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WO2011116123A1 - Tafamidis pour le traitement de troubles ophtalmiques - Google Patents

Tafamidis pour le traitement de troubles ophtalmiques Download PDF

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Publication number
WO2011116123A1
WO2011116123A1 PCT/US2011/028710 US2011028710W WO2011116123A1 WO 2011116123 A1 WO2011116123 A1 WO 2011116123A1 US 2011028710 W US2011028710 W US 2011028710W WO 2011116123 A1 WO2011116123 A1 WO 2011116123A1
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Prior art keywords
dichlorophenyl
oxazole
benzo
carboxylic acid
tafamidis
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PCT/US2011/028710
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English (en)
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Hank Michael James Petrassi
Van Nguyen-Tran
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Irm Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the invention relates to compounds, compositions and methods for the treatment of ophthalmic diseases and disorders.
  • Vitamin A and its various metabolites play diverse roles in physiology.
  • vitamin A deficiency is the major cause of blindness in children.
  • Excess vitamin-A levels in organs and tissues, such as the eye, may also cause blindness in a variety of retinal diseases, including macular degeneration.
  • Age-related macular degeneration (AMD) or dystrophy leads to gradual loss of vision, and eventually severe damage to the central vision.
  • AMD Age-related macular degeneration
  • Abnormal levels of vitamin A, and/or its associated transport proteins, retinol binding protein (RBP) and transthyretin (TTR) are also correlated with the manifestation of other diseases, including metabolic disorders. Abnormal levels of retinol were seen in type I and type II diabetic patients, but not in normal patients. Other diseases include idiopathic intracranial hypertension (IIH), and bone -related disorders, including cervical spondylosis, spinal hyperostosis, and diffuse idiopathic skeletal hyperostosis (DISH).
  • IIH intracranial hypertension
  • DISH diffuse idiopathic skeletal hyperostosis
  • vitamin A and/or its associated transport proteins, particularly TTR may play a role in protein misfolding and aggregation disease, including Alzheimer's disease and systemic amyloidosis.
  • TTR transthyretin
  • the ophthalmic disease is a macular degenearation disease or any retinol or retinol binding protein 4 (RBP4) mediated disease.
  • the macular degeneration disease is selected from age related macular degeneration (AMD) Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile
  • the subject is a human subject, while in other embodiments the subject is an animal subject.
  • the method further comprises the administration a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an antiinflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin.
  • TTR transthyretin
  • Another aspect provided herein are methods for modulating the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR) in a cell, wherein such methods comprise contacting the cell with an effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) or a physiologically acceptable salt thereof, thereby modulating the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR).
  • RBP4 retinol binding protein 4
  • TTR transthyretin
  • A2E N-retinylidene-N- retinylethanolamine
  • the administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid modulates the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), thereby modulating the serum concentration of RBP which has an effect on A2E progression.
  • A2E N-retinylidene-N- retinylethanolamine
  • Another aspect provided herein are methods for treating dry form age-related macular degeneration in an eye of a mammal comprising administering to the mammal an effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • Talamidis 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • the method comprises multiple administrations of the effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), and the time between multiple administrations is at least one day.
  • Tafamidis 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • the method further comprising a drug holiday, wherein the administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is temporarily suspended or the dose of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) administered is temporarily reduced.
  • the drug holiday lasts at least seven days.
  • the effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid is administered orally to the mammal. In certain embodiments of such methods, the effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered ophthalmically to the mammal.
  • the mammal is a human having a macular degeneration disease.
  • the macular degeneration disease is selected from Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.
  • afamidis 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid
  • afamidis 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid
  • a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of ophthalmic diseases or conditions.
  • diseases or conditions include age related macular degeneration, Stargardt' s disease or any retinol or retinol binding protein 4 (RBP4) mediated disease.
  • compositions for treating ophthalmic diseases comprise 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and a physiologically acceptable carrier.
  • a compound for use in a method of medical treatment wherein the method of medical treatment is for treating an ophthalmic disease, wherein the disease is selected from age related macular degeneration, Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration, and wherein the compound is 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid or a physiologically acceptable salt thereof.
  • FIG. 1 shows the serum RBP4 levels in a female RBP4-abcr-83 mice as a function of time after administration of vehicle, fenretinide and 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis).
  • FIG. 2 shows the serum RBP4 levels in a male RBP4-abcr-85 mice as a function of time after administration of vehicle, 100 mg/kg of fenretinide, 50 mg/kg of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and 30 mg/kg of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • FIG. 3 shows the serum RBP4 levels in a male RBP4-abcr-82 mice as a function of time after administration of vehicle, 100 mg/kg of fenretinide and 100 mg kg of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • FIG. 4 shows the change in accumulation of A2E in the eye with and without the administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). DETAILED DESCRIPTION OF THE INVENTION
  • administering means providing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), a
  • carrier refers to chemical compounds or agents that facilitate the incorporation of a compound described herein into cells or tissues.
  • co-administration or “combined administration” or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single subject or patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • dilute a compound described herein prior to delivery refers to chemical compounds that are used to dilute a compound described herein prior to delivery. Diluents can also be used to stabilize compounds described herein.
  • an effective amount refers to an amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or prodrug thereof that will elicit a biological or medical response in a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the terms refers to an amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), a
  • pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or prodrug thereof which, as compared to a corresponding subject who has not received such an amount, results in improved treatment, healing, prevention, or amelioration of an ophthalmic disease, or a decrease in the rate of advancement of such a disease.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • iatrogenic means a condition, disorder, or disease created or worsened by medical or surgical therapy.
  • mammal means all mammals including humans. Mammals include, by way of example only, humans, non-human primates, cows, dogs, cats, goats, sheep, pigs, rats, mice and rabbits.
  • ophthalmically acceptable means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. Transient effects such as minor irritation or a "stinging" sensation are common with topical ophthalmic administration of agents and consistent with the formulation, composition or ingredient in question being "ophthalmically acceptable.”
  • pharmaceutically acceptable refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compounds described herein.
  • ком ⁇ онент or “pharmaceutical combination,” as used herein mean a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, by way of example, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) and an additional therapeutic agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, by way of example, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) and an additional therapeutic agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.
  • composition refers to a mixture of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • pharmaceutical composition refers to a mixture of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • subject or "patient,” as used herein, encompasses mammals.
  • mammals include, but are not limited to, humans, chimpanzees, apes monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guinea pigs, and the like.
  • treat refers to methods of alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactic ally and/or therapeutically.
  • ophthalmic diseases are methods, compounds and pharmaceutical compositions thereof for the treatment of ophthalmic diseases, wherein such methods of treatment is the administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), to a patient in need thereof.
  • the ophthalmic diseases treated using such methods include, but are not limited to, a macular degenearation disease or any retinol or retinol binding protein 4 (RBP4) mediated disease.
  • the macular degeneration disease is age related macular degeneration (AMD), Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration or wet macular degeneration.
  • AMD age related macular degeneration
  • Stargardt's Disease Cone-Rod Dystrophy
  • Corneal Dystrophy Corneal Dystrophy
  • Fuch's Dystrophy Sorsby's Macular Dystrophy
  • Best Disease Best Disease
  • Juvenile Retinoschisis dry macular degeneration or wet macular degeneration.
  • retinol binding protein 4 (RBP4) to transthyretin (TTR)
  • the methods include administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), to a patient in need thereof, thereby treating an ophthalmic diseases.
  • ophthalmic diseases include but are not limited to a macular degenearation disease or any retinol or retinol binding protein 4 (RBP4) mediated disease.
  • the macular degeneration disease is age related macular degeneration (AMD), Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration or wet macular degeneration.
  • AMD age related macular degeneration
  • Stargardt's Disease Cone-Rod Dystrophy
  • Corneal Dystrophy Fuch's Dystrophy
  • Sorsby's Macular Dystrophy Best Disease
  • Juvenile Retinoschisis dry macular degeneration or wet macular degeneration.
  • A2E N-retinylidene-N- retinylethanolamine
  • the administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid modulates the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), thereby modulating the serum concentration of RBP which has an effect on A2E progression.
  • A2E N-retinylidene-N- retinylethanolamine
  • the method further comprises administration of a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid, a complement inhibitor, a fish oil, and a statin.
  • a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid, a complement inhibitor, a fish oil, and a statin.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid used in the methods provided herein is an isotopically labeled form, wherein one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid include isotopes of hydrogen, carbon, nitrogen, oxygen and chlorine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N and 36 C1.
  • Isotopic variations of the compounds have the potential to change a compound' s metabolic fate and/or create small changes in physical properties such as hydrophobicity, and the like. Isotopic variations also have the potential to enhance efficacy and safety, enhance bioavailability and half- life, alter protein binding, change biodistribution, increase the proportion of active metabolites and/or decrease the formation of reactive or toxic metabolites.
  • Retinol binding protein 4 is a circulatory protein that is part of an extracellular transport system for retinol.
  • RBP4 is synthesized in an apo form in the rough endoplasmic reticulum, but is not efficiently transferred out of the endoplasmic reticulum until it is complexed with retinol.
  • RBP4 is predominately found in the serum bound to transthyretin (TTR). TTR itself can bind two molecules of thyroid protein, but in the context of retinal homeostasis, is thought to prevent RBP4 from being excreted during plasma filtration in the kidney.
  • the activity level of RBP4 can be altered by changing the level of RBP4 produced or maintained in the body, which in turn can be altered by changing 1) the rate of production of nascent RBP4, 2) the ability of RBP4 to interact with retinol, 3) the ability of RBP4 to interact with TTR and 4) the half life of RBP4 in the body.
  • RBP4 activity can be altered by changing the ability of RBP4 to deliver retinol to the cells such that, for example, retinal dependent signaling is affected.
  • compositions and methods for modulating A2E progression by modulating the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR) upon the administration of an effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid.
  • retinol binding protein 4 RBP4
  • TTR transthyretin
  • RBP4 retinol binding protein 4
  • TTR transthyretin
  • Phototransduction is the biological conversion of a photon into an electrochemical signal in the retina.
  • the vertebrate retina contains two types of photoreceptor cells: rods and cones.
  • Rods are specialized for vision under low light conditions, whereas cones are less sensitive, provide vision at high temporal and spatial resolutions, and provide color perception. During daylight the rod response is saturated and vision is mediated entirely by cones.
  • Both rods and cones contain a structure called the outer segment which comprises a stack of membranous discs. The reactions of phototransduction take place on the surfaces of these discs. Part of the cycle occurs within the outer segment of the rods and part of the cycle occurs in the retinal pigment epithelium (RPE).
  • RPE retinal pigment epithelium
  • the first step in the phototransduction cascade is mediated by light sensitive G-protein coupled receptors (GPCRs) called opsins located in the photoreceptor cells of the retina.
  • GPCRs light sensitive G-protein coupled receptors
  • Rhodopsin is found in the rod cells of the eye and is the active visual chromophore of the phototransduction pathway. Specifically, rhodopsin is a retinylidene protein that consists of 11-cis retinal covalently linked via a Schiff base to the opsin receptor (GPCR). Rhodopsin, G protein- coupled receptor, has two physiological pathways: phototransduction and/or recovery from bleaching (return of activated components to the dark state) and the retinoid cycle (production of 11-cis-retinal).
  • Absorption of a photon by an opsin-pigment molecule causes the 11-cis retinal to undergo photoisomerization to all-trans retinal, which subsequently changes the conformation of the opsin GPCR. This leads to signal a transduction cascade which causes closure of a cyclic GMP-gated cation channel, and hyperpolarization of the photoreceptor cell.
  • This all-trans-retinal is then reduced to all-trans retinol by NADPH-dependent all-trans-retinol dehydrogenase, a membrane-associated enzyme that belongs to large gene family of short-chain alcohol dehydrogenases (SCAD), before returning to the retinal pigment epithelium to regenerate 11-cis retinal.
  • SCAD short-chain alcohol dehydrogenases
  • the process by which all-trans-retinol translocates to the RPE is poorly defined but it may involve components like IRBP (a protein that transports Vitamin A within the retina) and retinol binding protein (RBP) present in the interphotoreceptor matrix (IPM), or passive diffusion driven by trapping retinoids (e.g., insoluble fatty acid retinyl esters) in RPE.
  • IRBP a protein that transports Vitamin A within the retina
  • RBP retinol binding protein
  • IPM interphotoreceptor matrix
  • passive diffusion driven by trapping retinoids
  • the regeneration of 11-cis retinal involves esterification of all-trans retinol and conversion of the resulting product to 11-cis retinol by the isomerohydrolase RPE65. Esterification occurs in the retinal pigment epithelial cell (RPE) and involves the catalyzed transfer of an acyl group from lecithin to retinol by lecithin:retinol acyltransferase (LRAT).
  • RPE retinal pigment epithelial cell
  • the 11-cis retinol is then oxidized to 11-cis-retinal in a reaction catalyzed by NAD- and NADP-dependent 11-cis-retinol dehydrogenases, which are other short chain dehydrogenase family members. Finally 11-cis-retinal moves back to the rod photoreceptors, either in IRBP-dependent or -independent fashion, where it joins with opsin to regenerate a new, functional visual pigment (rhodopsin). Reduction of all trans- retinal to all-trans-retinol takes place in photoreceptor outer segments whereas all other reactions, including isomerization, occur within the RPE.
  • Retinal photoreceptors and associated RPE cells also regenerate photochemically altered chromophores.
  • photochemically activated chromophores can also chemically react with other molecules in the retina, especially lipids, to form toxic by-products.
  • the most common by-products of phototransduction comprise the lipofuscins, which are very stable toxic substances, and not readily eliminated from the eye.
  • Lipofuscin is the name given to finely granular yellow brown pigment granules composed of lipid-containing residues of lysosomal digestion.
  • Lipofuscin is primarily responsible for the intrinsic fluorescence of the human ocular fundus, and by the ninth decade of life, lipofuscin granules occupy approximately 19% of the area of a macular RPE cell.
  • One important constituent of lipofuscin is derived from the inability of the retinal pigment epithelium (RPE) to convert all all-irans-retinol into 11-cz ' s-retinal.
  • This component is the compound 2-[2,6-dimethyl-8-(2,6,6-trimethyl- l-cyclohexen-l-yl)- lE,3E,5E,7E- octatetraenyl]-l-(2-hydroxyethyl)-4-[4-methyl-6-(2,6,6-trimethyl-l-cyclohexen-l-yl)-lE,3E,5E- hexatrienyl]-pyridinium, also referred to as N-retinyl-N-retinylidene ethanolamine or A2E.
  • A2E is a major fluorophore of lipofuscin that increases the sensitivity of the RPE to blue light and has several toxic effects on RPE cells.
  • A2E formation begins in photoreceptor outer segments from condensation reactions between phosphatidylethanolamine (PE) and all-trans-retmal (atRAL) (1 :2 stoichiometry) that generate A2-PE, the immediate precursor of A2E.
  • PE phosphatidylethanolamine
  • atRAL all-trans-retmal
  • Photoreceptor outer segments are shed from the photoreceptors in a circadian regulated process and are phagocytosed by the RPE.
  • A2-PE is deposited in RPE cells during the normal process of outer-segment phagocytosis.
  • Subsequent phosphate cleavage of A2-PE generates A2E. Since the eye is exposed to light, photoisomers of A2E are also generated, including iso-A2E.
  • Macular degeneration (also referred to as retinal degeneration) is a disease of the eye that involves deterioration of the central portion of the retina, known as the macula, which is a portion of the retina that is responsible for sharp central vision. Such deterioration involves thinning, atrophy, and in some cases, bleeding and/or scarring. Macular degeneration results in loss of central vision, which entails inability to see fine details, to read, or to recognize faces. According to the American Academy of Ophthalmology, it is the leading cause of central vision loss (blindness) in the United States today for those over the age of fifty years. Macular degeneration is used to refer to macular dystrophies affecting younger individuals, however macular degeneration is predominantly found in elderly adults and the term generally refers to age- related macular degeneration (AMD or ARMD).
  • AMD age- related macular degeneration
  • dry macular degeneration also known as atrophic, nonexudative, drusenoid or non-neovascular macular degeneration
  • wet also known as choroidal neovascularization, subretinal neovascularization, exudative, or disciform degeneration
  • Stargardt' s Disease also known as Stargardt' s Macular Dystrophy or Fundus
  • Flavimaculatus is a macular dystrophy that manifests as a recessive form of macular degeneration with an onset typically during childhood, and is characterized clinically by progressive loss of central vision and progressive atrophy of the RPE overlying the macula. Mutations in the human ABCA4 gene (also known as the ABCR gene) for Rim Protein (RmP) are responsible for
  • Stargardt' s Disease Early in the disease course, patients show delayed dark adaptation but otherwise normal rod function. Histologically, Stargardt' s Disease is associated with deposition of lipofuscin pigment granules in RPE cells. In the case of Stargardt' s disease, the RPE is confronted with photoreceptor outer segments that contain abnormally high levels of all-irans-retinal and N- retinylidine-PE. As a consequence, during enzymatic digestion within phagosomes N-retinylidine- N-retinylethanolamine (A2E) is generated. A2E is a major fluorophore of lipofuscin and has several toxic effects on the RPE.
  • A2E is a major fluorophore of lipofuscin and has several toxic effects on the RPE.
  • ABCA4 ATP-binding cassette transporter
  • macular degenerations that affect children, teenagers or adults that are commonly known as early onset or juvenile macular degeneration. Many of these types are hereditary and are looked upon as macular dystrophies instead of degeneration. Some examples of macular dystrophies include: Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile
  • A2E a major fluorophore of lipofuscin, accumulates abnormally in some types of macular or retinal degeneration or dystrophy, including Stargardt' s Disease and probably age-related macular degeneration, presumably due to excess production of the photo transduction retinoid, all- trans-retinaldehyde; a precursor of A2E.
  • lipofuscin is amassed by the RPE cells by phagocytosis of the large number of outer segment disc membranes that are shed daily by the photoreceptor cells.
  • the greatest accumulation of lipofuscin by RPE cells occurs in the macula, due to the high concentration of photoreceptors in this area. Similar to Stargardt' s Disease, lipofuscin deposition in RPE cells is also seen prominently in AMD, and some cases of retinitis pigmentosa.
  • lipofuscin and potentially drusen (extracellular deposits that accumulate below the RPE) under the macula are risk factors for developing age-related macular degeneration.
  • the presence of excessive lipofuscin is detected by fundus autofluorescence, wherein the fluorescence is associated with A2E, an orange-emitting fluorophore, and A2E-related compounds.
  • lipofuscin accumulates progressively in a number or retinal diseases, such as recessive and dominant Stargardt's disease, age-related macular degeneration (AMD), ABCA4-mediated autosomal recessive cone-rod dystrophy, and a form of autosomal recessive retinitis pigmentosa (RP19).
  • AMD age-related macular degeneration
  • ABCA4-mediated autosomal recessive cone-rod dystrophy and a form of autosomal recessive retinitis pigmentosa (RP19).
  • RP19 autosomal recessive retin
  • Transgenic mice that express a mutant form of cathepsin D (mcd) in RPE cells manifest many features of AMD including autofluorescent lipofuscin pigments in the RPE.
  • Mice with knockout mutations in the genes for monocyte chemoattractant protein- 1 (Ccl-2), or its cognate chemokine receptor-2 (Ccr-2), show clinical features of AMD and A2E accumulation in RPE cells.
  • Sodl-/- reported to be a good animal model for AMD, also have elevated A2E levels compared to WT controls.
  • Non-diseased eyes contain low concentrations A2E, indicating that certain levels of A2E are tolerated by the photoreceptors and the RPE.
  • diseased eyes have elevated concentrations of A2E, and at high concentrations A2E sensitizes the RPE to light-induced damage, including lysosomal rupture which leads to cell death.
  • high concentrations of A2E are cytotoxic to the RPE, which leads to retinal damage and destruction.
  • A2E has many toxic properties in vitro, such as inhibition of lysosomal function. For example, in Stargardt' s Disease A2E levels can be over lOx higher than that in normal eyes.
  • A2E-mediated diseases involve the slowing down or arrest of A2E biosynthesis, and are not designed to affect the existing pool of A2E in the eye. For example, fenretinide is reported to reduce vitamin A delivery to the eye, thereby reducing the flow of retinoids in the retinoid cycle. The latter reduces the rate of phototransduction and therefore, the rate of A2E biosynthesis.
  • the methods provided herein use 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)or pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to modulate the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), which effects the amount of A2E in the RPE and thereby treats ophthalmic diseases, such as the macular degeneration diseases listed herein.
  • RBP4 retinol binding protein 4
  • TTR transthyretin
  • the methods provided herein use 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis)or pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to modulate the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), which reduces vitamin A delivery to the eye, thereby reducing the flow of retinoids in the retinoid cycle and effects the amount of A2E in the RPE.
  • RBP4 retinol binding protein 4
  • TTR transthyretin
  • Such methods are thereby used to treat ophthalmic diseases, such as the macular degeneration diseases listed herein.
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid is administered either alone, included in a pharmaceutical composition, or as part of a combination therapy.
  • such retinal disease are retinal diseases that involve genetic variations in the ABCA4 gene including, but not limited to, recessive Stargardt's macular degeneration, age-related macular degeneration, recessive retinitis pigmentosa, and cone-rod dystrophy.
  • such retinal disease are retinal diseases where ABCR deficiency is not necessarily involved, such as, by way of example only, age-related macular degeneration associated with mutations in complement factors or other genes, Best vitelliform macular dystrophy (BMD), and dominant Stargardt' s macular degeneration.
  • the methods and compositions described herein are useful for the modulation of vitamin A (all-trans retinol) levels in a mammalian subject.
  • modulation of vitamin A levels can occur through the regulation of retinol binding protein (RBP) and transthyretin (TTR) availability or activity in a mammal.
  • RBP retinol binding protein
  • TTR transthyretin
  • the methods and compositions described herein provide for the modulation of RBP and TTR levels or activity in a mammalian subject, and subsequently modulation of vitamin A levels.
  • Increases or decreases in vitamin A levels in a subject can have effects on retinol availability in target organs and tissues. Therefore, providing a means of modulating retinol or retinol derivative availability may correspondingly modulate disease conditions caused by a lack of or excess in local retinol or retinol derivative concentrations in the target organs and tissues.
  • retinol from food material is transported to the liver bound to lipid aggregates. Once in the liver, retinol forms a complex with retinol binding protein (RBP) and is then secreted into the blood circulation.
  • RBP retinol binding protein
  • holoprotein Before the retinol-RBP holoprotein can be delivered to extra-hepatic target tissues, such as by way of example, the eye, it must bind with transthyretin (TTR). Zanotti and Berni, Vitam. Horm., 69:271-95 (2004). It is this secondary complex which allows retinol to remain in the circulation for prolonged periods. Association with TTR facilitates RBP release from hepatocytes, and prevents renal filtration of the RBP-retinol complex.
  • TTR transthyretin
  • the retinol-RBP-TTR complex is delivered to target tissues where retinol is taken up and utilized for various cellular processes. Delivery of retinol to cells through the circulation by the RBP-TTR complex is the major pathway through which cells and tissue acquire retinol. Retinol uptake from its complexed retinol-RBP-TTR form into cells occurs by binding of RBP to cellular receptors on target cells. This interaction leads to endocytosis of the RBP-receptor complex and subsequent release of retinol from the complex, or binding of retinol to cellular retinol binding proteins (CRBP), and subsequent release of apoRBP by the cells into the plasma. Other pathways contemplate alternative mechanisms for the entry of retinol into cells, including uptake of retinol alone into the cell.
  • CRBP cellular retinol binding proteins
  • A2E the major fluorophore of lipofuscin
  • macular or retinal degeneration or dystrophy including age-related macular degeneration and Stargardt Disease
  • Reduction of vitamin A and all-trans retinaldehyde in the retina therefore, would be beneficial in reducing A2E and lipofuscin build-up, and treatment of age-related macular degeneration.
  • reducing serum retinol may have a beneficial effect of reducing A2E and lipofuscin in RPE.
  • modulators that inhibit delivery of retinol to cells either through interruption of binding of retinol to apo RBP or holo RBP (RBP + retinol) to its transport protein, TTR, or the increased renal excretion of RBP and TTR would be useful in decreasing serum vitamin A levels, and buildup of retinol and its derivatives in target tissues such as the eye.
  • modulators that reduce the availability of the retinol transport proteins, retinol binding protein (RBP) and transthyretin (TTR) would also be useful in decreasing serum vitamin A levels, and buildup of retinol and its derivatives and physical manifestations in target tissues, such as the eye.
  • TTR for example, has been shown to be a component of Drusen constituents, suggesting a direct involvement of TTR in age-related macular degeneration. Mullins, RF, FASEB J. 14:835-846 (2000); Pfeffer BA, et al., Molecular Vision 10:23-30 (2004).
  • Another embodiment of the methods and compositions disclosed herein therefore, provides for the modulation of RBP or TTR levels or activity in a mammal by administering to a mammal an effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • RBP binding to retinol is modulated by competitive binding of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • TTR 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • one embodiment of the methods and compositions disclosed herein provides using 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) for modulation of RBP levels or activity in the blood stream.
  • another embodiment provided herein is to modulate availability of RBP or TTR for complexing to retinol or retinol-RBP in the blood stream by using 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to modulate RBP or TTR binding characteristics or clearance rates.
  • TTR binding to RBP holoprotein decreases the clearance rate of RBP and retinol, and therefore retinol levels are modulated in a subject in need thereof, by modulating either RBP or TTR availability or activity.
  • Figures 1-3 show that 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) has improved reduction of serum RBP4 compared with fenretinide.
  • Figures 1 and 2 demonstrate that a lower concentration of 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid (Tafamidis) is able to achieve better or comparable serum RBP4 reduction as that obtained with fenretinide
  • Figure 3 shows that, at the same concentration, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) significantly decreases serum RBP4 in comparison to fenretinide.
  • compositions which comprise 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and pharmaceutical compositions containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered singly or in combination with one or more additional therapeutic agents.
  • the routes of administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and such pharmaceutical compositions include, but are not limited to, oral administration, intravitreal administration, rectal administration, parenteral, intravenous administration, intraperitoneal administration, intramuscular administration, inhalation, transmucosal administration, pulmonary administration, intestinal administration, subcutaneous administration, intramedullary
  • administration intrathecal administration, direct intraventricular, intranasal administration, topical administration, ophthalmic administration or otic administration.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered locally, while in other embodiments 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical composite described herein are administered systemically.
  • Local administration includes, but is not limited to, injection into an organ, optionally in a depot or sustained release formulation.
  • Systemic administration includes, but is not limited to, oral administration or intravenous administration.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered in a targeted drug delivery system, such as, by way of example only, in a liposome coated with organ- specific antibody.
  • the liposome is targeted to and taken up selectively by the organ.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered in the form of a rapid release formulation, while in other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered in the form of an extended release formulation . In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered in the form of an intermediate release formulation.
  • such processes include admixing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutically acceptable carriers include diluents or excipients.
  • compositions comprise 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in free form or in a pharmaceutically acceptable salt or solvate form.
  • the pharmaceutical compositions comprising 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in free form or in a pharmaceutically acceptable salt or solvate form, in association with at least one pharmaceutically acceptable carrier, diluent or excipient are manufactured by mixing, dissolving, granulating dragee -making, levigating, emulsifying, encapsulating, entrapping or compression processes and/or coating methods.
  • compositions are optionally contain excipients, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • excipients such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • such compositions are sterilized.
  • the 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical composition described herein is ophthalmic ally administered to the eye. Administration to the eye generally results in direct contact of the agents with the cornea, through which at least a portion of the administered agents pass.
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions have an effective residence time in the eye of about 2 to about 24 hours.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions have an effective residence time in the eye of about 4 to about 24 hours. In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions have an effective residence time in the eye of about 6 to about 24 hours.
  • Ophthalmic administration includes, but is not limited to, topical administration, intraocular injection, subretinal injection, intravitreal injection, periocular administration, subconjuctival injections, retrobulbar injections, intracameral injections (including into the anterior or vitreous chamber), sub-Tenon's injections or implants, ophthalmic solutions, ophthalmic suspensions, ophthalmic ointments, ocular implants and ocular inserts, intraocular solutions, use of iontophoresis, incorporation in surgical irrigating solutions, and packs (by way of example only, a saturated cotton pledget inserted in the fornix).
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical composition described herein are formulated as an ophthalmic composition and are administered topically to the eye.
  • Such topically administered ophthalmic compositions include, but are not limited to, solutions, suspensions, gels or ointments.
  • the pharmaceutical compositions comprising 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) used for ophthalmic administration take the form of a liquid where the compositions are present in solution, in suspension or both.
  • a liquid composition includes a gel formulation.
  • the liquid composition is aqueous.
  • such liquid compositions take the form of an ointment.
  • compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid are administered ophthamically as eye drops formulated as aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a desired dosage is administered via a known number of drops into the eye. By way of example only, for a drop volume of 25 ⁇ , administration of 1-6 drops delivers 25-150 ⁇ of the composition.
  • the aqueous compositions contain from about 0.01% to about 50% weight/volume of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In other embodiments, the aqueous compositions contain from about 0.1% to about 20% weight/volume of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In still other embodiments, the aqueous compositions contain from about 0.2% to about 10% weight/volume of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In certain embodiments, the aqueous compositions contain from about 0.5% to about 5%, weight/volume of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • the aqueous compositions have an ophthalmically acceptable pH and osmolality.
  • the aqueous compositions include one or more ophthalmically acceptable pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an ophthalmically acceptable range.
  • compositions also include also include one or more ophthalmically acceptable salts in an amount required to bring osmolality of the composition into an ophthalmically acceptable range.
  • ophthalmically acceptable salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • the aqueous compositions also contain one or more polymers as suspending agents.
  • polymers include, but are not limited to, water-soluble polymers such as cellulosic polymers described herein, (for example only, hydroxypropyl methylcellulose), and water-insoluble polymers described herein (for example only, cross-linked carboxyl-containing polymers).
  • the aqueous compositions also include an ophthalmically acceptable mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • compositions also include ophthalmically acceptable solubilizing agents to aid in the solubility of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
  • ophthalmically acceptable nonionic surfactants including, but not limited to, polysorbate 80 are used as solubilizing agents.
  • ophthalmically acceptable glycols including, but not limited to, polyglycols, polyethylene glycol 400, and glycol ethers are used as solubilizing agents.
  • compositions also include one or more ophthalmically acceptable surfactants to enhance physical stability or for other purposes.
  • nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils (by way of example only, polyoxyethylene (60) hydrogenated castor oil) and polyoxyethylene alkylethers and alkylphenyl ethers (by way of example only, octoxynol 10 and octoxynol 40).
  • compositions also include one or more ophthalmically acceptable preservatives to inhibit microbial activity.
  • preservatives include, but are not limited to mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride,
  • cetyltrimethylammonium bromide and cetylpyridinium chloride are examples of cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • compositions also include one or more antioxidants to enhance chemical stability where required.
  • antioxidants include, but are not limited to, ascorbic acid and sodium metabisulfite.
  • the aqueous compositions provided herein are packaged in single-dose non-reclosable containers, while in other embodiments the aqueous compositions provided herein are packaged in multiple-dose reclosable containers wherein a preservative is included in the composition.
  • the ophthalmic compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid take the form of a solid article that can be inserted between the eye and eyelid or in the conjunctival sac, where it releases the 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). Release is to the lacrimal fluid that bathes the surface of the cornea, or directly to the cornea itself, with which the solid article is generally in intimate contact.
  • Solid articles suitable for implantation in the eye in such fashion are generally composed primarily of polymers and can be biodegradable or non-biodegradable.
  • the pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid are administered orally as discrete dosage forms, wherein such dosage forms include, but are not limited to, capsules, gelatin capsules, caplets, tablets, chewable tablets, powders, pills, dragees, granules, liquids, gels, syrups, flavored syrups, elixirs, slurries, solutions or suspensions in aqueous or non-aqueous liquids, edible foams or whips, and oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • dosage forms include, but are not limited to, capsules, gelatin capsules, caplets, tablets, chewable tablets, powders, pills, dragees, granules, liquids, gels, syrups, flavored syrups, elixirs, slurries, solutions or suspensions in aqueous or non-aque
  • the capsules, gelatin capsules, caplets, tablets, chewable tablets, powders or granules, used for the oral administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are prepared by admixing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) (active ingredient) together with at least one excipient using conventional pharmaceutical compounding techniques.
  • excipients used in oral dosage forms described herein include, but are not limited to, binders, fillers, disinte grants, lubricants, absorbents, colorants, flavors, preservatives and sweeteners.
  • Non-limiting examples of such binders include, but are not limited to, corn starch, potato starch, starch paste, pre- gelatinized starch, or other starches, sugars, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (by way of example only, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose,
  • hydroxypropyl methylcellulose and microcrystalline cellulose magnesium aluminum silicate, polyvinyl pyrrolidone and combinations thereof.
  • Non-limiting examples of such fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions provided herein are present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Non-limiting examples of such disintegrants include, but are not limited to, agar-agar, alginic acid, sodium alginate, calcium carbonate, sodium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and combinations thereof.
  • the amount of disintegrant used in the pharmaceutical compositions provided herein is from about 0.5 to about 15 weight percent of disintegrant, while in other embodiments the amount is from about 1 to about 5 weight percent of disintegrant.
  • Non-limiting examples of such lubricants include, but are not limited to, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, talc, hydrogenated vegetable oil (by way of example only, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, agar, silica, a syloid silica gel (AEROSIL 200, manufactured by W.R.
  • AEROSIL 200 AEROSIL 200, manufactured by W.R.
  • the amount of lubricants used in the pharmaceutical compositions provided herein is in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms.
  • Non-limiting examples of such diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine or combinations thereof.
  • tablets and capsules are prepared by uniformly admixing 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) (active ingredients) with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • tablets are prepared by compression.
  • tablets are prepared by molding.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid is orally administered as a controlled release dosage form.
  • dosage forms are used to provide slow or controlled-release of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • Controlled release is obtained using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof.
  • controlled-release dosage forms are used to extend activity of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), reduce dosage frequency, and increase patient compliance.
  • (Tafamidis) as oral fluids such as solution, syrups and elixirs are prepared in unit dosage forms such that a given quantity of solution, syrups or elixirs contains a predetermined amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • Syrups are prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions are formulated by dispersing the compound in a nontoxic vehicle.
  • Non-limiting examples of excipients used in as oral fluids for oral administration include, but are not limited to, solubilizers, emulsifiers, flavoring agents, preservatives, and coloring agents.
  • solubilizers and emulsifiers include, but are not limited to, water, glycols, oils, alcohols, ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers.
  • Non-limiting examples of preservatives include, but are not limited to, sodium benzoate.
  • Non-limiting examples of flavoring agents include, but are not limited to, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners.
  • compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid are administered parenterally by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial.
  • parenteral dosage forms are administered in the form of sterile or sterilizable injectable solutions, suspensions, dry and/or lyophylized products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection (reconstitutable powders) and emulsions.
  • Vehicles used in such dosage forms include, but are not limited to, Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, physiological saline buffer, Ringer's Injection solution, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection solution; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, physiological saline buffer, Ringer's Injection solution, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection solution
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is parenteral administration by bolus injection.
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or composition containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is parenteral administration by continuous infusion.
  • Formulations for injection are presented in unit dosage form, by way of example only, in ampoules or formulations for injection are presented in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid are administered transdermally.
  • Such transdermal dosage forms include "reservoir type” or “matrix type” patches, which are applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • matrix transdermal formulations are used.
  • transdermal administration is used to provide continuous, while in other embodiments transdermal administration is used to provide discontinuous infusion of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in controlled amounts.
  • the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
  • transdermal delivery is via a transdermal patches placed over different portions of the patient's body, including over the eye.
  • Formulations for transdermal delivery of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid include an effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), a carrier and an optional diluent.
  • a carrier includes, but is not limited to, absorbable pharmacologically acceptable solvents to assist passage through the skin of the host, such as water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.
  • such transdermal delivery systems include penetration enhancers to assist in delivering 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to the tissue.
  • penetration enhancers to assist in delivering 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to the tissue.
  • Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
  • the pH of such a transdermal pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied is adjusted to improve delivery of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • the polarity of a solvent carrier, its ionic strength, or tonicity are adjusted to improve delivery.
  • compounds such as stearates are added to improve delivery.
  • such stearates serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration- enhancing agent.
  • transdermal delivery of 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid is accomplished by means of iontophoretic patches and the like.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid is administered by topical application of pharmaceutical composition containing 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in the form of lotions, gels, ointments solutions, emulsions, suspensions or creams.
  • Suitable formulations for topical application to the skin are aqueous solutions, ointments, creams or gels, while formulations for ophthalmic administration are aqueous solutions.
  • Such formulations optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Such topical formulations include at least one carrier, and optionally at least one diluent.
  • Such carriers and diluents include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.
  • topical formulations include penetration enhancers to assist in delivering 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to the tissue.
  • penetration enhancers to assist in delivering 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to the tissue.
  • Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; KoUidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
  • compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid are administered by inhalation.
  • Dosage forms for inhaled administration are formulated as aerosols or dry powders.
  • Aerosol formulations for inhalation administration comprise a solution or fine suspension of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in a pharmaceutically acceptable aqueous or non-aqueous solvent.
  • compositions optionally comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, and optionally a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
  • a powder base such as lactose, glucose, trehalose, mannitol or starch
  • a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid is administered directly to the lung by inhalation using a Metered Dose Inhaler ("MDI"), which utilizes canisters that contain a suitable low boiling propellant, e.g., MDI
  • MDI Metered Dose Inhaler
  • capsules and cartridges of gelatin for use in an inhaler or insufflator are formulated containing a powder mixture of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • Tafamidis 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is delivered to the lung using a liquid spray device, wherein such devices use extremely small nozzle holes to aerosolize liquid drug formulations that can then be directly inhaled into the lung.
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid is delivered to the lung using a nebulizer device, wherein a nebulizers creates an aerosols of liquid drug formulations by using ultrasonic energy to form fine particles that can be readily inhaled.
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid is delivered to the lung using an electrohydrodynamic (“EHD”) aerosol device wherein such EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions.
  • EHD electrohydrodynamic
  • the pharmaceutical composition containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts and solvates thereof also contain one or more absorption enhancers.
  • absorption enhancers include, but are not limited to, sodium glycocholate, sodium caprate, N- lauryl- -D-maltopyranoside, EDTA, and mixed micelles.
  • compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid are administered nasally.
  • the dosage forms for nasal administration are formulated as aerosols, solutions, drops, gels or dry powders.
  • compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid are administered rectally in the form of suppositories, enemas, retention enemas ointment, creams rectal foams or rectal gels.
  • suppositories are prepared from fatty emulsions or suspensions, cocoa butter or other glycerides.
  • compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid are formulated as a depot preparation.
  • Such long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • such formulations include polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • injectable depot forms are made by forming microencapsulated matrices of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in
  • the rate of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) release is controlled by varying the ratio of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) to polymer and the nature of the particular polymer employed.
  • depot injectable formulations are prepared by entrapping 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in liposomes or microemulsions.
  • posterior juxtascleral depots are used as a mode of administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered as a depot into the scleral layer of the eye by injection through a cannula with small diameter suitable for injection into the scleral layer.
  • the sclera is a thin avascular layer, comprised of highly ordered collagen network surrounding most of vertebrate eye. Since the sclera is avascular it can be utilized as a natural storage depot from which injected material cannot rapidly removed or cleared from the eye.
  • compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid are administered otically as ear drops.
  • Such formulations are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • the ophthalmic disease is a macular degeneration disease, while in other embodiments the ophthalmic diseases is any retinol or retinol binding protein 4 (RBP4) mediated disease.
  • RBP4 retinol or retinol binding protein 4
  • such modulation of binding of retinol binding protein 4 (RBP4) to transthyretin (TTR) affects A2E progression, thereby preventing or treating macular degeneration diseases.
  • the macular degeneration disease is selected from age related macular degeneration (AMD)
  • Tafamidis 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • a pharmaceutically acceptable salt, solvate either alone or as part of a pharmaceutical composition as described herein.
  • the ophthalmic disease is a macular degeneration disease, while in other embodiments the ophthalmic diseases is any retinol or retinol binding protein 4 (RBP4) mediated disease.
  • the macular degeneration disease is selected from age related macular degeneration (AMD)
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), are administered alone (without an additional therapeutic agent) for the treatment of one or more opthalmic diseases described herein.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salts or solvates thereof, or pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), are administered in combination with one or more additional therapeutic agents or methods for the treatment of one or more opthalmic diseases described herein.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salts or solvates thereof, or pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are formulated in combination with one or more additional therapeutic agents and administered for the treatment of one or more opthalmic diseases described herein.
  • the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), sequentially with one or more additional therapeutic agents for the treatment of one or more opthalmic diseases described herein.
  • the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), prior to administration of one or more additional therapeutic agents for the of one or more opthalmic diseases described herein.
  • the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), subsequent to
  • the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), concurrently with one or more additional therapeutic agents for the treatment of one or more ophthalmic diseases described herein.
  • the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) formulated with one or more additional therapeutic agents for the treatment of macular degeneration.
  • Tafamidis 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • Tafamidis 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, and the additional therapeutics agent(s) act additively.
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, and the additional therapeutics agent(s) act synergistically.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered to a patient who has not previously undergone or is not currently undergoing treatment with another therapeutic agent.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), are administered for prophylactic treatments.
  • 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in combination with one or more additional therapeutic agents or methods, are administered for prophylactic treatments.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), are administered for therapeutic treatments.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in combination with one or more additional therapeutic agents or methods, are administered for therapeutic treatments.
  • 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered chronically either alone or in combination with one or more additional therapeutic agents or methods.
  • Chronic administration is for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • the administration of the compounds is temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the additional therapeutic methods used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, photodynamic therapy (PDT), low dose radiation therapy, submacular surgery, RPE transplantation, macular translocation surgery, implantable miniature telescopes, laser photocoagulation of drusen, microstimulation therapy and laser treatment of drusen.
  • PDT photodynamic therapy
  • low dose radiation therapy include, but are not limited to, photodynamic therapy (PDT), low dose radiation therapy, submacular surgery, RPE transplantation, macular translocation surgery, implantable miniature telescopes, laser photocoagulation of drusen, microstimulation therapy and laser treatment of drusen.
  • the additional therapeutic agents used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to an effective amount of a retinyl derivative, including derivatives of all-trans-retinal and 13-cis-retinal, fenretinide and its active metabolites, an adjuvant, a second compound that modulates RBP or TTR levels or activity, nitric oxide (NO) inducers, statins, negatively charged phospholipids, anti-oxidants, minerals, anti-inflammatory agents, anti-angiogenic agents, matrix metalloproteinase inhibitors, and carotenoids.
  • a retinyl derivative including derivatives of all-trans-retinal and 13-cis-retinal, fenretinide and its active metabolites
  • an adjuvant a second compound that modulates RBP or TTR levels or activity
  • the anti-oxidants used in combination with 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, vitamin C, vitamin E, beta-carotene and other carotenoids, coenzyme Q, 4- hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (also known as Tempol), lutein, butylated hydroxytoluene, resveratrol, a trolox analogue (PNU-83836-E), and bilberry extract.
  • the minerals used in combination with 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, copper-containing minerals, such as cupric oxide (by way of example only); zinc-containing minerals, such as zinc oxide (by way of example only); and selenium-containing compounds.
  • the negatively-charged phospholipids used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, cardiolipin and phosphatidylglycerol.
  • positively-charged and/or neutral phospholipids also provide benefit for patients with macular degenerations and dystrophies when used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof.
  • Carotenoids are naturally-occurring yellow to red pigments of the terpenoid group that can be found in plants, algae, bacteria, and certain animals, such as birds and shellfish.
  • Carotenoids are a large class of molecules in which more than 600 naturally occurring carotenoids have been identified. The use of carotenoids has been correlated with the maintenance of photoprotection necessary in photoreceptor cells.
  • the carotenoids used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, hydrocarbons (carotenes) and their oxygenated, alcoholic derivatives (xanthophylls), actinioerythrol, astaxanthin, canthaxanthin, capsanthin, capsorubin, .beta.-8'-apo-carotenal (apo-carotenal), -12'-apo-carotenal, a-carotene, ⁇ - carotene, "carotene” (a mixture of a- and ⁇ -carotenes), ⁇ -carotenes,
  • nitric oxide inducers used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRFJ in vivo or are substrates for nitric oxide synthase.
  • EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide or a closely related derivative thereof.
  • Such compounds include, bit are not limited to, L-arginine, L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated and nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylated L-homoarginine), precursors of L-arginine and/or physiologically acceptable salts thereof, including, for example, citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and the substrates for nitric oxide synthase, cytokines,
  • the nitric oxide inducers used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, statins such as, by way of example only, rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, atorvastatin, atorvastatin calcium (which is the hemicalcium salt of atorvastatin), and dihydrocompactin.
  • statins such as, by way of example only, rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, compactin, lovastat
  • the anti-inflammatory agents used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, cromolyn, nedocromil, theophylline, zileuton, zafirlukast, montelukast, pranlukast, indomethacin, and lipoxygenase inhibitors; nonsteroidal antiinflammatory drugs (NSAIDs) (such as ibuprofen and naproxin); prednisone, dexamethasone, cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such as
  • statins by way of example only, rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, atorvastatin, atorvastatin calcium (which is the hemicalcium salt of atorvastatin), and dihydrocompactin); disassociated steroids, non-steroidal anti-inflammatory drugs such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibu
  • halcinocide medrysone, methylprednisolone, methprednisolone acetate, methylprednisolone sodium succinate, mometasone furoate, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebuatate, prednisone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, and triamcinolone hexacetonide and other anti-inflammatory agents including, but not limited to, methotrexate, colchicine, allopurinol, probenecid, thalidomide or a derivative thereof, 5-aminosalicylic acid, retinoid, dithranol or calcipotriol, sulfinpyrazone and benzbromarone.
  • MMPs matrix metalloproteinases
  • Tafamidis 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • Tafamidis 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • Tafamidis 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • Tafamidis 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, Tissue Inhibitors of Metalloproteinases (TIMPs) (e.g., ⁇ -1, T P-2, TIMP-3, or TIMP4), a 2 -macroglobulin, tetracyclines (e.g., tetracycline, minocycline, and d
  • the antiangiogenic or anti-VEGF drugs used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, Rhufab V2 (LUCENTISTM), Tryptophanyl- tRNA synthetase (TrpRS), EyeOOl (Anti-VEGF Pegylated Aptamer), squalamine, RETAANETM (anecortave acetate for depot suspension; Alcon, Inc.), Combretastatin A4 Prodrug (CA4P), MACUGENTM, MIFEPREXTM (mifepristone-ru486), subtenon triamcinolone acetonide, intravitreal crystalline triamcinolone acetonide, Prinomastat (AG3340— synthetic matrix metalloproteinase inhibitor, Pfizer), fluocinol
  • VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo- 2-fluoroanilino)-6- methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474), 4-(4-fIuoro-2-methylindol-5- yloxy)-6-methoxy-7-(3- pyrrolidin- 1 -ylpropoxy)quinazoline (AZD2171), vatalanib (PTK787) and SU1 1248 (sunitinib), linomide, and inhibitors of integrin ⁇ 3 function and angiostatin.
  • VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo- 2-fluoroanilino)-6- methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474), 4-(4-fIuoro-2-methylindol
  • Other pharmaceutical therapies used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, VISUDYNETM with use of a non-thermal laser, PKC 412, Endovion (NeuroSearch A/S), neurotrophic factors, including by way of example Glial Derived Neurotrophic Factor and Ciliary Neurotrophic Factor, diatazem, dorzolamide, Phototrop, 9-cis-retinal, eye medication (including Echo Therapy) including phospholine iodide or echothiophate or carbonic anhydrase inhibitors, AE-941 (AEterna Laboratories, Inc.), Sirna-027 (Sima Therapeutics, Inc.), pegaptanib (NeXstar Pharmaceuticals/Gilead Sciences), neurotrophins (including, by way of example only, NT-4/5
  • talaporfin sodium with PDT Nippon Petroleum
  • motexafin lutetium Pharmacyclics, Inc.
  • antisense oligonucleotides including, by way of example, products tested by Novagali Pharma SA and ISIS-13650, Isis Pharmaceuticals
  • laser photocoagulation drusen lasering, macular hole surgery, macular translocation surgery, implantable miniature telescopes, Phi-Motion Angiography (also known as Micro-Laser Therapy and Feeder Vessel Treatment), Proton Beam Therapy, microstimulation therapy, Retinal Detachment and Vitreous Surgery, Scleral Buckle, Submacular Surgery, Transpupillary Thermotherapy, Photosystem I therapy, use of RNA interference (RNAi), extracorporeal rheopheresis (also known as membrane differential filtration and Rheotherapy), microchip implantation, stem cell therapy, gene replacement therapy, ribozyme gene therapy (including gene therapy for hypoxia response element, Oxford Biomedica; Lenti
  • the subject in conjunction with administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), pharmaceutical composition or combination therapy described herein are also monitored for physiological manifestations of ophthalmic diseases.
  • the subject, in conjunction with administration of 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are also monitored for physiological manifestations of retinoid-related disease processes.
  • the subject may be monitored for physiological manifestations of age-related macular degenerations or dystrophies, including the formation of drusen in the eye of the subject, measuring the levels of lipofuscin in the eye of the subject, measuring the auto-fluorescence of A2E and precursors of A2E, and measuring N- retinylidene-N-retinylethanolamine levels in the eye of the subject.
  • the subject is monitored for changes or perturbations in vitamin A levels, as well as RBP and TTR levels or activity in a biological sample.
  • kits that include one or more containers containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) useful for the treatment or prevention of an ophthalmic disease.
  • Tefamidis 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
  • pharmaceutical packs or kits include one or more containers containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) useful for the treatment or prevention of an ophthalmic disease and one or more containers containing an additional therapeutic agent, including but not limited to those listed above.
  • such pharmaceutical packs or kits optionally include instructions for its administration 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).
  • Serum RBP4 was measured using the dual mouse/rat RBP4 ELISA kit (RB0642PP; AdipoGen, Seoul, Korea; assay range: 0.19-12 ng/ml, sensitivity > 60 pg/ml). Mice were treated with either vehicle, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or fenretinide.
  • Figures 1-3 show the serum RBP4 levels obtained for various concentration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) relative to vehicle and fenretinide.
  • HPLC method Extracted samples of A2E in methanol were injected onto a heated (45°C) Waters Acquity HSS T3 column, 1.8 ⁇ , 2.1 x 50mm. Using an Agilent 1200SL binary pump, the mobile phases were delivered at 650 ⁇ / ⁇ ., and used 0.1% TFA in A. H20 and B. MeOH. A gradient elution method began with 82% B for 3 minutes, then increased in a linear fashion to 90% over 5 minutes. After a one minute washout at 100% B, the gradient was returned to starting conditions and held until the end of the run at 10.5 minutes.
  • Mass Spectrometry The column eluent was directed into either an Applied Biosystems API4000 or a Thermo Quantum Ultra mass spectrometer using positive mode electrospray ionization.
  • the MRM transitions for A2E, and internal standard A2H were m/z 592.5—105.0 and m/z 648.6— 358.4 respectively.
  • the declustering potential (DP) and collision energy (CE) was 76 and 45 for A2E, and 161 and 55 for A2H.
  • the MRM transitions were m/z 592.5— 105.2 for A2E, and m/z 648.5 -145.1 for A2H.
  • a tube lens setting of 147 was used for both analytes, with collision energies of 58 for A2E and 47 for A2H.

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  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés d'utilisation de l'acide 2-(3,5-dichlorophényl)benzo[d]oxazole-6-carboxylique (Tafamidis) pour traiter des troubles ophtalmiques.
PCT/US2011/028710 2010-03-19 2011-03-16 Tafamidis pour le traitement de troubles ophtalmiques WO2011116123A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150057320A1 (en) * 2012-05-01 2015-02-26 The Trustees Of Columbia University In The City Of New York Transthyretin ligands capable of inhibiting retinol-dependent rbp4-ttr interaction for treatment of age-related macular degeneration, stargardt disease, and other retinal disease characterized by excessive lipofuscin accumulation
US9249112B2 (en) 2011-09-16 2016-02-02 Pfizer Inc. Solid forms of a transthyretin dissociation inhibitor
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
WO2019071206A1 (fr) 2017-10-06 2019-04-11 Prothena Biosciences Limited Méthodes de détection de la transthyrétine
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
WO2019108689A1 (fr) 2017-11-29 2019-06-06 Prothena Biosciences Limited Formulation lyophilisée d'un anticorps monoclonal contre la transthyrétine
WO2020243720A1 (fr) * 2019-05-31 2020-12-03 Plex Pharmaceuticals, Inc. Agents pharmacologiques pour le traitement de maladies d'agrégation de protéines de l'oeil
WO2021154842A1 (fr) * 2020-01-28 2021-08-05 Protego Biopharma, Inc. Composés, compositions et procédés de stabilisation de la transthyrétine et d'inhibition du mauvais repliement de la transthyrétine
US20220370365A1 (en) * 2021-05-21 2022-11-24 Sawai Pharmaceutical Co., Ltd. Solid preparation containing tafamidis and method for producing the same
WO2024023710A1 (fr) * 2022-07-28 2024-02-01 Pfizer Inc. Compositions pharmaceutiques de tafamidis
US11980685B1 (en) * 2022-12-23 2024-05-14 Tap Pharmaceuticals, Ag Liquid pharmaceutical formulations of tafamidis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040152140A1 (en) * 2002-12-19 2004-08-05 Kelly Jeffery W. Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
WO2009040405A1 (fr) * 2007-09-25 2009-04-02 Pentraxin Therapeutics Limited Composé et son utilisation pour le traitement d'une amylose
WO2009114729A2 (fr) * 2008-03-14 2009-09-17 Irm Llc Composés, compositions et procédés de traitement des maladies et des troubles liés au stockage lysosomal
WO2010120741A1 (fr) * 2009-04-13 2010-10-21 Irm Llc Compositions et procédés pour moduler la liaison du rétinol à la protéine 4 de liaison au rétinol (rbp4)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040152140A1 (en) * 2002-12-19 2004-08-05 Kelly Jeffery W. Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
WO2009040405A1 (fr) * 2007-09-25 2009-04-02 Pentraxin Therapeutics Limited Composé et son utilisation pour le traitement d'une amylose
WO2009114729A2 (fr) * 2008-03-14 2009-09-17 Irm Llc Composés, compositions et procédés de traitement des maladies et des troubles liés au stockage lysosomal
WO2010120741A1 (fr) * 2009-04-13 2010-10-21 Irm Llc Compositions et procédés pour moduler la liaison du rétinol à la protéine 4 de liaison au rétinol (rbp4)

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
FORMELLI ET AL., CANCER RES., vol. 49, 1989, pages 6149 - 52
FORMELLI ET AL., J. CLIN ONCOL., vol. 11, 1993, pages 2036 - 42
HOLVEN ET AL., INT. J. CANCER, vol. 71, 1997, pages 654 - 9
KATZ ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 924, 1987, pages 432 - 41
KATZ ET AL., MECH. AGEING DEV., vol. 35, 1986, pages 291 - 305
KATZ ET AL., MECH. AGEING DEV., vol. 39, 1987, pages 81 - 90
MALPELI ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1294, 1996, pages 48 - 54
MULLINS, RF, FASEB J., vol. 14, 2000, pages 835 - 846
PFEFFER BA ET AL., MOLECULAR VISION, vol. 10, 2004, pages 23 - 30
RADU ET AL., PROC. NATL. ACAD. SCI. USA, vol. 100, 2003, pages 4742 - 7
RADU ET AL., PROC. NATL. ACAD. SCI. USA, vol. 101, 2004, pages 5928 - 33
TORRISI ET AL., CANCER EPIDEMIOL. BIOMARKERS PREV., vol. 3, 1994, pages 507 - 10
ZANOTTI, BERNI, VITAM. HORM., vol. 69, 2004, pages 271 - 95

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9249112B2 (en) 2011-09-16 2016-02-02 Pfizer Inc. Solid forms of a transthyretin dissociation inhibitor
US20150057320A1 (en) * 2012-05-01 2015-02-26 The Trustees Of Columbia University In The City Of New York Transthyretin ligands capable of inhibiting retinol-dependent rbp4-ttr interaction for treatment of age-related macular degeneration, stargardt disease, and other retinal disease characterized by excessive lipofuscin accumulation
US10421720B2 (en) 2013-03-14 2019-09-24 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10787453B2 (en) 2013-03-14 2020-09-29 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US9926271B2 (en) 2013-03-14 2018-03-27 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10570148B2 (en) 2013-03-14 2020-02-25 The Trustees Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US10913746B2 (en) 2014-04-30 2021-02-09 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10407433B2 (en) 2014-04-30 2019-09-10 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10072016B2 (en) 2014-04-30 2018-09-11 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US11649240B2 (en) 2014-04-30 2023-05-16 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
WO2019071206A1 (fr) 2017-10-06 2019-04-11 Prothena Biosciences Limited Méthodes de détection de la transthyrétine
WO2019108689A1 (fr) 2017-11-29 2019-06-06 Prothena Biosciences Limited Formulation lyophilisée d'un anticorps monoclonal contre la transthyrétine
CN114173771A (zh) * 2019-05-31 2022-03-11 普莱克斯医药公司 用于治疗眼部蛋白质聚集疾病的药理学试剂
US20220241247A1 (en) * 2019-05-31 2022-08-04 Plex Pharmaceuticals, Inc. Pharmacological agents for treating protein aggregation diseases of the eye
WO2020243720A1 (fr) * 2019-05-31 2020-12-03 Plex Pharmaceuticals, Inc. Agents pharmacologiques pour le traitement de maladies d'agrégation de protéines de l'oeil
WO2021154842A1 (fr) * 2020-01-28 2021-08-05 Protego Biopharma, Inc. Composés, compositions et procédés de stabilisation de la transthyrétine et d'inhibition du mauvais repliement de la transthyrétine
CN115298168A (zh) * 2020-01-28 2022-11-04 普罗泰格生物制药公司 用于稳定甲状腺素运载蛋白和抑制甲状腺素运载蛋白错误折叠的化合物、组合物和方法
US20220370365A1 (en) * 2021-05-21 2022-11-24 Sawai Pharmaceutical Co., Ltd. Solid preparation containing tafamidis and method for producing the same
WO2024023710A1 (fr) * 2022-07-28 2024-02-01 Pfizer Inc. Compositions pharmaceutiques de tafamidis
US11980685B1 (en) * 2022-12-23 2024-05-14 Tap Pharmaceuticals, Ag Liquid pharmaceutical formulations of tafamidis

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