Company for polymeric emulsifiers and is now owned by and available from Lubrizol Advanced Materials, Inc.).
  • Pemulen® materials including acrylate/Cl0-30 alkyl acrylate cross- polymers, or high molecular weight co-polymers of acrylic acid and a long chain alkyl methacrylate cross-linked with allyl ethers of pentaerythritol.
  • all artificial tear compositions of the present invention are capable of being used as contact lens compositions.
  • Contact lens composition of the present invention include contact lens storage compositions, contact lens infusion compositions, and contact lens wetting solutions.
  • contact lens storage compositions of the present invention may be combined with or used as enhancers for available contact lens soaking solutions including but not limited to Optifree PureMoist®, Optifree Replenish® and Complete Moisture Plus®; Renu; Clear Care®; Biotrue®, Suaflon® One Step; All Comfort Formula®; Purecon® Puresoft; Members Mark® Multi-Purpose Solution; and Aquify® Multi-Purpose Solutions. These compositions may be used in blister packaging.
  • “available contact lens soaking solutions” refers to contact lens soaking solutions that may be purchased by the end-user.
  • the contact lens storage compositions of the present invention may exclude the addition of sodium chloride and phosphate buffer.
  • the vehicle may further be diluted in 0.9% sodium chloride.
  • the vehicle comprises from about 45% to about 55% of an available contact lens soaking solution, preferably about 45% or about 55%, and from about 45% to about 55% of 0.9% sodium chloride, preferably about 45% or about 55%.
  • the contact lens storage compositions of the present invention may be diluted with 0.9% sodium chloride, preferably the dilution is from about 45% to about 55% of a contact lens storage composition of the present invention, preferably about 45% or about 55%, and from about 45% to about 55% of 0.9% sodium chloride, preferably about 45% or about 55%.
  • the contact lens storage composition comprises:
  • composition is used for soaking a contact lens sold under the tradename Oasys® Accuvue® or Air Optix® Aqua.
  • the contact lens storage composition comprises:
  • composition further comprises a contact lens soaking solution under the tradename Puremoist® or Replenish®.
  • the present invention is directed to a method of improving distance vision in a contact lens wearer comprising the steps of:
  • Optifree PureMoist® refers to a sterile, buffered, aqueous solution containing sodium citrate, sodium chloride, boric acid, sorbitol, aminomethylpropanol, disodium EDTA, two wetting agents (TETRONIC® 1304 and HydraGlyde Moisture Matrix [EOBO-41- polyoxy ethylene- polyoxybutylene]) with POLYQETAD (polyquaternium-l) 0.001% and ALDOX (myristamidopropyl dimethylamine) 0.0006% preservatives. HydraGlyde Moisture Matrix is a proprietary multi-functional block copolymer that is primarily designed for wetting and lubricating silicone hydrogel lenses.
  • Optifree Replenish® refers to a sterile, buffered, isotonic, aqueous solution containing sodium citrate, sodium chloride, sodium borate, propylene glycol, TEARGLYDE proprietary dual action reconditioning system (TETRONIC® 1304, nonanoyl ethylenediaminetriacetic acid) with POLYQETAD (polyquaternium-l) 0.001% and ALDOX (myristamidopropyl dimethylamine) 0.0005% preservatives.
  • TETRONIC® 1304, nonanoyl ethylenediaminetriacetic acid POLYQETAD (polyquaternium-l) 0.001%
  • ALDOX myristamidopropyl dimethylamine
  • Renu Clear Care® refers to a sterile solution containing micro- filtered hydrogen peroxide 3%, sodium chloride 0.79%, stabilized with phosphonic acid, a phosphate buffered system, and PLLTRONIC 17R4.
  • Biotrue® refers to a sterile, isotonic solution that contains hyaluronan, sulfobetaine, poloxamine, boric acid, sodium borate, edetate disodium and sodium chloride and preserved with a dual disinfection system (polyaminopropyl biguanide) 0.00013% and polyquaternium 0.0001%.
  • Complete® refers to sterile, isotonic, buffered solution, preserved with polyhexamethylene biguanide (0.0001%), a phosphate buffer, Poloxamer 237, edetate disodium, sodium chloride, potassium chloride, and purified water.
  • the artificial tears composition described herein further comprise a contact lens cleaning capability.
  • the present invention is further directed to a contact lens storage composition
  • a contact lens storage composition comprising: two or more nonionic surfactants selected from the group consisting of polysorbate 80, polyoxyls, poloxamer 407, poloxamer 188, polyoxyl castor oil, hydroxypropyl-gamma- cyclodextrin at a total concentration from about 1.5% to about 5.9% w/v;
  • a polyol from about 0.1% to about 0.4% w/v;
  • a viscosity agent selected from the group consisting of cellulose derivatives, carbomers, gums, dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycol, propylene glycol, chitosans, and hyaluronates and hyaluronic acids wherein the composition has a viscosity from about 5 to about 500 centipoise.
  • the present invention is further directed to a contact lens storage composition
  • a contact lens storage composition comprising:
  • the two or more nonionic surfactants selected from the group consisting of polysorbate 80, polyoxyls, poloxamer 407, poloxamer 188, polyoxyl castor oil, hydroxypropyl-gamma- cyclodextrin at a total concentration from about 1.5% to about 5.9% w/v, preferably the two or more nonionic surfactants are selected from the group consisting of from about 0.01% to about 4.0% w/v of polysorbate 80, from about 0.01% to about 3.0% w/v of poloxamer 407, from about 0.01% to about 3.0% w/v of poloxamer 188, from about 0.01% to about 0.25% w/v of polyoxyl castor oil and from about 0.01% to about 5.0% w/v hydroxypropyl-gamma-cyclodextrin;
  • a cellulose derivative preferably from about 0.05% to about 1.5% w/v of a cellulose derivative, preferably from about 0.05% to about 0.37% w/v carboxymethyl cellulose;
  • the present invention is further directed to a contact lens storage composition
  • a contact lens storage composition comprising:
  • the present invention is further directed to a contact lens coating composition
  • a contact lens coating composition comprising:
  • nonionic surfactants selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma- cyclodextrin at a total concentration from about 1.5% to about 5.9% w/v;
  • a cellulose derivative preferably from about 0.1% to about 2.0% w/v of a cellulose derivative, preferably from about 0.05% to about 0.37% w/v carboxymethyl cellulose;
  • magnesium chloride optionally, from about 0.1% to about 0.3% w/v magnesium chloride;
  • the present invention is further directed to a contact lens storage composition
  • a contact lens storage composition comprising:
  • nonionic surfactants selected from the group consisting of from about 2.0% to about 3.5% w/v polysorbate 80, from about 0.1% to about 0.2% w/v poloxamer 407, from about 0.1% to about 0.5% w/v poloxamer 188, about 0.01% w/v polyoxyl castor oil and from about 0.25% to about 1.5% w/v hydroxypropyl-gamma-cyclodextrin at a total concentration from about 1.5% to about 5.9% w/v;
  • the present invention is further directed to a contact lens storage composition
  • a contact lens storage composition comprising:
  • the present invention is further directed to a contact lens storage composition
  • a contact lens storage composition comprising:
  • polyethylene glycol selected from the group consisting of polyethylene glycol 400, polyethylene glycol 6000, polyethylene glycol
  • 3 millimolar phosphate buffer optionally, about 1.5% w/v hydroxypropyl gamma cyclodextrin; and optionally, from about 0.1 to about 0.2 millimolar menthol.
  • HPMC concentrations may also be 0.2% w/v
  • All contact lens and artificial tear compositions of the present invention may include either 3 millimolar phosphate buffer or 4 millimolar citrate buffer with 0.1% w/v sorbate.
  • contact lens compositions of the present invention do not contain polyacrylates such as Pemulen® materials including acrylate/Cl0-30 alkyl acrylate cross-polymers, or high molecular weight co-polymers of acrylic acid and a long chain alkyl methacrylate cross-linked with allyl ethers of pentaerythritol.
  • polyacrylates such as Pemulen® materials including acrylate/Cl0-30 alkyl acrylate cross-polymers, or high molecular weight co-polymers of acrylic acid and a long chain alkyl methacrylate cross-linked with allyl ethers of pentaerythritol.
  • all artificial tear compositions of the present invention are capable of being used as drug vehicle compositions.
  • the present invention is further directed to a drug vehicle composition
  • an active agent preferably selected from the group consisting of diquafosol, an antibiotic, a steroidal anti-inflammatory, a nonsteroidal anti-inflammatory, a glaucoma drug, a prostaglandin, a muscarinic receptor agonist, a miotic agent, acetylsalicylic acid
  • the active agent is selected from the group consisting of diquafosol, bimatoprost, cyclosporine-A, GLC, prednisolone forte, ketorolac, gentamycin, polytrim, ciprofloxacin, moxifloxacin, gatifloxacin, lifitegrast, besifloxacin, pilocarpine, brimonidine, timolol, dexmedetomidine, timoptic, dorzolamide, latanoprost and a combination thereof;
  • composition has a pH of about 5.0. This latter combination of preservatives and anti oxidants has demonstrated enhanced anterior chamber permeation, and duration to achieve greater clinical benefit in some cases.
  • a drug vehicle gel composition comprising:
  • nonionic surfactants selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls at a total concentration from about 1.5% to about 5.9% w/v; from about 0.5% to about 5% w/v hydroxypropylmethyl cellulose (hypromellose) or an amount of a viscosity agent selected from the group consisting of cellulose derivatives, carbomers, gums, dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycol, propylene glycol, chitosans, and hyaluronates and hyaluronic acids that yields a total viscosity of the composition equal to the total viscosity of the composition provided by from about 0.5% to about 5% w/v hydroxypropylmethyl cellulose;
  • composition has a pH of at least 5.0.
  • the present invention is further directed to a drug vehicle composition
  • cyclosporine-A from about 0.05% to about 2.0% w/v cyclosporine-A, preferably, from about 0.05% to about 0.09% w/v;
  • Captisol® from about 1% to about 5% w/v of Captisol®, b-cyclodextrin or a combination of Tween® b-cyclodextrin, preferably from about 3% to about 4% w/v;
  • the alcohol is selected from the group consisting of a polyvinyl alcohol, glycofurol, octoxynol 40 and a combination thereof;
  • hydroxypropylmethyl cellulose optionally, from about 0.5% to about 1.25% hydroxypropylmethyl cellulose or a concentration of carboxymethyl cellulose that yields a total viscosity of the composition equal to the total viscosity of the composition provided by from about 0.5% to about 1.25% w/v hydroxypropylmethyl cellulose;
  • composition has a pH of about 7.0.
  • the present invention is further directed to a drug vehicle composition
  • composition has a pH of about 7.0.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • cyclosporine-A preferably from about 0.01% to about 2.0% w/v cyclosporine-A, preferably from about 0.05% to about 0.09% w/v, more preferably about 0.05%, about 0.075% or about 0.09% w/v; from about 1.0% to about 5.0% w/v polysorbate 80, preferably from about 1.0% to about 4.0% w/v, more preferably from about 1.0% to about 1.5% w/v;
  • polyoxyl castor oil preferably from about 0.001% to about 1.0% w/v polyoxyl castor oil, preferably from about 0.005% to about 0.01% w/v, even more preferably about 0.01% w/v;
  • mannitol preferably from about 0.5% to about 4.0% w/v mannitol, preferably from about 0.5% to about 3.0% w/v, more preferably from about 0.5% to about 2.5% w/v;
  • magnesium chloride from about 0.05% to about 0.1% w/v magnesium chloride, more preferably about 0.05% w/v;
  • hydroxypropylmethyl cellulose preferably from about 0.1% to about 2.0% w/v hydroxypropylmethyl cellulose, preferably from about 0.5% to about 1.35% w/v;
  • PEG-400 polyethylene glycol 400
  • composition has a pH of about 7.0.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • the one or more nonionic surfactants is selected from the group consisting of polysorbates, poloxamers, polyoxyl castor oils, and cyclodextrins, more preferably selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl gamma cyclodextrin;
  • millimolar menthol optionally, from about 0.1 to about 5.0 millimolar menthol, preferably from about 0.2 to about 2.5 millimolar, more preferably from about 0.2 to about 1.6 millimolar and most preferably from about 0.1 to about 0.45 millimolar; and
  • composition has a pH from about 5.5 to about 7.0.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • the one or more nonionic surfactants is selected from the group consisting of polysorbates, poloxamers, polyoxyl castor oils, and cyclodextrins, more preferably selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl gamma cyclodextrin, preferably comprising about 1.00% w/v polysorbate 80, about 1.00% w/v poloxamer 407, about 0.20% w/v poloxamer 188 and about 0.25% w/v polyoxyl castor oil;
  • composition has a pH from about 5.5 to about 6.5.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • cyclosporine- A preferably 0.05%, 0.075% or 0.09% w/v;
  • polysorbate 80 from about 1.0% to about 3.5% w/v polysorbate 80, preferably 1.5% or 3.5% w/v;
  • polyoxyl castor oil from about 0.01% to about 0.75% polyoxyl castor oil, preferably about 0.01% w/v polyoxyl castor oil;
  • hydroxypropylmethyl cellulose preferably from aboutl.25% to about 1.35% w/v, more preferably about 0.5%, 0.75%, 0.85%, 1.0%, 1.25% or 1.35% w/v;
  • composition has a pH of about 7.0.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising: from about 0.1 to about 1% w/v ketorolac tromethamine, preferably 0.5% w/v; from about 1.0 to about 3.5% w/v polysorbate 80, preferably 1.5% or 3.5% w/v;
  • polyoxyl castor oil from about 0.01% to about 0.75% polyoxyl castor oil, preferably about 0.01% w/v polyoxyl castor oil;
  • hydroxypropylmethyl cellulose preferably from aboutl.25% to about 1.35% w/v, more preferably about 0.5%, 0.75%, 0.85%, 1.0%, 1.25% or 1.35% w/v;
  • composition has a pH of about 7.0.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • the composition has a pH of about 7.0.
  • the ratio of cyclosporine A to polyoxyl castor oil is greater than 0.08: 1, more preferably from about 10:1 to about 9: 1, even more preferably from about 5 : 1 to about 9: 1.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • composition has a pH of about 7.0.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • hydroxypropylmethyl cellulose preferably 0.65%, 0.85%, 1.0% or 1.25% w/v;
  • composition has a pH of about 7.0.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • the present invention is further directed to a drug vehicle composition comprising: about 0.09% w/v cyclosporine-A;
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • composition has a pH of about 7.0 and wherein optionally, the composition is for MGD or allergies.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising:
  • composition has a pH of about 7.0 and wherein optionally, the composition is for acne.
  • the present invention is further directed to a drug vehicle composition
  • a drug vehicle composition comprising from about 5.0% to about 10% w/v ASA in a composition of the present invention and optionally, from about 1% to about 10% w/v benzoyl peroxide or octynol including octynol 11 or 309.
  • the present invention is further directed to a drug vehicle gel composition
  • a drug vehicle gel composition comprising:
  • an active agent preferably selected from the group consisting of an antibiotic, a steroid anti-inflammatory, a nonsteroidal anti-inflammatory, a glaucoma drug, a prostaglandin, a muscarinic receptor agonist, a miotic agent, acetylsalicylic acid and a combination thereof, more preferably the active agent is selected from the group consisting of bimatoprost, cyclosporine-A, GLC, prednisolone forte, ketorolac, gentamycin, polytrim, ciprofloxacin, moxifloxacin, gatifloxacin, lifitegrast, besifloxacin, pilocarpine, brimonidine, timolol, dexmedetomidine, timoptic, dorzolamide, latanoprost and a combination thereof;
  • nonionic surfactants selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls at a total concentration from about 1.5% to about 5.9% w/v, preferably about 2.0% w/v polysorbate 80, about 1.0% w/v poloxamer 188 and about 1.0% w/v hydroxypropyl-gamma-cyclodextrin;
  • benzalkonium chloride about 3 millimolar citrate or phosphate buffer; and optionally one or more excipients selected from about 0.01% to about 0.12% w/v sorbate, from about 0.01% to about 0.12% w/v EDTA, and from about 0.005% to about 0.02% benzalkonium chloride,
  • composition has a pH of about 5.0.
  • the present invention is further directed to a drug vehicle gel composition
  • a drug vehicle gel composition comprising from about 0.0075% to about 0.02% w/v brimonidine, preferably from about 0.015% to about 0.02% w/v and one or more nonionic surfactants selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, and polyoxyls at a total concentration from about 1.5% to about 5.9% w/v, preferably about 2.0% w/v polysorbate 80, about 1.0% w/v poloxamer 188 and about 1.0% w/v hydroxypropyl-gamma-cyclodextrin.
  • the present invention is further directed to a composition
  • a composition comprising one or more nonionic surfactants and at least one excipient selected from the group consisting of one or more viscosity enhancers, a polyol and an electrolyte, wherein micelles having an average diameter from about 12 to about 20 nanometers are formed, preferably from about 15 to about 20 nanometers and more preferably about 16 nanometers.
  • the present invention is further directed to a composition
  • a composition comprising an active agent selected from the group consisting of bimatoprost, cyclosporine-A, GLC, prednisolone forte, ketorolac, gentamycin, polytrim, ciprofloxacin, moxifloxacin, gatifloxacin, lifitegrast, besifloxacin, pilocarpine, brimonidine, timolol, dexmedetomidine, timoptic, dorzolamide, latanoprost, acetylsalicylic acid and a combination thereof, preferably cyclosporine-A, one or more nonionic surfactants and at least one excipient selected from the group consisting of one or more viscosity enhancers, a polyol and an electrolyte, wherein micelles having an average diameter from about 12 to about 20 nanometers are formed, preferably from about 15 to about 20 nanometers and more
  • drug vehicle compositions of the present invention do not contain polyacrylates such as Pemulen® materials including acrylate/Cl0-30 alkyl acrylate cross-polymers, or high molecular weight co-polymers of acrylic acid and a long chain alkyl methacrylate cross-linked with allyl ethers of pentaerythritol.
  • polyacrylates such as Pemulen® materials including acrylate/Cl0-30 alkyl acrylate cross-polymers, or high molecular weight co-polymers of acrylic acid and a long chain alkyl methacrylate cross-linked with allyl ethers of pentaerythritol.
  • the present invention is directed to a topical ophthalmological lidocaine gel composition comprising lidocaine or a salt thereof and magnesium chloride.
  • lidocaine is lidocaine hydrochloride.
  • the lidocaine or salt thereof is at a concentration from about 1% to about 5% w/v.
  • the present invention further comprises one or more excipients selected from the group consisting of a nonionic surfactant, a polyethylene glycol, mannitol, carboxymethyl cellulose and sodium chloride.
  • magnesium chloride is from about 0.01% to about 0.5% w/v.
  • the nonionic surfactant is polysorbate 80.
  • polysorbate 80 is at a concentration from about
  • the polyethylene glycol having a molecular weight of from about 400 to about 20,000 Daltons including polyethylene glycol 400 and polyethylene glycol 20000.
  • polyethylene glycol is at a concentration from about 0.1% to about 5% w/v.
  • mannitol is at a concentration from about 0.1% to about 5% w/v.
  • carboxymethyl cellulose is at a concentration from about 1% to about 5% w/v.
  • sodium chloride is at a concentration from about
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising lidocaine or a salt thereof, magnesium chloride, a nonionic surfactant, a polyethylene glycol, mannitol, a viscosity enhancer and sodium chloride.
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising:
  • polyethylene glycol having a molecular weight of from about 400 to about 20,000 Daltons;
  • magnesium chloride from about 0.05% to about 0.2% w/v magnesium chloride.
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising:
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising:
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising:
  • the present invention is directed to a topical ophthalmological lidocaine gel composition
  • a topical ophthalmological lidocaine gel composition comprising:
  • the present invention is directed to a method of inducing local anesthesia in an eye of a patient comprising topically applying compositions of the present invention to the eye of the patient.

Landscapes

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

Abstract

L'invention concerne des compositions de larmes artificielles, des compositions de larmes artificielles sous forme de gel, des compositions de stockage de lentilles de contact, des compositions de traitement de lentilles de contact, des compositions de véhicule pour médicament ophtalmologique et des compositions de véhicule pour médicament topique comprenant un ou plusieurs tensioactifs non ioniques avec un ou plusieurs excipients d'amélioration de la viscosité non newtonienne et un ou plusieurs éléments parmi un polyol et/ou un électrolyte et leurs procédés d'utilisation.
EP19863887.6A 2018-09-21 2019-09-19 Larmes artificielles, lentilles de contact et compositions de véhicule pour médicament et leurs procédés d'utilisation Pending EP3853317A4 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US16/137,738 US20190021990A1 (en) 2016-10-12 2018-09-21 Artificial tear compositions and methods of use thereof
US16/372,582 US20190224136A1 (en) 2016-10-12 2019-04-02 Artificial tear compositions and methods of use thereof
US16/372,625 US11583496B2 (en) 2016-10-12 2019-04-02 Drug vehicle compositions and methods of use thereof
US16/372,596 US20190225917A1 (en) 2016-10-12 2019-04-02 Contact lens compositions and methods of use thereof
US16/412,943 US20190262290A1 (en) 2016-10-12 2019-05-15 Drug vehicle compositions and methods of use thereof
PCT/US2019/051825 WO2020061249A2 (fr) 2018-09-21 2019-09-19 Larmes artificielles, lentilles de contact et compositions de véhicule pour médicament et leurs procédés d'utilisation

Publications (2)

Publication Number Publication Date
EP3853317A2 true EP3853317A2 (fr) 2021-07-28
EP3853317A4 EP3853317A4 (fr) 2022-06-22

Family

ID=69887791

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19863887.6A Pending EP3853317A4 (fr) 2018-09-21 2019-09-19 Larmes artificielles, lentilles de contact et compositions de véhicule pour médicament et leurs procédés d'utilisation

Country Status (6)

Country Link
EP (1) EP3853317A4 (fr)
JP (1) JP2022511335A (fr)
CN (1) CN113227304A (fr)
BR (1) BR112021005097A2 (fr)
CA (1) CA3112278A1 (fr)
WO (1) WO2020061249A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220350163A1 (en) * 2021-04-29 2022-11-03 Coopervision International Limited Ws12-releasing contact lens
CN115671256B (zh) * 2021-07-30 2024-04-09 四川大学华西医院 环孢素a与地夸磷索钠联合使用在制备治疗干眼症的药物中的用途

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60143615D1 (de) * 2000-09-13 2011-01-20 Asahi Glass Co Ltd Augentropfen
CN101854939B (zh) * 2007-09-14 2012-10-24 乐敦制药株式会社 眼科用组合物
AU2010339993A1 (en) * 2009-12-15 2012-07-26 Foresight Biotherapeutics, Inc. Non-irritating ophthalmic povidone-iodine compositions
US20140377210A1 (en) * 2013-06-21 2014-12-25 Gnt, Llc Artificial tear compositions
US8597629B1 (en) * 2013-06-21 2013-12-03 Premium Ocular Solutions LLC. Artificial tear compositions comprising a combination of nonionic surfactants
HUE059639T2 (hu) * 2015-01-26 2022-12-28 Bausch & Lomb Szemészeti szuszpenzió kompozíció
JP7324566B2 (ja) * 2015-05-28 2023-08-10 ロート製薬株式会社 水性眼科組成物
CN110114119B (zh) * 2016-10-12 2022-05-31 Ps治疗有限公司 人工泪液、隐形眼镜和药物载体组合物及其使用方法

Also Published As

Publication number Publication date
WO2020061249A3 (fr) 2020-07-23
CA3112278A1 (fr) 2020-03-26
BR112021005097A2 (pt) 2021-06-08
WO2020061249A2 (fr) 2020-03-26
CN113227304A (zh) 2021-08-06
EP3853317A4 (fr) 2022-06-22
JP2022511335A (ja) 2022-01-31

Similar Documents

Publication Publication Date Title
EP4008311B1 (fr) Larmes artificielles, lentilles de contact et compositions de véhicule pour médicament et leurs procédés d'utilisation
US11583496B2 (en) Drug vehicle compositions and methods of use thereof
US11260035B2 (en) Topical compositions and methods of use thereof
US20050288197A1 (en) Silicone polymer topical eye compositions and methods of use
CA2851398A1 (fr) Compositions pour le traitement de l'oeil sec
US20200009044A1 (en) Artificial tear, contact lens and drug vehicle compositions and methods of use thereof
US20220080048A1 (en) Opthalmological compositions and methods of use thereof
EP3853317A2 (fr) Larmes artificielles, lentilles de contact et compositions de véhicule pour médicament et leurs procédés d'utilisation
US20190262290A1 (en) Drug vehicle compositions and methods of use thereof
US20190021990A1 (en) Artificial tear compositions and methods of use thereof
WO2021087051A1 (fr) Compositions topiques et leurs procédés d'utilisation
US20200397727A1 (en) Drug vehicle compositions and methods of use thereof
US20220133626A1 (en) Topical compositions and methods of use thereof
US20230285286A1 (en) Drug vehicle compositions and methods of use thereof
US20230235247A1 (en) Contact lens compositions and methods of use thereof
US20190224136A1 (en) Artificial tear compositions and methods of use thereof
US20190225917A1 (en) Contact lens compositions and methods of use thereof
KR100938233B1 (ko) 프로스타글란딘계 점안용 조성물과 그의 제조 방법
Akers et al. Practical Aspects of Ophthalmic Drug Devlopment
CA2567418C (fr) Epaississant a usage ophthalmique

Legal Events

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

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

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

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

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

Free format text: ORIGINAL CODE: 0009012

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

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20210329

AK Designated contracting states

Kind code of ref document: A2

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

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20220524

RIC1 Information provided on ipc code assigned before grant

Ipc: A61L 12/12 20060101ALN20220518BHEP

Ipc: A61K 9/08 20060101ALI20220518BHEP

Ipc: C09K 3/00 20060101AFI20220518BHEP

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: PS THERAPY, INC.

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230426