WO2017152129A2 - Traitement du glaucome et/ou de maladies rétiniennes, et formulations utiles pour ce traitement - Google Patents

Traitement du glaucome et/ou de maladies rétiniennes, et formulations utiles pour ce traitement Download PDF

Info

Publication number
WO2017152129A2
WO2017152129A2 PCT/US2017/020795 US2017020795W WO2017152129A2 WO 2017152129 A2 WO2017152129 A2 WO 2017152129A2 US 2017020795 W US2017020795 W US 2017020795W WO 2017152129 A2 WO2017152129 A2 WO 2017152129A2
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
inhibitor
rtk
hco
tyrosine kinase
Prior art date
Application number
PCT/US2017/020795
Other languages
English (en)
Other versions
WO2017152129A3 (fr
Inventor
Sidney L. WEISS
Original Assignee
Ocular Technologies Sarl
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
Application filed by Ocular Technologies Sarl filed Critical Ocular Technologies Sarl
Publication of WO2017152129A2 publication Critical patent/WO2017152129A2/fr
Publication of WO2017152129A3 publication Critical patent/WO2017152129A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K47/44—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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present disclosure relates to the field of formulations for topical administration, such as ophthalmic formulations, and methods of using such formulations.
  • United States Patent Application Nos US2010/0310462 and US2009/0092665 disclose drug delivery systems for ophthalmic use that have nanomicelles that include vitamin E TPGS.
  • PCT publication number WO/2014/032026 also describes drug delivery systems for ophthalmic use.
  • Travoprost involves a formulation for glaucoma or ocular hypertension that includes HCO-40 and a prostaglandin analog as the active ingredient. See
  • the present disclosure relates to topical formulations such as formulations suitable for ophthalmic administration of an active ingredient (the term active ingredient is used herein interchangably with the term active agent).
  • active ingredients include iloprost, macitentan,and the like, optionally in the further presence of one or more receptor tyrosine kinase (RTK) inhibitors (especially RTK inhibitors for retinal disease(s)), prostaglandins (e.g., latanoprost, travoprost, bimatoprost, iloprost, and the like), prostacyclins, ET-1 inhibitors (e.g., bosentan, ambrisentan, macitentan, sitaxentan, and the like), steroids, and the like, as well as combinations of any two or more thereof.
  • RTK receptor tyrosine kinase
  • the formulations of the present disclosure may include a polyoxyl lipid or fatty acid, and or a polyalkoxylated alcohol and may include nanomicelles.
  • formulations as described herein may have certain surprising features and advantages that could not have been predicted prior to the present disclosure.
  • formulations of the instant disclosure may be able to support a dose of an active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor, a prostaglandin, a prostacyclin, an ET-1 inhibitor, a steroid, and the like, as well as combinations of any two or more thereof) that is surprisingly higher than many prior art formulations.
  • an active ingredient e.g., a receptor tyrosine kinase (RTK) inhibitor, a prostaglandin, a prostacyclin, an ET-1 inhibitor, a steroid, and the like, as well as combinations of any two or more thereof
  • the dose of active ingredient used in the formulations described herein may be selected based on various criteria, including the amount that the formulation can support, the desired dose for various therapeutic applications, etc.
  • the active ingredient (such as for ophthalmic administration), may be at least about 0.05%, or at least about 0.08%, or at least about 0.09%, or at least about 0.1%, or at least about 0.15%; or at least about 0.2%: or at least about 0.3%: or at least about 0.4%; or at least about 0.5%; or at least about 0.6%; or at least about 0.7%; or at least about 0.8%; or at least about 0.9%; or at least about 1.0%; or at least about 1.5%; or at least about 2%; or at least about 3%; or at least about 4%; or at least about 5%; or between 0.05 and 5%; or between 0.05 and 0.5%; or between 0.05 and 0.2%, or between 0.08 and 0.12%; or between 0.1 and 0.5%, or between 0.5 and 1%, or between 0.15%; or between 0.5 and
  • the formulation has nanomicelles with a relatively increased entrapment efficiency; in such embodiments the active ingredient (for ophthalmic administration) may be at least about 0.05%, or at least about 0.08%, or at least about 0.09%, or at least about 0.1%, or at least about 0.15%; or at least about 0.2%: or at least about 0.3%: or at least about 0.4%; or at least about 0.5%; or at least about 0.6%; or at least about 0.7%; or at least about 0.8%; or at least about 0.9%; or at least about 1.0%; or at least about 1.5%; or at least about 2%; or at least about 3%; or at least about 4%; or at least about 5%; or between 0.05 and 5%; or between 0.05 and 0.5%; or between 0.05 and 0.2%, or between 0.08 and 0.12%; or between 0.1 and 0.5%, or between 0.5 and 1%, or between 0.5 and 1.5%; or between 1 and 5%; or between 2 and 4%; or between 4 and 6% of
  • the formulations of the disclosure are surprisingly effective in dissolving and/or delivering active ingredient, without a need for organic solvents (such as propylene glycol) that can be an irritant when included in ophthalmic formulations.
  • organic solvents such as propylene glycol
  • the formulations of the present disclosure are surprisingly stable at high temperatures, for example, temperatures above about 40 degrees C.
  • nanomicellular nature of some formulations described herein allow for improved ocular tissue distribution.
  • formulations as described herein are particularly suitable for anterior eye delivery, or posterior eye delivery, or anterior and posterior eye delivery.
  • the formulations of certain aspects and embodiments of the disclosure may have the surprising advantage of being adaptable to facilitate deliv ery of active ingredient(s) having various sizes or properties; for example, in certain embodiments in formulations that include a polyoxyl castor oil, HCO-60 could be used for active ingredients having relatively small molecule sizes and HCO-80 and/or HCO-100 could be used for relatively larger sized active ingredients.
  • an ophthalmic formulation that includes (1) iloprost, macitentan,and the like, optionally in the further presence of one or more additional active ingredients (e.g., a receptor tyrosine kinase (RTK) inhibitor, a prostaglandin, a prostacyclin, an ET-1 inhibitor, a steroid, and the like, as well as
  • additional active ingredients e.g., a receptor tyrosine kinase (RTK) inhibitor, a prostaglandin, a prostacyclin, an ET-1 inhibitor, a steroid, and the like, as well as
  • RTK receptor tyrosine kinase
  • the formulations includes nanomicelles.
  • the polyoxyl lipid or fatty acid is a polyoxyl castor oil.
  • the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO- 60, HCO-80 or HCO-100.
  • the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is present between 1 and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3 and 5%; or 2 and 6%; or about 4%; or greater than 0.7%; or greater than 1%, or greater than 1.5%; or greater than 2%; or greater than 3%; or greater than 4% by weight of the formulation.
  • the polyoxyl lipid is HCO-60.
  • the polyoxyl lipid is HCO-80.
  • the polyoxyl lipid is HCO-100.
  • the formulation includes a polyalkoxylated alcohol that is octoxynol-40.
  • the formulation includes a polyalkoxylated alcohol (such as octoxynol- 40) present between 0.002 and 4%; or between 0.005 and 3%; or 0.005 and 2%; or 0.005 and 1%; or 0.005 and 0.5%; or 0.005 and 0.1%; or 0.005 and 0.05%; or 0.008 and 0.02%; or about 0.01% by weight of the formulation.
  • active ingredient includes iloprost, macitentan,and the like, optionally in the further presence of one or more receptor tyrosine kinase (RTK) inhibitors (especially RTK inhibitors for retinal disease(s)), prostaglandins (e.g., latanoprost, travoprost, bimatoprost, iloprost, and the like), prostacyclins, ET-1 inhibitors (e.g., bosentan, ambrisentan, macitentan, sitaxentan, and the like), steroids, and the like, as well as combinations of any two or more thereof
  • RTK receptor tyrosine kinase
  • RTK inhibitor means a compound that can bind to the active site of a RTK and prevent phosphorylation.
  • an RTK inhibitor can inhibit, regulate or modulate cell signaling, upon binding to an RTK site.
  • RTK inhibitors as contemplated herein may be small molecules, for example aromatic molecules.
  • an RTK inhibitor of the present disclosure may inhibit one or more selected from the group consisting of Vascular Endothelial Growth Factor Receptor (VEGFR) kinases, Platelet Derived Growth Factor Receptor (PDGFR) tyrosine kinases and Epidermal Growth Factor Receptor (EGFR) tyrosine kinases.
  • VEGFR Vascular Endothelial Growth Factor Receptor
  • PDGFR Platelet Derived Growth Factor Receptor
  • EGFR Epidermal Growth Factor Receptor
  • tyrosine phosphate inhibitors are potent and selective inhibitors of Vascular Endothelial Growth Factor Receptor (VEGFR) kinases, but weak inhibitors of Platelet Derived Growth Factor Receptor (PDGFR) tyrosine kinases and Epidermal Growth Factor Receptor (EGFR) tyrosine kinases.
  • VEGFR Vascular Endothelial Growth Factor Receptor
  • PDGFR Platelet Derived Growth Factor Receptor
  • EGFR Epidermal Growth Factor Receptor
  • prostaglandins refers to hormone-like substances that participate in a wide range of body functions such as the contraction and relaxation of smooth muscle, the dilation and constriction of blood vessels, control of blood pressure, and modulation of inflammation.
  • Prostaglandins are derived from arachidonic acid.
  • Exemplary prostaglandins include latanoprost, iloprost, and the like. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.
  • prostaglandins account for their different biological activities.
  • a given prostaglandin may have different and even opposite effects in different tissues.
  • the ability of the same prostaglandin to stimulate a reaction in one tissue and inhibit the same reaction in another tissue is determined by the type of receptor to which the prostaglandin binds. They act as autocrine or paracrine factors with their target cells present in the immediate vicinity of the site of their secretion.
  • Prostaglandins differ from endocrine hormones in that they are not produced at a specific site but in many places throughout the human body.
  • prostaglandin 12 As used herein, the term "prostacyclin” (also called prostaglandin 12 or PGI 2 ) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. As a drug, it is also known as "epoprostenol”.
  • Exemplary prostaglandins include latanoprost, travoprost, bimatoprost, iloprost, and the like.
  • Latanoprost eye solution is a medication administered into the ey es to control the progression of glaucoma or ocular hypertension by reducing intraocular pressure. It is a prostaglandin analog (more specifically an analog of prostaglandin F 2a ) that lowers the pressure by increasing the outflow of aqueous fluid from the eyes through the uvealsclearal tract.
  • Latanoprost is an isopropyl ester prodrug (i.e., it is inactive until it is hydrolyzed by esterases in the cornea to the biologically active acid.
  • Latanoprost is also known by the brand name of Xalatan manufactured by
  • Pfizer and has the structure:
  • Travoprost ophthalmic solution is a topical medication used for controlling the progression of glaucoma or ocular hypertension, by reducing intraocular pressure. It is a synthetic prostaglandin analog (or more specifically, an analog of prostaglandin F 2a ) that works by increasing the outflow of aqueous fluid from the eyes. It is also available under the brand names of Travatan and Travatan Z, manufactured by Alcon, and Travo-Z,
  • Travoprost has the structure:
  • Bimatoprost is marketed in the U.S., Canada and Europe by Allergan, under the trade name Lumigan.
  • Bimatoprost is a prostaglandin analog/prodrug used topically (as eye drops) to control the progression of glaucoma and in the management of ocular hypertension. It reduces intraocular pressure (IOP) by increasing the outflow of aqueous fluid from the eyes.
  • IOP intraocular pressure
  • Iloprost is a drug used to treat pulmonary arterial hypertension (PAH), scleroderma, Raynaud's phenomenon and other diseases in which the blood vessels are constricted and blood can't flow to the tissues. This damages the tissues and causes high blood pressure. Iloprost works by opening (dilating) the blood vessels to allow the blood to flow through again. It was developed by the Schering AG and is marketed by Bayer Schering Pharma AG in Europe and Actelion Pharmaceuticals in the USA, and has the structure:
  • Macitentan (trade name Opsumit) is an endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH). Other ERAs are marketed as bosentan and ambrisentan. Macitentan is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ET B . However, macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ET B subtype. Macitentan has the structure:
  • ET-1 inhibitors refers to endothelin receptor antagonists (ERA), i.e., drugs that block endothelin receptors (e.g., bosentan, ambrisentan, macitentan, sitaxentan, and the like).
  • ERA endothelin receptor antagonists
  • drugs that block endothelin receptors e.g., bosentan, ambrisentan, macitentan, sitaxentan, and the like.
  • steroids refers to estrogens and derivatives thereof, corticosteroids and derivatives thereof, and the like.
  • polyoxyl lipid or fatty acid refers to mono- and diesters of lipids or fatty acids and polyoxyethylene diols. Polyoxyl lipids or fatty acids may be numbered ("n") according to the average polymer length of the oxy ethylene units (e.g., 40, 60, 80, 100) as is well understood in the art. The term “n > 40 polyoxyl lipid” means that the ployoxyl lipid or fatty acid has an average oxy ethylene polymer length equal to or greater than 40 units.
  • Stearate hydrogenated castor oil and castor oil are common lipids/fatty acids commercially available as polyoxyl lipids or fatty acid, however, it is understood that any lipid or fatty acid could polyoxylated to become a polyoxyl lipid or fatty acid as contemplated herein.
  • polyoxyl lipid or fatty acids include without limitation HCO-40, HCO-60, HCO-80, HCO-100, polyoxyl 40 stearate, polyoxyl 35 castor oil.
  • the average polymer length of the oxy ethylene units of a polyoxyl lipid or fatty acid is longer for a relatively larger active ingredient and is shorter for a relatively smaller active ingredient; for example in some embodiments in which the active ingredient is a resolvin or resolvin-like compound the polyoxyl lipid is HCO-60 and in some embodiments where the active ingredient is cyclosporine A (which is larger than a resolvin) the polyoxyl lipid is HCO-80 or HCO-100.
  • micelle or “nanomicelle” refers to an aggregate (or cluster) of surfactant molecules. Micelles only form when the concentration of surfactant is greater than the critical micelle concentration (CMC).
  • CMC critical micelle concentration
  • Surfactants are chemicals that are amphipathic, which means that they contain both hydrophobic and hydrophilic groups.
  • Micelles can exist in different shapes, including spherical, cylindrical, and discoidal.
  • a micelle comprising at least two different molecular species is a mixed micelle.
  • ophthalmic compositions of the present disclosure include an aqueous, clear, mixed micellar solution
  • an ophthalmic formulation comprising an active ingredient, and a n> 40 polyoxyl lipid or fatty acid.
  • the formulations includes nanomicelles.
  • the polyoxyl lipid or fatty acid is a polyoxyl castor oil.
  • the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100.
  • the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-40, HCO-60, HCO-80 or HCO- 100) is present between 0.5 and 2%, or 0.7 and 2%, or 1 and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3 and 5%; or 2 and 6%; or about 4%; or greater than 0.7%; or greater than 1%, or greater than 1.5%; or greater than 2%; or greater than 3%; or greater than 4% by weight of the formulation.
  • the polyoxyl lipid is HCO-60.
  • the polyoxyl lipid is HCO-80.
  • the polyoxyl lipid is HCO-100.
  • the formulation further includes polyalkoxylated alcohol.
  • the formulation further includes polyalkoxylated alcohol that is octoxynol-40.
  • the formulation includes a polyalkoxylated alcohol (such as octoxynol-40) present between 0.002 and 4%; or between 0.005 and 3%; or between 0.005 and 2%; or between 0.005 and 1%; or between 0.005 and 0.5%; or between 0.005 and 0.1%; or between 0.005 and 0.05%; or between 0.008 and 0.02%; or between 0.01 and 0.1%; or between 0.02 and 0.08%; or between 0.005 and 0.08%; or about 0.05%, or about 0.01% by weight of the formulation.
  • an ophthalmic formulation that includes an active ingredient and a polyoxyl lipid or fatty acid; wherein said polyoxyl lipid or fatty acid is present in an amount equal to or greater than 1% of said formulation.
  • an ophthalmic formulation that includes an active ingredient and a polyoxyl lipid or fatty acid; wherein said polyoxyl lipid or fatty acid is present in an amount equal to or greater than 0.05% of said formulation.
  • the formulations includes nanomicelles.
  • the polyoxyl lipid or fatty acid is a polyoxyl castor oil.
  • the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100.
  • the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-60, HCO-80 or HCO-100) is present between 0.5 and 2%, or 0.7 and 2%, or between 1 and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3 and 5%; or 2 and 6%; or about 4%; or greater than 1.5%; or greater than 2%; or greater than 3%; or greater than 4% by weight of the formulation.
  • the polyoxyl lipid is HCO-40. In some embodiments the polyoxyl lipid is HCO-60. In some embodiments the polyoxyl lipid is HCO-80. In some embodiments the polyoxyl lipid is HCO-100. In some embodiments, the formulation further includes polyalkoxylated alcohol. In some embodiments, the formulation further includes polyalkoxylated alcohol that is octoxynol-40.
  • the formulation includes a polyalkoxylated alcohol (such as octoxynol-40) present between 0.002 and 4%; or between 0.005 and 3%; or between 0.005 and 2%; or between 0.005 and 1%; or between 0.005 and 0.5%; or between 0.005 and 0.1%; or between 0.005 and 0.05%; or between 0.008 and 0.02%; or between 0.01 and 0.1%; or between 0.02 and 0.08%; or between 0.005 and 0.08%; or about 0.05%, or about 0.01% by weight of the formulation.
  • a polyalkoxylated alcohol such as octoxynol-40
  • an ophthalmic formulation that includes an active ingredient and a polyoxyl lipid or fatty acid; wherein said formulation comprises nanomicelles.
  • the polyoxyl lipid or fatty acid is a polyoxyl castor oil.
  • the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100.
  • the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is present between 0.5 and 2%, or 0.7 and 2%, or between 1 and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3 and 5%; or 2 and 6%; or about 4%; or greater than 0.7%; or greater than 1%, or greater than 1.5%; or greater than 2%; or greater than 3%; or greater than 4% by weight of the formulation.
  • the polyoxyl lipid is HCO-40.
  • the polyoxyl lipid is HCO-60.
  • the polyoxyl lipid is HCO-80. In some embodiments the polyoxyl lipid is HCO-100. In some embodiments, the formulation further includes polvalkoxylated alcohol. In some embodiments, the formulation further includes polvalkoxylated alcohol that is octoxynol-40.
  • the formulation includes a polyalkoxylated alcohol (such as octoxynol-40) present between 0.002 and 4%; or between 0.005 and 3%; or between 0.005 and 2%; or between 0.005 and 1%; or between 0.005 and 0.5%; or between 0.005 and 0.1%; or between 0.005 and 0.05%; or between 0.008 and 0.02%; or between 0.01 and 0.1%; or between 0.02 and 0.08%; or between 0.005 and 0.08%; or about 0.05%, or about 0.01% by weight of the formulation.
  • a polyalkoxylated alcohol such as octoxynol-40
  • an ophthalmic formulation comprising an active ingredient, 1-5% of one or more selected from the group consisting of HCO-40, HCO- 60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.
  • ophthalmic formulation comprising an active ingredient, 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.
  • an ophthalmic formulation comprising an active ingredient, 1-5% of one or more selected from the group consisting of HCO-40, HCO- 60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.
  • an ophthalmic formulation comprising an active ingredient, 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.
  • an ophthalmic formulation comprising an active ingredient, about 4% of HCO-60 and about 0.01% octoxynol-40.
  • an ophthalmic formulation comprising an active ingredient, 0.7-1.5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-lOO; and about 0.05% octoxynol-40.
  • ophthalmic formulation comprising an active ingredient, 0.7-1.5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-lOO; and about 0.05% octoxynol-40.
  • an ophthalmic formulation comprising an active ingredient, 0.7-1.5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-lOO; and about 0.05% octoxynol-40.
  • an ophthalmic formulation comprising an active ingredient, 0.7-1.5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-lOO; and about 0.05% octoxynol-40.
  • an ophthalmic formulation comprising an active ingredient, about 1% of HCO-60 and about 0.05% octoxynol-40.
  • the formulation includes nanomicelles.
  • the formulation includes a polyoxyl lipid or fatty acid.
  • the polyoxyl lipid or fatty acid is a polyoxyl castor oil.
  • the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-lOO.
  • the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-60, HCO-80 or HCO-lOO) is present between 0.5 and 2%, or 0.7 and 2%, or 1 and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3 and 5%; or 2 and 6%; or about 4%; or greater than 0.7%; or greater than 1%, or greater than 1.5%; or greater than 2%; or greater than 3%; or greater than 4% by weight of the formulation.
  • the polyoxyl lipid is HCO-40.
  • the polyoxyl lipid is HCO-60.
  • the polyoxyl lipid is HCO-80. In some embodiments the polyoxyl lipid is HCO-lOO. [0048] In some embodiments of the aspects and embodiments disclosed herein, includes a polyalkoxylated alcohol. In some embodiments, the formulation includes a polyalkoxylated alcohol that is octoxynol-40.
  • the formulation includes a polyalkoxylated alcohol (such as octoxynol-40) present between 0.002 and 4%; or between 0.005 and 3%; or between 0.005 and 2%; or between 0.005 and 1%; or between 0.005 and 0.5%; or between 0.005 and 0.1%; or between 0.005 and 0.05%; or between 0.008 and 0.02%; or between 0.01 and 0.1%; or between 0.02 and 0.08%; or between 0.005 and 0.08%; or about 0.05%, or about 0.01% by weight of the formulation.
  • a polyalkoxylated alcohol such as octoxynol-40
  • the formulation further comprises one or more additionsl active agents selected from the group consisiting of calcineurin inhibitors, mTOR inhibitors, peptides, eicosanoids (e.g. prostacyclins and prostaglandins), anti-inflammatory drugs (such as NSAIDS), autonomic drugs (e.g. beta- blockers, alpha-blockers, beta-agonists, and alpha-agonists), biologies, gene therapy agents (e.g. viral vectors), anti-infectives (e.g.
  • retinoids retinoids
  • RNAi photo sensitizers
  • steroids e.g., estrogens and derivatives thereof, and corticosteroids
  • mixture drugs immuno-modulators, chemotherapeutic agents, G-coupled protein receptor antagonists, growth hormone inhibitors, integrin inhibitors, Sdfl/CXCR4 pathway inhibitors, and nACh receptor antagonists, resolvins (resolvin-like compounds), lipoxins,
  • neuroprotectins are neuroprotectins, maresins, oxylipins, and the like.
  • the formulation further comprises at least one active agent selected from the group consisiting of cyclosporine A, voclosporin, ascomycin, tacrolimus, pimecrolimus, an analog thereof, or a pharmaceutically acceptable salt thereof.
  • the optional, additional active agent is cyclosporine A.
  • the optional, additional active agent is voclosporin.
  • the optional, additional active agent is one or more selected from the group consisting of sirolimus (rapamycin), temsirolimus, everolimus, an analog thereof, or a pharmaceutically acceptable salt thereof
  • the additional active agent is a receptor tyrosine kinase (RTK) inhibitor, a receptor tyrosine kinase (RTK) inhibitor having anti-VEGF and/or a receptor tyrosine kinase (RTK) inhibitor having anti-PDGF activity.
  • RTK receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • exemplary compounds contemplated for use herein include sunitinib (marketed by Pfizer as Sutent):
  • regorafenib (marketed by Bayer as Stivarga):
  • sorafenib (marketed by Bayer as Nexavar):
  • imatinib (marketed by Novartis as Gleevec):
  • dasatinib produced by Bristol-Myers Squibb and sold under the trade name S ry eel:
  • dovitinib a benzimidazole- quinolinone compound with potential antineoplastic activity
  • Nilotinib (tradenameTasigna, from Novartis):
  • gefitinib an analog thereof, or a pharmaceutically acceptable salt thereof; gefitinib (available under the trade name Iressa, is marketed by AstraZeneca and Teva), is used for certain breast, lung and other cancers.
  • Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR:
  • erlotinib an epidermal growth factor receptor inhibitor (EGFR inhibitor).
  • the drug follows Iressa (gefitinib), which was the first drug of this type.
  • Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. For the signal to be transmitted, two EGFR molecules need to come together to form a homodimer.
  • EGFR epidermal growth factor receptor
  • ATP adenosine triphosphate
  • the optional additional active agent is a prostaglandin (e.g., latanoprost, bimatoprost, and the like, including prostacylin and analogues thereof).
  • a prostaglandin e.g., latanoprost, bimatoprost, and the like, including prostacylin and analogues thereof.
  • the optional additional active agent is a prostacyclin.
  • the optional additional active agent is an ET-1 inhibitor (also known as endothelin receptor antagonists).
  • Examplary ET-1 inhibitors include bosentan, ambrisentan, sitaxentan, and the like.
  • Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary artery hypertension (PAH). It is licensed in the United States, the European Union and other countries by Actelion Pharmaceuticals for the management of PAH under the trade name Tracleer, and has the structure:
  • Macitentan (trade name Opsumit) is an endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH).
  • ERA endothelin receptor antagonist
  • PAH pulmonary arterial hypertension
  • Two other ERAs marketed for the same purpose are bosentan and ambrisentan.
  • Macitentan is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ET B .
  • ETA and ET B endothelin receptor subtypes
  • Macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype.
  • Macitentan has the structure:
  • Ambrisentan (U.S. trade name Letairis; E.U. trade name Vohbris; India trade name pulmonext by MSN labs ) is a drug indicated for use in the treatment of pulmonary hypertension.
  • Ambrisentan has the structure:
  • Sitaxentan sodium (TBC-11251) is a medication for the treatment of pulmonary arterial hypertension (PAH). It was marketed as Thelin by Encysive
  • Sitaxentan has the structure:
  • the optional additional active agent is a steroid.
  • the active agent is a combination of iloprost and/or macitentan, with one or more of the active ingredients described herein, e.g., a combination of a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s)) and a prostaglandin; or a combination of a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s)), and the like) and a prostacyclin; or a combination of a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s)), and an ET-1 inhibitor; or a combination of a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s)), and a
  • the instant disclosure further relates to treating or preventing ocular diseases or disorders, for example by local administration of the formulations as described herein.
  • a patient or subject to be treated by any of the compositions or methods of the present disclosure can mean either a human or a non-human animal.
  • the present disclosure provides methods for the treatment of an ocular disease in a human patient in need thereof.
  • the present disclosure provides methods for the treatment of an inflammatory ocular disease in a human patient in need thereof.
  • the present disclosure provides methods for the treatment of an ocular disease in a veterinary patient in need thereof, including, but not limited to dogs, horses, cats, rabbits, gerbils, hamsters, rodents, birds, aquatic mammals, cattle, pigs, camelids, and other zoological animals.
  • the formulation comprising iloprost and/or macitentan as an active ingredient, optionally in the further presence of one or more active agents selected from a receptor tyrosine kinase (RTK), a prostaglandin, a prostacyclin, an ET-1 inhibitor, or a steroid, as well as combinations of any two or more thereof, is administered in combination with one or more different active ingredients.
  • active agents selected from a receptor tyrosine kinase (RTK), a prostaglandin, a prostacyclin, an ET-1 inhibitor, or a steroid, as well as combinations of any two or more thereof.
  • the active agent includes a receptor tyrosine kinase (RTK) inhibitor, plus one or more additional active agents selected from the group consisting of a resolvin or resolvin-like compound, a steroid (such as a corticosteroid), cyclosporine A, and voclosporin.
  • the formulation comprises a receptor tyrosine kinase (RTK) inhibitor, a resolvin and/or cyclosporine A.
  • the formulation comprises a receptor tyrosine kinase (RTK) inhibitor, a resolvin and a corticosteroid.
  • the formulation comprises a receptor tyrosine kinase (RTK) inhibitor, cyclosporine A and a corticosteroid. In some embodiments, the formulation comprises a receptor tyrosine kinase (RTK) inhibitor, a resolvin, cyclosporine A and a corticosteroid.
  • RTK receptor tyrosine kinase
  • the formulation comprises a receptor tyrosine kinase (RTK) inhibitor, plus two or more active agents and one of said active agents is an antibiotic, for example one or more antibiotics selected from the group consisting of azythromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin, and levofloxacin.
  • RTK receptor tyrosine kinase
  • the formulation comprises a receptor tyrosine kinase (RTK) inhibitor, plus two or more active agents and one of said active agents is an antiviral, for example one or more antivirals selected from the group consisting of ganciclovir, triflundine, acyclovir, famciclovir, valacyclovir, penciclovir and cidofovir.
  • RTK receptor tyrosine kinase
  • treating refers to: preventing a disease, disorder or condition from occurring in a cell, a tissue, a system, animal or human which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; stabilizing a disease, disorder or condition, i.e., arresting its development; and/or relieving one or more symptoms of the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • ocular disease As used herein, the terms "ocular disease,” “ocular condition,” “eye disease,” and “eye condition” refer to diseases/conditions of the eye(s) that can be sight threatening, lead to eye discomfort, and may signal systemic health problems.
  • anterior segment disease refers to all disorders that affect the eye surface, anterior chamber, iris and ciliary body and lens of the eye.
  • the eye surface is composed of the cornea, conjunctiva, eyelids, lacrimal and meibomian glands, and the interconnecting nerves.
  • posterior segment ey e disease and "back-of-the- eye disease” refer to all disorders that affect the posterior segment of the eye.
  • a posterior eye disease is a disease which primarily affects a posterior ocular site such as choroid or sclera, vitreous, vitreous chamber, retina, optic nerve, and blood vessels and nerves which vascularize or innervate a posterior ocular site.
  • the ocular disease is an anterior segment disease.
  • the ocular disease is a posterior segment disease.
  • the ocular disease is one or more selected from the group consisting of dry eye syndrome, Sjogren's syndrome, uveitis, anterior uveitis (iritis), chorioretinitis, posterior uveitis, conjunctivitis, allergic conjunctivitis, keratitis,
  • keratoconjunctivitis vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis, systemic immune mediated diseases such as cicatrizing conjunctivitis and other autoimmune disorders of the ocular surface, blepharitis, scleritis, age-related macular degeneration (AMD), geographic atrophy, diabetic retinopathy (DR), diabetic macular edema (DME), ocular neovascularization, retinopathy of prematurity, proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis, optic neuritis, retrobulbar neuritis, and macular pucker.
  • systemic immune mediated diseases such as cicatrizing conjunctivitis and other autoimmune disorders of the ocular surface, blepharitis, scleritis, age-related macular degeneration (AMD), geographic atrophy, diabetic retinopathy
  • the ocular disease is dry eye. In one embodiment, the ocular disease is allergic conjunctivitis. In one embodiment the ocular disease is age-related macular degeneration (AMD). In one embodiment the ocular disease is diabetic retinopathy. In one embodiment the ocular disease is retinopathy of prematurity.
  • AMD age-related macular degeneration
  • an optional additional active agent in addition to iloprost and/or macitentan, can be any of a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s)), a prostaglandin, a prostacyclin, an ET-1 inhibitor, a steroid, and the like, as well as combinations of any two or more thereof).
  • RTK receptor tyrosine kinase
  • Such agents may optionally be combined with one or more drugs, hormones, cytokines, toxins, therapeutic agents, vitamins, and the like.
  • an active agent in accordance with the aspects and embodiments disclosed herein is a receptor tyrosine kinase (RTK) inhibitor, in combination with an optional, additional agent capable of, or approved for, treating or preventing a disease or condition, for example in some embodiments an optional, additional active agent is capable of, or approved for, treating or preventing an ocular disease or condition.
  • RTK receptor tyrosine kinase
  • compositions of the present disclosure can be used as a topically applied or locally injected drug deliver ⁇ ' platform for delivery of a variety of active agents including hydrophobic, water-insoluble drugs.
  • Active agents include receptor ty rosine kinase (RTK) inhibitors (especially an RTK inhibitor for retinal disease(s), prostaglandins, prostacyclins, ET-1 inhibitors, steroids, and the like, as well as combinations of any two or more thereof), and may optionally include additional agents such as calcineurin inhibitors or mTOR inhibitors, peptides, eicosanoids (e.g. prostacyclins and prostaglandins), anti-inflammatory drugs, autonomic drugs (e.g.
  • beta-blockers alpha-blockers, beta-agonists, and alpha- agonists
  • biologies gene therapy agents (e.g. viral vectors), anti-infectives (e.g. antifungals, antibiotics, and antivirals), retinoids, RNAi, photo sensitizers, steroids (e.g., estrogens and derivatives thereof), mixture drugs, immuno-modulators, chemotherapeutic agents, G- coupled protein receptor antagonists, receptor tyrosine kinase (RTK) inhibitors, receptor tyrosine kinase (RTK) inhibitors having anti-VEGF and/or anti-PDGF activity, growth hormone inhibitors, integrin inhibitors, Sdfl/CXCR4 pathway inhibitors, and nACh receptor antagonists, resolvins, lipoxins, oxylipins and the like.
  • gene therapy agents e.g. viral vectors
  • anti-infectives e.g. antifungals, antibiotics, and antivirals
  • the optional, additional active agent is a corticosteroid, including prednisolone, hydrocortisone, triamcinolone and budesonide.
  • the optional, additional active ingredient may be a non-steroidal anti-inflammatory drug (NSAID), for example Cox-2 inhibitors such as celecoxib, ruboxistaurin and nimesulide.
  • NSAID non-steroidal anti-inflammatory drug
  • an optional, additional active agent may be an anti-growth factor molecule including, but not limited to, vascular endothelial growth factor (VEGF) inhibitors such as, pegaptanib (macugen), ranibizumab (lucentis), and bevacizumab (avastin).
  • VEGF vascular endothelial growth factor
  • the optional, additional active agent is an antibiotic, for example one or more antibiotics selected from the group consisting of azythromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifioxacin, and levofloxacin.
  • the optional, additional active agent is an antiviral, for example one or more antivirals selected from the group consisting of ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir and cidofovir.
  • a combination of two active agents may be used, including but not limited to a vascular endothelial growth factor (VEGF) inhibitor and an antagonist of platelet-derived growth factor (PDGF).
  • VEGF vascular endothelial growth factor
  • PDGF platelet-derived growth factor
  • a combination of two active agents may be used, including but not limited to a receptor tyrosine kinase (RTK) inhibitor having vascular endothelial growth factor (VEGF) inhibitory activity and/or platelet-derived growth factor (PDGF) inhibitory activity.
  • RTK receptor tyrosine kinase
  • VEGF vascular endothelial growth factor
  • PDGF platelet-derived growth factor
  • the active agent may be a receptor tyrosine kinase (RTK) inhibitor, a receptor tyrosine kinase (RTK) inhibitor having anti-VEGF and/or a receptor tyrosine kinase (RTK) inhibitor having anti-PDGF activity.
  • RTK receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • exemplary compounds contemplated for use herein include sunitinib (marketed by Pfizer as Sutent):
  • regorafenib (marketed by- Bayer as Stivar a):
  • sorafenib (marketed by Bayer as Nexavar): an analog thereof, or a pharmaceutically acceptable salt thereof;
  • imatinib (marketed by Novartis as Gleevec):
  • dasatinib produced by Bristol-Myers Squibb and sold under the trade name Spry eel:
  • dovitinib a benzimidazole- quinolinone compound with potential antineoplastic activity
  • Nilotinib (tradenameTasigna, from Novartis):
  • the optional, additional active agent may be a calcineurin inhibitor such as cyclosporine A, voclosporin, ascomvcin, tacrolimus, pimecrolimus, an analog thereof, or a pharmaceutically acceptable salt thereof.
  • a calcineurin inhibitor such as cyclosporine A, voclosporin, ascomvcin, tacrolimus, pimecrolimus, an analog thereof, or a pharmaceutically acceptable salt thereof.
  • the optional, additional active agent may be a mTOR inhibitor such as sirolimus (rapamycin), temsirolimus, everolimus, an analog thereof, or a pharmaceutically acceptable salt thereof.
  • a mTOR inhibitor such as sirolimus (rapamycin), temsirolimus, everolimus, an analog thereof, or a pharmaceutically acceptable salt thereof.
  • a calcineurin inhibitor of the present disclosure is preferably an
  • Immunophilin-binding compound having calcineurin inhibitory activity are compounds forming calcineurin inhibiting complexes with immunophilins, e.g. cyclophilin and macrophilin.
  • Examples of cyclophilin-binding calcineurin inhibitors are cyclosporines or cyclosporine derivatives (hereinafter
  • cyclosporines and examples of macrophilin-binding calcineurin inhibitors are ascomycin (FR 520) and ascomycin derivatives (hereinafter ascomycins).
  • ascomycins A wide range of ascomycin derivatives are known, which are either naturally occurring among fungal species or are obtainable by manipulation of fermentation procedures or by chemical derivatization.
  • Ascomycin-type macrolides include ascomycin, tacrolimus (FK506), sirolimus and pimecrolimus.
  • Cyclosporine originally extracted from the soil fungus Potypaciadium infilatum, has a cyclic 11 -amino acid structure and includes e.g. Cyclosporines A through I, such as Cyclosporine A, B, C, D and G. Cy closporine binds to the cytosolic protein cyclophilin of immunocompetent lymphocytes, especially T-lymphocytes, forming a complex. The complex inhibits calcineurin, which under normal circumstances induces the transcription of interleukin-2 (IL-2). Cyclosporine also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.
  • Cyclosporine originally extracted from the soil fungus Potypaciadium infilatum, has a cyclic 11 -amino acid structure and includes e.g. Cyclosporines A through I, such as Cyclosporine A, B, C, D and G. Cy closporine binds to the cytosolic protein
  • Voclosponn is a next-generation calcineurin inhibitor that is a more potent and less toxic semi-synthetic derivative of cyclosporine A. Like other molecules of this class, voclosponn reversibly inhibits immunocompetent lymphocytes, particularly T-lymphocytes, and also inhibits lymphokine production and release. This action is primarily mediated through inhibition of calcineurin, a phosphatase enzy me found in the cytoplasm of cells. Voclosponn has a single carbon extension with double bond that has been shown to extend deeper into the latch/regulatory region of calcineurin.
  • compositions of the present disclosure comprise the trans-version of voclosponn, trans-ISA247 CAS RN 368455-04-3 which is described in, for example, US Patent Publication No. : 2006/0217309, which is hereby incorporated herein by reference. Further compositions of voclosporin are described, for example, in U.S. Pat. No. 7,060,672, which is hereby incorporated herein by reference.
  • Tacrolimus (FK506) is another calcineurin inhibitor which is also a fungal product, but has a macrohde lactone structure. Tacrolimus has been used as an
  • Tacrolimus has also been shown to inhibit the production of IL-2. Tacrolimus binds to an immunophilin (FK-binding protein 12, FKBP12), followed by binding of the complex to calcineurin to inhibit its phosphatase activity.
  • FK-binding protein 12 FKBP12
  • Sirolimus is a microbial product isolated from the actinomycete
  • Sirolimus binds to an immunophilin (FK-binding protein 12, FKBP12) forming a complex, which inhibits the mammalian target of rapamycin (mTOR) pathway through directly binding the rtiTOR Complexl (mTORCl).
  • mTOR mammalian target of rapamycin
  • mTORCl rtiTOR Complexl
  • Sirolimus inhibits the response to interleukin-2 (IL-2) and thereby blocks activation of T- and B-cells.
  • IL-2 interleukin-2
  • tacrolimus and cyclosporine inhibit the production of IL-2.
  • Pimecrolimus is a new calcineurin inhibitor which has been found to have antifungal properties against Malassezia spp., as does tacrolimus.
  • Calcineurin inhibitors such as cyclosporine A, voclosporin, ascomycin, tacrolimus, pimecrolimus, an analog thereof, or a pharmaceutically acceptable salt thereof, can be utilized in a mixed micellar composition of the present disclosure.
  • the calcineurin inhibitor is voclosporin.
  • mTOR inhibitors such as sirolimus (rapamycin), temsirolimus, everolimus, an analog thereof, or a pharmaceutically acceptable salt thereof, can be utilized in a mixed micellar composition of the present disclosure.
  • Other compounds useful as active agents are compounds that are chemically similar variants to any of the compounds set forth above.
  • chemically similar variants includes, but is not limited to. replacement of various moieties with known biosteres; replacement of the end groups of one of the compounds above with a
  • the formulations as disclosed herein may be used to treat or prevent an ocular disease or disorder.
  • Ocular diseases and disorders contemplated herein include anterior segment diseases and posterior segment diseases.
  • Exemplary ocular diseases that may in certain embodiments be treated with formulations as disclosed herein include the following.
  • Dry eye syndrome (DES, Chronic dry eye, Keratitis sicca; Xerophthalmia;
  • Keratoconjunctivitis sicca can be defined as a condition that includes a variety of disorders that result in a loss of, or altered composition of, the natural tear film, which maintains the surface of the eye. Without this tear film, vision is impaired and patients may suffer severe ocular discomfort.
  • DES can be caused by excessive tear ev aporation or by a reduction of tear production in the lacrimal gland, which is the site of tear production. Though the exact causes of this condition are unknown, there is evidence supporting the link between reduced tear production and inflammation of one or more components of the lacrimal apparatus.
  • Currently available medications for DES are leaving substantial room for more effective and better tolerated products.
  • DES may also be a manifestation of Sjogren's syndrome which is an autoimmune disorder in which the glands that produce tears and saliva are destroyed. This leads to dry mouth, decreased tearing, and other dry mucous membranes.
  • Noninfectious uveitis is a chronic inflammatory, putative Thl/Thl7-mediated autoimmune disease associated with substantial visual morbidity and is potentially blinding. Blindness from uveitis usually does not occur from a single inflammatory episode; rather, cumulative damage results from recurrent episodes of inflammation.
  • the inflammatory sequelae resulting in vision loss may include one or more of cystoid macular edema, cataracts, vitreous debris, glaucoma, macular pathology (scarring and atrophy), optic neuropathy, and retinal detachment.
  • Anterior uveitis occurs in the front of the eye and is the most common form of uveitis.
  • Par planitis is an inflammation of the pars plana, a narrow area between the iris and the choroid. This condition occurs more frequently in young men, but is usually not associated with another disease.
  • Posterior uveitis chondroitis
  • Posterior uveitis affects primarily the choroid; the back portion of the uveal tract. If the retina is also involved, it is called chorioretinitis.
  • Posterior uveitis may occur in association with an autoimmune disease, or follow a systemic infection. In posterior uveitis, inflammation can last from months to years and may cause permanent vision damage, even with treatment.
  • Uveitis can cause vision impairment, ocular pain, and loss of vision. It is estimated that about 10% of new cases of blindness in the U.S. are caused by uveitis.
  • Conjunctivitis pink eye describes a group of diseases that cause swelling, itching, burning, and redness of the conjunctiva, the protective membrane that lines the eyelids and covers exposed areas of the sclera, or white of the eye.
  • Keratitis is an inflammation of the cornea (clear portion in the front of the eye). Keratitis can be caused by an infection (bacterial, fungal, viral, parasite, etc.) or a noninfectious agent (e.g., certain types of auto-immune diseases are associated with a variety of non-infectious keratitises).
  • an infection bacterial, fungal, viral, parasite, etc.
  • a noninfectious agent e.g., certain types of auto-immune diseases are associated with a variety of non-infectious keratitises.
  • Keratoconjunctivitis refers to an inflammation of the cornea and conjunctiva.
  • Vernal keratoconjunctivitis is a recurrent ocular inflammatory disease characterized by hard, elevated, cobblestone like bumps on the upper eyelid. There may also be swellings and thickening of the conjunctiva.
  • the conjunctiva is the outermost membrane which lines the eyelids as well as the exposed parts of the eye, except for the cornea.
  • Atopic keratoconjunctivitis is the result of a condition called atopy.
  • Atopy is a genetic condition whereby the immune system produces higher than normal antibodies in response to a given allergen.
  • Systemic immune mediated diseases such as cicatrizing conjunctivitis and other autoimmune disorders of the ocular surface represent a clinically heterogeneous group of conditions where acute and chronic autoreactive mechanisms can cause significant damage to the ey e.
  • cicatrization can ensue, leading to significant mechanical alterations as a result of the fibrosis.
  • These conditions though generally infrequent, can be the cause of profound pathology and visual disability.
  • Blepharitis is a common condition that causes inflammation of the eyelids.
  • Scleritis is a serious inflammatory disease that affects the white outer coating of the eye, known as the sclera.
  • Glaucoma is a disease that damages the eye's optic nerve. It usually happens when fluid builds up in the front part of the eye. The extra fluid increases the pressure i eye, damaging the optic nerve.
  • Retinopathies include age-related macular degeneration (AMD), a disease associated with aging that gradually destroys sharp, central vision. AMD affects the macula, which is located at the center of the retina. AMD occurs in two forms: wet and dry. Wet AMD occurs when abnormal blood vessels behind the retina start to grow under the macula. These new blood vessels tend to be very fragile and often leak blood and fluid. The blood and fluid raise the macula from its normal place at the back of the eye. Damage to the macula occurs rapidly. Dry AMD occurs when the light-sensitive cells in the macula slowly break down, gradually blurring central vision in the affected ey e.
  • AMD age-related macular degeneration
  • Diabetic retinopathy is a complication of diabetes that results from damage to the blood vessels of the light-sensitive tissue at the back of the eye (the retina). At first, diabetic retinopathy may cause no symptoms or only mild vision problems. Eventually, however, diabetic retinopathy can result in blindness. Diabetic macular edema (DME) is the swelling of the retina in diabetes mellitus due to leaking of fluid from blood vessels within the macula.
  • DME Diabetic macular edema
  • Ocular neovascularization is the abnormal or excessive formation of blood vessels in the ey e. Ocular neovascularization has been shown in diabetic retinopathy, age- related macular degeneration (AMD) and retinopathy of prematurity.
  • AMD age-related macular degeneration
  • PVR Proliferative vitreoretinopathy
  • CMV cytomegalovirus
  • HAV disease
  • organ or bone marrow transplant or chemotherapy
  • CMV virus can cause damage and disease to the eye and the rest of the body.
  • CMV affects the eye in about 30% of the cases by causing damage to the retina. This is called CMV retinitis.
  • Optic neuritis occurs when the optic nerve becomes inflamed and the myelin sheath becomes damaged or is destroyed. Nerve damage that occurs in the section of the optic nerve located behind the eye, is called retrobulbar neuritis, which is another term sometimes used for optic neuritis.
  • epiretinal membrane is a scar-tissue like membrane that forms over the macula. It typically progresses slowly and affects central vision by causing blurring and distortion. As it progresses, the pulling of the membrane on the macula may cause swelling.
  • the compositions can be used for preventing transplant rejection of, for example, corneal allografts following transplantation. It is well known that in inflammation T-lymphocytes play a critical role in mediating rejection of foreign tissues. Prevention of rejection is of paramount importance in maintaining the health of transplanted corneas. Rejection may occur in any of the layers comprising the cornea, for example, the corneal epithelium, the corneal stroma or the comeal endothelium. The functioning of the cornea can be compromised following endothelial rejection. The endothelial layer serves to maintain the cornea in a compact state, acting as a pump by removing water from the comeal stroma.
  • compositions of the present disclosure can be used for the prevention of rejection following corneal allograft transplantation.
  • compositions of the present disclosure may also contain other components such as, but not limited to, additives, adjuvants, buffers, tonicity agents, bioadhesive polymers, and preservatives.
  • the mixtures are preferably formulated at about pH 5 to about pH 8. This pH range may be achieved by the addition of buffers to the composition as described in the examples.
  • the pH range in the composition in a formulation is about pH 6.6 to about pH 7.0.
  • compositions of the present disclosure may be buffered by any common buffer system such as phosphate, borate, acetate, citrate, carbonate and borate-polyol complexes, with the pH and osmolality adjusted in accordance with well- known techniques to proper physiological values.
  • the mixed micellar compositions of the present disclosure are stable in buffered aqueous solution. That is, there is no adverse interaction between the buffer and any other component that would cause the compositions to be unstable.
  • Tonicity agents include, for example, mannitol, sodium chloride, xylitol, etc. These tonicity agents may be used to adjust the osmolality of the compositions. In one aspect, the osmolality of the formulation is adjusted to be in the range of about 250 to about 350 mOsmol/kg. In a preferred aspect, the osmolality of the formulation is adjusted to between about 280 to about 300 mOsmol/kg.
  • An additive such as a sugar, a glycerol, and other sugar alcohols, can be included in the compositions of the present disclosure.
  • Pharmaceutical additives can be added to increase the efficacy or potency of other ingredients in the composition.
  • a pharmaceutical additive can be added to a composition of the present disclosure to improve the stability of the calcineurin inhibitor or mTOR inhibitor and/or RTK inhibitor, to adjust the osmolality of the composition, to adjust the viscosity of the composition, or for another reason, such as effecting drug delivery.
  • Non-limiting examples of pharmaceutical additives of the present disclosure include sugars, such as, trehalose, mannose, D-galactose, and lactose.
  • the sugars can be incorporated into a composition prior to hydrating the thin film (i.e., internally). In another embodiment, the sugars can be incorporated into a composition during the hydration step (i.e., externally). In an embodiment, an aqueous, clear, mixed micellar solution of the present disclosure includes additives such as sugars.
  • compositions of the present disclosure further comprise one or more bioadhesive polymers.
  • Bioadhesion refers to the ability of certain synthetic and biological macromolecules and hydrocolloids to adhere to biological tissues. Bioadhesion is a complex phenomenon, depending in part upon the properties of polymers, biological tissue, and the surrounding environment. Several factors have been found to contribute to a polymer's bioadhesive capacity: the presence of functional groups able to form hydrogen bridges (--OH, COOH), the presence and strength of anionic charges, sufficient elasticity for the polymeric chains to interpenetrate the mucous layer, and high molecular weight.
  • Bioadhesion systems have been used in dentistry, orthopedics, ophthalmology, and in surgical applications. However, there has recently emerged significant interest in the use of bioadhesive materials in other areas such as soft tissue-based artificial replacements, and controlled release systems for local release of bioactive agents. Such applications include systems for release of drugs in the buccal or nasal cavity, and for intestinal or rectal administration.
  • a composition of the present disclosure includes at least one bioadhesive polymer.
  • the bioadhesive polymer can enhance the viscosity of the composition and thereby increase residence time in the eye.
  • Bioadhesive polymers of the present disclosure include, for example, carboxylic polymers like Carbopol.RTM.
  • carboxymethylcellulose gums like locust beam, xanthan, agarose, karaya, guar, and other polymers including but not limited to polyvinyl alcohol, polyvinyl pyrollidone, polyethylene glycol, Pluronic.RTM.
  • phase-transition polymers for providing sustained and controlled delivery of enclosed medicaments to the eye
  • alginic acid carrageenans (e.g., Eucheuma), xanthan and locust bean gum mixtures, pectins, cellulose acetate phthalate, alkylhydroxy alkyl cellulose and derivatives thereof, hydroxyalkylated polvacrylic acids and derivatives thereof, poloxamers and their derivatives, etc.
  • Physical characteristics in these polymers can be mediated by changes in environmental factors such as ionic strength, pH, or temperature alone or in combination with other factors.
  • the optional one or more bioadhesive polymers is present in the composition from about 0.01 wt % to about 10 wt %/volume, preferably from about 0.1 to about 5 wt %/volume.
  • the compositions of the present disclosure further comprise at least one hydrophilic polymer excipient selected from, for example, PVP-K-30, PVP-K-90, HPMC, HEC, and polycarbophil.
  • the polymer excipient is selected from PVP-K-90, PVP-K-30 or HPMC.
  • the polymer excipient is selected from PVP-K-90 or PVP-K-30.
  • compositions may optionally be preserved with any of many well-known preservatives, including benzyl alcohol with/without EDTA, benzalkonium chloride, chlorhexidine, Cosmocil.RTM. CQ, or
  • preservatives may in some embodiments not be necessary or desirable in formulations included in single use containers. In other embodiments it may be advantageous to include preservatives, such as in certain embodiments in which the formulations are included in a multiuse container.
  • the ophthalmic compositions can be administered topically to the eye as biocompatible, aqueous, clear mixed micellar solutions.
  • the compositions have the drugs incorporated and/or encapsulated in micelles which are dispersed in an aqueous medium.
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), a polyoxyl lipid or fatty acid and a polyalkoxylated alcohol.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), and a n> 40 polyoxyl lipid or fatty acid.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), and a polyoxyl lipid or fatty acid; wherein said polyoxyl lipid or fatty acid is present in an amount equal to or greater than 1% of said formulation.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), and a polyoxyl lipid or fatty acid; wherein said formulation comprises nanomicelles.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-lOO; and about 0.01-0.1% octoxynol-40.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-lOO; and about 0.01-0.1% octoxynol-40.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising greater than 0.2% of iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-lOO; and about 0.01-0.1% octoxynol-40.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1.5-4% of one or more polyoxl lipids selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-lOO; and about 0.01-0.1% octoxynol-40.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof).
  • RTK receptor tyrosine kinase
  • ET-1 inhibitor e.g., bosentan, macitentan, and the like
  • steroid e.g., bosentan, macitentan, and the like
  • An ophthalmic formulation comprising a receptor tyrosine kinase (RTK) inhibitor, 1.5-4% of polyoxl lipids or fatty acids; and about 0.01-0.1% octoxynol-40; wherein the formulation comprises nanomicelles.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1.5-4% of polyoxl lipids or fatty acids; and about 0.01-0.1% octoxynol-40; wherein the formulation comprises nanomicelles.
  • a receptor tyrosine kinase (RTK) inhibitor especially an RTK inhibitor for retinal disease(s)
  • a prostaglandin e.g., latanoprost, iloprost
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), about 4% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.1% octoxynol-40.
  • active ingredient e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g.
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), about 4% of HCO-60 and about 0.01-0.1% octoxynol-40.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.
  • active ingredient e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., lat
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.
  • active ingredient e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., lat
  • An ophthalmic formulation comprising greater than 0.2% of iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% octoxy nol-40.
  • active ingredient e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1.5-4% of one or more polyoxl lipids selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.
  • RTK receptor tyrosine kinase
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1.5-4% of polyoxl lipids or fatty acids; and about 0.01% octoxynol-40.
  • active ingredient e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1.5-4% of polyoxl lipids or fatt acids; and about 0.01% octoxynol-40; wherein the formulation comprises nanomicelles.
  • a receptor tyrosine kinase (RTK) inhibitor especially an RTK inhibitor for retinal disease(s)
  • a prostaglandin e.g., latanoprost, iloprost, and
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), 1.5-4% of polyoxl lipids or fatt acids; and about 0.01% octoxynol-40; wherein the formulation comprises nanomicelles.
  • a receptor tyrosine kinase (RTK) inhibitor especially an RTK inhibitor for retinal disease(s)
  • a prostaglandin e.g., latanoprost, iloprost, and
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), about 4% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.
  • active ingredient e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., la
  • An ophthalmic formulation comprising iloprost, macitentan, and the like, optionally in the further presence of one or more active ingredient (e.g., a receptor tyrosine kinase (RTK) inhibitor (especially an RTK inhibitor for retinal disease(s), a prostaglandin (e.g., latanoprost, iloprost, and the like), a prostacyclin, an ET-1 inhibitor (e.g., bosentan, macitentan, and the like), a steroid, and the like, as well as combinations of any two or more thereof), about 4% of HCO-60 and about 0.01% octoxynol-40.
  • RTK receptor tyrosine kinase
  • RT receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • polyoxyl lipid or fatty acid is one or more selected from HCO-60, HCO-80 or HCO-100.
  • said formulation further comprises at least one active agent selected from the group consisiting of calcineurin inhibitors, mTOR inhibitors, peptides, eicosanoids (e.g. prostacy clins and prostaglandins), anti-inflammatory drugs (such as NSAIDS), autonomic drugs (e.g. beta- blockers, alpha-blockers, beta-agonists, and alpha-agonists), biologies, gene therapy agents (e.g. viral vectors), anti-infectives (e.g.
  • retinoids retinoids
  • RNAi photo sensitizers
  • steroids e.g., estrogens and derivatives thereof, and corticosteriods
  • mixture drugs immuno-modulators, chemotherapeutic agents, G-coupled protein receptor antagonists, growth hormone inhibitors, integrin inhibitors, Sdfl/CXCR4 pathway inhibitors, and nACh receptor antagonists, resolvins (or resolvin-like compounds), lipoxins, and oxylipins.
  • RT receptor tyrosine kinase
  • the receptor tyrosine kinase (RT ) inhibitor is sunitinib, regorafenib, sorafenib, imatinib, dasatinib, dovitinib, nilotinib, or hnifinib, an analog thereof, or a pharmaceutically acceptable salt thereof.
  • RTK receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • RTK receptor tyrosine kinase
  • the active agent comprises a receptor tyrosine kinase (RTK) inhibitor, and one or more active agents selected from the group consisting of a resolvin or resolvin-like compound, a steroid (such as a corticosteroid), cyclosporine A, and voclosporin.
  • RTK receptor tyrosine kinase
  • the active agent comprises a receptor tyrosine kinase (RTK) inhibitor, a resolvin and/or a corticosteroid.
  • RTK receptor tyrosine kinase
  • the active agent comprises a receptor tyrosine kinase (RTK) inhibitor, cyclosporine A and/or a corticosteroid.
  • RTK receptor tyrosine kinase
  • the active agent comprises a receptor tyrosine kinase (RTK) inhibitor, a resolvin, cyclosporine A and/or a corticosteroid.
  • RTK receptor tyrosine kinase
  • a method of treating or preventing an ocular disease or condition comprising topically administering a formulation of any of the preceding embodiments.
  • 97. A method of treating or preventing an ocular disease or condition, said method comprising topically administering a formulation of any of the preceding embodiments; wherein said disease is an anterior segment disease.
  • a method of treating or preventing an ocular disease or condition comprising topically administering a formulation of any of the preceding embodiments; wherein said disease is an posterior segment disease.
  • a method of treating or preventing an ocular disease or condition comprising topically administering a formulation of any of the preceding embodiments; wherein said disease is one or more selected from the group consisting of dry eye syndrome, Sjogren's syndrome, uveitis, anterior uveitis (iritis), chorioretinitis, posterior uveitis, conjunctivitis, allergic conjunctivitis, keratitis, keratoconjunctivitis, vernal
  • VKC keratoconjunctivitis
  • atopic keratoconjunctivitis systemic immune mediated diseases such as cicatrizing conjunctivitis and other autoimmune disorders of the ocular surface, blepharitis, scleritis, age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), ocular neovascularization, retinopathy of prematurity, proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis, optic neuritis, retrobulbar neuritis, and macular pucker.
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • DME diabetic macular edema
  • PVR proliferative vitreoretinopathy
  • CMV cytomegalovirus
  • a method of treating or preventing an ocular disease or condition comprising topically administering a formulation of any of the preceding embodiments; wherein said disease is dry eye syndrome.
  • a method of treating or preventing an ocular disease or condition comprising topically administering a formulation of any of the preceding embodiments; wherein said disease is allergic conjunctivitis.
  • a method of treating or preventing an ocular disease or condition comprising topically administering a formulation of any of the preceding embodiments; wherein said disease is age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • the contents of the dialysis bag were carefully transferred to a 15-mL centrifuge tube and formulations were subjected to sonication in water bath (time range from 0 min to 5 min).
  • the final volume was made up with 2X phosphate buffer saline and adjusted pH of the formulation to 6.5 ⁇ 0.1.
  • the resultant formulation was filtered with 0.22 micrometer nylon filter to remove any foreign particulate matter.
  • the prepared formulations were subjected to various tests such as entrapment efficiency, loading efficiency, mixed nanomicellar size and polydispersity index.
  • Entrapment efficiency To determine the entrapment efficiency of the formulation, all the prepared formulations were subjected to entrapment efficiency test. Briefly, formulations were vortex mixed for homogeneity and ImL was transferred to a fresh (1.5 mL) eppendorf tube. Each formulation was lyophilized to obtain a solid at the bottom of eppendorf tube. The obtained solid was suspended in ImL of organic solvent (diethyl ether) to generate reverse micelles and release the drug into the external organic solvent. The organic solvent was evaporated overnight in speed vacuum.
  • organic solvent diethyl ether
  • Entrapment efficiency (amount of drug quantified in MNF) X 100
  • the mobile phase comprised methanol (MeOH), water and trifiuoroacetic acid (TFA) (70:30:0.05% v/v) which was set at a flow rate of 0.5 mL/min. Detection wavelength was set at 272 nm. The sample tray temperature was maintained at 4° C. Calibration curve (0.5 to 5 ⁇ g/mL) for compound 1001 was prepared by making appropriate dilutions from the stock solution in 2- propanol. An injection volume of 10 ⁇ was injected into the HPLC column for analysis. All the standards and samples prepared were stored at 4°C before and during the analysis.
  • step one compound 1001, HCO-60 and octoxynol-40 were dissolved separately in 0.3mL of ethyl acetate. These three solutions were mixed together in 15-mL centrifuge tube. The resultant mixture was vortexed to obtain a homogenous solution. Ethyl acetate solvent was removed with speed vacuum to obtain a solid thin film. The residue was kept overnight under high vacuum at room temperature to remove residual organic solvent. In step two, the resultant thin film was hydrated with ImL of double distilled deionized water by vortexing the solution.
  • the rehydrated formulation was suspended in 2X phosphate buffer solution, (pH 6.5). It was filtered through 0.2 ⁇ nylon filter membrane to remove the unentrapped drug aggregates and other foreign particulates.
  • the entrapment of compound 1001 was determined by RP-HPLC following disruption of the micelles and solubilization of 1001 in the diluent (2-propanol) as described below
  • Weight percent of drug loaded into MNF was determined following the method for entrapment efficiency. Size and polydispersity index of the formulations was determined with Malvern zetasizer as described above. The results obtained are summarized in Table 2 below. The formulations appear clear and have small size and narrow size distribution.
  • HCO-60 hydrogenated castor oil-60
  • RBF round bottom flask
  • the neck of the round bottom flask was closed with an aluminum foil, sealed with parafilm and transferred to water bath set at 40 C.
  • the round bottom flask was left overnight in water bath to liquefy/melt the HCO-60.
  • octoxynol-40 was diluted 100 folds and allowed to equilibrate at 40 C for lh in water bath.
  • compound 1001 (neat oil) was allowed to equilibrate at 40 C in the water bath for 1 h.
  • phosphate buffer was previously prepared and the pH was adjusted to 5.5.
  • the volume of the formulation was made up to 5 mL with the 2X phosphate buffer saline.
  • the prepared formulation was filtered with 0.2 ⁇ nylon filter and stored at 4 C.
  • MNF encapsulating compound 1001 (neat oil) can be divided into two steps. As an example for the development of 3.0 wt% HCO-40 or HCO-60 MNF encapsulating 0.4% compound 1001 is described below.
  • step 1 HCO-40 or HCO-60, 150 mg, was thermostated at 40° C in water bath to melt and result in a clear thick viscous liquid.
  • step 2 To this melt polymer compound 1001 (-20 mg), thermostated at 40° C, was added and mixed for homogenous distribution. The mixture was allowed to reach room
  • step 2 the pellet and/or viscous liquid was allowed to reach room temperatures under natural conditions.
  • the pellet and/or viscous liquid was thermostated in water bath at 40° C and resuspended in 2.0 mL of distilled water (thermostated at 40° C) under constant stirring. This resulted in spontaneous development of a clear aqueous solution of 0.4% compound 1001 MNF. This aqueous solution was allowed to reach room
  • the waxy solid developed with HCO-60 and compound 1001 mixture may be helpful to protect the drug and prevent the drug degradation with a surface blanket of an inert gas.
  • the other polymer (HCO-40) did not result in development of waxy solid at room temperature or at low refrigerated conditions (4° C) when used up to approx. 3.0 wt%.
  • Tables 3a - 3c The results obtained for physical appearance of the mixture, different phases, at different temperatures and appearance of final formulation are summarized in Tables 3a - 3c.
  • Table 3a the physical appearance of melt mixture of HCO-60 and Compound 1001 at 25° C, resuspending in water at 40° C and final formulation of mixed nanomi cellar formulation encapsulating compound 1001 (HCO-60 was melted and compound 1001 was added to melt, then allowed to cool to room temperature and the physical appearance was noted.
  • MNF formulation of cyclosporineA was prepared by solvent evaporation method in two steps: 1. Preparation of basic formulation and 2. rehydration.
  • step one cyclosporine, HCO-40 and octoxynol-40 were dissolved separately in 0.5 mL of ethanol aliquots. These three solutions were mixed together in a round bottom flask. The resultant mixture was stirred to obtain a homogenous solution. Ethanol solvent was removed by high speed vacuum evaporation overnight to obtain a solid thin film.
  • step two the resultant thin film was hydrated with 2.0 mL of double distilled deionized water and resuspended with stirring overnight. The rehydrated formulation was pH adjusted and volume was made up with 2X phosphate buffer solution, (pH 6.8). Further the formulation was filtered through 0.2 ⁇ nylon filter membrane to remove the unentrapped drug aggregates and other foreign particulates.
  • MNF formulation of cyclosponnA was prepared by the water method.
  • One mL of double distilled deionized water was heated to 60°C in a round bottom flask. This heated water was kept under stirring.
  • HCO-40 was added to the heated water and allowed to dissolve under constant stirring.
  • Octoxynol-40 was then added to this mixture and allowed to dissolve.
  • phosphates, sodium chloride and CsA were blended by hand shaking for a few minutes. Under stirring conditions, the phosphates / CsA / sodium chloride blend was added to the solution of HCO-40 and octoxynol-40 to disperse the drug.
  • PVP K 90 solution was separately prepared using the remaining 1 mL double distilled deionized water. This PVP K 90 solution was added to the solution of polymer/surfactant/drug/phosphate/sodium chloride. Water was added to make up the final volume. Then the formulation was filtered through 0.2 ⁇ nylon membrane to remove the drug aggregates and other foreign particulates.
  • Healthy young adult New Zealand albino rabbits (3-4 Kg) used for the study the local tolerability of the instant formulations, for example a formulation of Examples 1-5.
  • One drop (approximately 30 .mu.L) of saline is placed in one eye and a drop of formulation is placed in the other eye of the rabbit. Both eyes of each animal are examined by a veterinary ophthalmologist using a hand-held slit lamp and indirect ophthalmoscope.
  • Both control and test eyes are graded according to conjunctival congestion, swelling, and discharge, aqueous flare, iris light reflex and involvement, corneal cloudiness severity and area, pannus, fluorescein examination and lens opacity using the Hackett/McDonald scoring system (see, for example, Hackett, R. B. and McDonald, T. 0. Ophthalmic Toxicology and Assessing Ocular Irritation. Dermatoxicology, 5.sup.th Edition. Ed. F. N. Marzulli and H. I. Maibach. Washington, D.C.: Hemisphere Publishing Corporation. 1996; 299-305 and 557-566.).
  • the crystalline lens is observed with the aid of the slit-lamp biomicroscope, and the location of lenticular opacity is discerned by direct and retro illumination.
  • the location of lenticular opacities are arbitrarily divided into the following lenticular regions beginning with the anterior capsule: Anterior subcapsular, Anterior cortical Nuclear Posterior cortical, Posterior subcapsular, Posterior capsular.
  • the lens is evaluated routinely during ocular evaluations and graded as either 0 (normal) or 1 (abnormal). The presence of lenticular opacities are described and the location noted.
  • NZW rabbits are used in a single dose (SD) and 7-day repeat dose (RD) studies.
  • DB rabbits will be used in a single dose study).
  • Animals are either untreated (controls) or given a single or a daily topical ocular dose for 7 days (0.05 wt%, 0.2 wt% or 0.5 wt% in a mixed micellar formulation to one or both eyes). Blood and ocular tissue concentrations are assessed.
  • compositions of the present disclosure make topical administration of the compositions of the present disclosure feasible for the treatment of diseases of the back-of-the-eye (e.g., retinal, diseases involving optic nerve such as glaucoma). Very high levels, especially in target tissues such as lachrymal gland, will be shown with the compositions of the present disclosure.
  • Mixed nanomi cellar formulations according to Examples 1-5 are administered to a patient having proliferative diabetic retinopathy at a concentration of between 0.2 wt% to 0.5 wt% b.i.d. over a period of 1 month to 1 year or more.
  • Samples of selected ocular tissues were collected 1 hour following the last dose on Day 5 from all two rabbits that received 0.1% CsA with HCO-40 (OD), and BSS (OS), and from one rabbit (No. 21) that received placebo HCO-40 formulation (OD) and BSS (OS).
  • the samples were assayed for cyclosporine (CsA) by liquid chromatography -tandem mass spectrometry (LC-MS/MS). The internal standard was d cyclosporine.
  • the established analytical ranges for CsA were 0.100 - 100 ng/mL for whole blood, and 2.00 - 2000 ng/mL for aqueous humor and vitreous humor.
  • the analytical ranges for the solid tissues were 0.125 - 30 ng (low range) and 1.00 - 2500 ng (high range).
  • the results of the solid tissue analyses were converted to ng/g by correcting for the amount of tissue analyzed.
  • Formulations [00156] A study was conducted in rabbits to test the tolerance and ocular tissue distribution of two nanomicellar formulations of compound 1001 (RX10045) against matching placebos (Table 7a and 7b) and balanced saline solution (BSS). Healthy New Zealand female white rabbits (2-3 kg) were used for this study. One drop (approximately 35 ⁇ ) of study drug was applied o.d. 4x / day at two hour intervals for 5 days. One drop of BSS was applied to the contralateral eye.
  • Selected ocular fluids/tissues aqueous humor, vitreous humor, conjunctiva, cornea, iris-ciliary body, lens, retina/choroid, and sclera
  • aqueous humor, vitreous humor, conjunctiva, cornea, iris-ciliary body, lens, retina/choroid, and sclera collected from two rabbits each in the RX- 10045 (0.15% in HCO-60, 0.1% in HCO-40) treatment groups, and from one rabbit in each of the matching placebo groups, were assayed for compound 1001 and another resolvin by liquid chromatography -tandem mass spectrometry (LC-MS/MS). Warfarin-ds and 5-HDA were used as internal standards for the analysis of RX- 10045 and its active metabolite, RX- 10008, respectively, in aqueous humor and vitreous humor.
  • solid tissues warfarin-d5 and phenyl acetic acid-d5 (PAA-ds) were used as the internal standards for compound 1001 and RX-10008, respectively.
  • the analytical range for the solid tissues were 0.125 - 100 ng.
  • the results of the solid tissue analyses were converted to ng/g by correcting for the amount of tissue analyzed.
  • RX- 10008 tissue concentrations are presented in Table 9. The highest concentrations of RX- 10008 were found in the cornea, followed by the iris-ciliary body, conjunctiva, and sclera. There were also relatively high concentrations of RX- 10008 in the aqueous humor. Lower amounts were found in the retina/choroid and lens. The lowest levels of RX- 10008 were found in the vitreous humor.
  • Formulations of sunitinib, analogs thereof, or pharmaceutically acceptable salts thereof are prepared according to the procedures described in Examples 1-5, and the resulting formulations are subjected to the assays of one or more of Examples 6-11 with positive results.
  • Formulations of regorafenib, analogs thereof, or pharmaceutically acceptable salts thereof are prepared according to the procedures described in Examples 1-5, and the resulting formulations are subjected to the assays of one or more of Examples 6-11 with positive results.
  • Formulations of sorafenib, analogs thereof, or pharmaceutically acceptable salts thereof are prepared according to the procedures described in Examples 1-5, and the resulting formulations are subjected to the assays of one or more of Examples 6-11 with positive results.
  • Formulations of imatinib, analogs thereof, or pharmaceutically acceptable salts thereof are prepared according to the procedures described in Examples 1-5, and the resulting formulations are subjected to the assays of one or more of Examples 6-11 with positive results.
  • Formulations of dasatinib, analogs thereof, or pharmaceutically acceptable salts thereof are prepared according to the procedures described in Examples 1-5, and the resulting formulations are subjected to the assays of one or more of Examples 6-11 with positive results.
  • Formulations of dovitinib, analogs thereof, or pharmaceutically acceptable salts thereof are prepared according to the procedures described in Examples 1-5, and the resulting formulations are subjected to the assays of one or more of Examples 6-11 with positive results.
  • Formulations of nilotinib, analogs thereof, or pharmaceutically acceptable salts thereof are prepared according to the procedures described in Examples 1-5, and the resulting formulations are subjected to the assays of one or more of Examples 6-11 with positive results.
  • Formulations of linifinib, analogs thereof, or pharmaceutically acceptable salts thereof are prepared according to the procedures described in Examples 1-5, and the resulting formulations are subjected to the assays of one or more of Examples 6-11 with positive results.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formulations destinées à être administrées par voie topique, telles que des formulations ophtalmiques; et des méthodes d'utilisation de telles formulations. Selon certains aspects et modes de réalisation de l'invention, lesdites formulations peuvent comprendre un acide gras ou un lipide à base de polyoxyl, et/ou un alcool polyalcoxylé, et éventuellement des nanomicelles. L'invention concerne également des méthodes de traitement ou de prévention de maladies ou d'affections, telles que des maladies ou affections oculaires.
PCT/US2017/020795 2016-03-03 2017-03-03 Traitement du glaucome et/ou de maladies rétiniennes, et formulations utiles pour ce traitement WO2017152129A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662303333P 2016-03-03 2016-03-03
US62/303,333 2016-03-03

Publications (2)

Publication Number Publication Date
WO2017152129A2 true WO2017152129A2 (fr) 2017-09-08
WO2017152129A3 WO2017152129A3 (fr) 2018-07-26

Family

ID=59744422

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/020795 WO2017152129A2 (fr) 2016-03-03 2017-03-03 Traitement du glaucome et/ou de maladies rétiniennes, et formulations utiles pour ce traitement

Country Status (1)

Country Link
WO (1) WO2017152129A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10441630B2 (en) 2012-08-24 2019-10-15 Sun Pharma Global Fze Topical formulations and uses thereof
WO2020081562A1 (fr) * 2018-10-15 2020-04-23 Ocuphire Pharma, Inc. Méthodes et compositions permettant le traitement du glaucome et d'affections apparentées
US10918694B2 (en) 2016-02-29 2021-02-16 Sun Pharma Global Fze Topical cyclosporine-containing formulations and uses thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030176356A1 (en) * 2001-04-24 2003-09-18 University Of North Texas Health Science Center Endothelin antagonists and endothelin-converting enzyme inhibitors for the treatment of glaucoma
US10946076B2 (en) * 2013-02-13 2021-03-16 The Research Foundation For The State University Of New York Glaucoma treatment
EP3145549A4 (fr) * 2014-05-23 2018-02-14 Ocular Technologies Sàrl Formulations topiques et leurs utilisations

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10441630B2 (en) 2012-08-24 2019-10-15 Sun Pharma Global Fze Topical formulations and uses thereof
US10918694B2 (en) 2016-02-29 2021-02-16 Sun Pharma Global Fze Topical cyclosporine-containing formulations and uses thereof
US11951153B2 (en) 2016-02-29 2024-04-09 Sun Pharmaceutical Industries Limited Topical cyclosporine-containing formulations and uses thereof
WO2020081562A1 (fr) * 2018-10-15 2020-04-23 Ocuphire Pharma, Inc. Méthodes et compositions permettant le traitement du glaucome et d'affections apparentées

Also Published As

Publication number Publication date
WO2017152129A3 (fr) 2018-07-26

Similar Documents

Publication Publication Date Title
US20210338769A1 (en) Ophthalmic compositions
US9937225B2 (en) Topical formulations and uses thereof
US20230083458A1 (en) Topical cyclosporine-containing formulations and uses thereof
US20200009137A1 (en) Topical formulations and uses thereof
WO2017152129A2 (fr) Traitement du glaucome et/ou de maladies rétiniennes, et formulations utiles pour ce traitement
US20210268114A1 (en) Topical formulations and uses thereof
JP2018532809A5 (fr)
EP3373924A1 (fr) Formulations topiques et leurs utilisations

Legal Events

Date Code Title Description
NENP Non-entry into the national phase in:

Ref country code: DE

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

Ref document number: 17760950

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 17760950

Country of ref document: EP

Kind code of ref document: A2