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WO2025146683A1 - Formulations topiques pour l'administration d'un composé actif au fond de l'œil - Google Patents

Formulations topiques pour l'administration d'un composé actif au fond de l'œil Download PDF

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Publication number
WO2025146683A1
WO2025146683A1 PCT/IL2025/050003 IL2025050003W WO2025146683A1 WO 2025146683 A1 WO2025146683 A1 WO 2025146683A1 IL 2025050003 W IL2025050003 W IL 2025050003W WO 2025146683 A1 WO2025146683 A1 WO 2025146683A1
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WIPO (PCT)
Prior art keywords
concentrate composition
ophthalmic formulation
concentrate
castor oil
surfactants
Prior art date
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Pending
Application number
PCT/IL2025/050003
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English (en)
Inventor
Nissim Garti
Sharon GARTI-LEVI
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Lyotropic Delivery Systems Ltd
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Lyotropic Delivery Systems Ltd
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Filing date
Publication date
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Publication of WO2025146683A1 publication Critical patent/WO2025146683A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present disclosure concerns ophthalmic formulations for topical delivery of active compounds to the back of the eye.
  • Formulations for back of the eye delivery of active compounds have been researched in recent years. Due to the poor solubility and limited diffusivity of these compounds and/or various delivery vehicles to reach the posterior segments of the eye, up to now direct injections to the posterior segments of the eye has been the preferred mode of administration. While such administration route provides for accurate delivery of the active compound, it requires proficient medical professionals and is often the main cause of patients’ incompliance to treatment. Topical delivery, e.g. by eye drops or ointments, of active compounds to the back of the eye has been the holy grail in the treatment of posterior segment conditions. Therefore, there is a need for formulations for topical delivery of active compounds to the back of the eye.
  • the present disclosure provides ophthalmic topical formulations, particularly in the form of eye drops, which contain one or more active compounds to be delivered to the posterior segments of the eye.
  • the formulations of this disclosure contain one or more pharmaceutically active agents for delivery to the back of the eye, and are based on a concentrate composition, which once diluted in an aqueous medium, forms homogenously dispersed coronated swollen micelles in the aqueous phase, in which the pharmaceutically active agent is stabilized and interfacially entrapped.
  • the concentrate composition is tailored for forming a micellar dispersion when mixed into an aqueous phase, such that the resulting dispersion has improved spreadability when topically administered to the eye, thereby forming a thin layer of the ophthalmic formulation over the surface of the eye.
  • Such spreading increases the contact surface of the formulation with the eye, resulting from a low contact angle of the formulation with the eye, and particularly increases the contact time of the swollen micelles with the eye, thereby enabling more active molecules released from the swollen micelles to cross the ocular epithelium barrier and deliver the active agent to the back of the eye.
  • composition of the concentrate permits stabilization of the active agent, typically a lipophilic active agent, for prolonged periods of time (e.g. during storage), while permitting substantially spontaneous formation of the swollen micelles when diluted in the aqueous medium (namely, without requiring rigorous mixing or high shear forces).
  • active agent typically a lipophilic active agent
  • the inventors have surprisingly found that utilizing a combination of at least two non-ionic hydrophilic surfactants and at least two co-surfactants, as will be disclosed herein, enables physical stabilization of relatively high loads of lipophilic pharmaceutically active agents within the concentrate composition and the coronated swollen micelles formed therefrom, typically at the interface of swollen micelles with the aqueous phase, as will be explained below, without requiring oily components (that are undesired due to their low tolerability when administered to the eye).
  • the present disclosure provides a concentrate composition for preparing an ophthalmic formulation for topical administration
  • the concentrate composition comprises: a) at least one pharmaceutically active agent, b) at least two non-ionic hydrophilic surfactants, and c) at least two co-surfactants, the concentrate composition being capable of forming a plurality of coronated swollen micelles carrying said at least one pharmaceutically active agent and having substantially zero interfacial tension when dispersed in an aqueous continuous phase, to form said ophthalmic formulation.
  • composition will refer to the concentrate, namely a composition that is designed for dilution in an aqueous phase.
  • the concentrate composition is substantially devoid of water (i.e. comprising no more than 5 wt% of water).
  • the concentrate composition is devoid of (i.e. free of) water.
  • formulation will refer to a liquid constituted by a continuous aqueous phase with swollen micelles of the concentrate dispersed therein.
  • the concentrate composition of this disclosure are designed for forming formulations for ophthalmic delivery of at least one pharmaceutically active agent, i.e. delivery of the active agent to one or more part of the eye, for example to the cornea, conjunctiva, aqueous humor, iris, vitreous humor, ciliary body, anterior chamber, posterior chamber, etc.
  • the formulation is preferably a topical formulation in the form of a dispersion or suspension of said swollen micelles in said continuous aqueous phase.
  • Swollen micelles are spherical structures formed out of the combination of the surfactants and co-surfactants, in which the non-ionic hydrophilic surfactants and cosurfactants form a dynamic interface with the continuous aqueous phase.
  • Coronated swollen micelles are swollen micelles that are loaded with the active agent, such that the active agent, typically a lipophilic molecule, is entrapped at the interface of the swollen micelle and the continuous aqueous phase.
  • the coronated swollen micelles Unlike classic micelles, in which the active agents, typically lipophilic compounds, are entrapped in an oily core that is surrounded by surfactants and co-surfactants, in the coronated swollen micelles the active agent is captured and stabilized in the interface, namely between the tails of the surfactants and co-surfactants, such that the active agent itself is integrated into the interface.
  • the coronated swollen micelles can vary in size, however, in some embodiments, have an average diameter of at most 50 nm (nanometers).
  • the pharmaceutically active agent is predominantly located at the interface formed by the surfactants and co-surfactants, where it is physically entrapped between the heads of the surfactants and co-surfactants interacting via hydrogen bonds and dipole-dipole interactions, thereby stabilizing and entrapping it when mixed with the aqueous phase.
  • average size refers to the arithmetic mean of measured diameters of the swollen micelles (or coronated swollen micelles).
  • the inventors have found that a combination of two or more non-ionic hydrophilic surfactants together with two or more co-surfactants enables to solubilize the pharmaceutical active agent in the concentrate composition, while also stabilize it for a sufficient period of time within the ophthalmic formulation to permit effective administration of the active agent to posterior segments of the eye.
  • the balance of ingredients permits not only high load and solubilization of the active agent in the concentrate composition, but also obtaining both kinetic and thermodynamic stabilization of the concentrate composition, hence permitting a long shelf-life of the concentrate composition with minimal precipitation and/or undesired discharge of the active agent - while also permitting easy dilution and spontaneous formation of coronated swollen micelles when mixed with an aqueous phase prior to administration.
  • the concentrate compositions are stable for prolonged periods of time, and as these are typically substantially devoid or entirely devoid of water, they lack a microorganisms’ life-supporting environment, and are readily dilutable for obtaining the ophthalmic formulations.
  • the inventors have surprisingly found that the unique combination of at least two non-ionic hydrophilic surfactants and at least two co-surfactants, as will be detailed herein, permits obtaining a stable concentrate of the active agent, while providing improved wetting and spreadability properties when formulated into the ophthalmic formulation.
  • the micellar structure of the ophthalmic formulation is characterized by a substantially zero interfacial tension between the micelles and the continuous phase.
  • the formulations of this disclosure are characterized by having substantially zero interfacial tension, and typically substantially zero surface energy.
  • the surface energy and interfacial tension are measures of the balance of inter-molecular forces operating in the concentrate when mixed into the aqueous phase.
  • the concentrates of this disclosure are tailored to have substantially zero interfacial tension and surface energy, namely that once mixed with the aqueous phase the concentrate will self-organize into spherical forms, i.e. the coronated swollen micelles, assuming the smallest surface area to volume ratio.
  • the concentrate composition comprises at least two non-ionic hydrophilic surfactants.
  • non-ionic hydrophilic surfactant(s) refers to surfaceactive agents which are not electrically charged, and have a hydrophilic head group and lipophilic tail(s) that are capable of self-arranging into swollen micelles in an aqueous medium.
  • the inventors have found that a combination of two or more such non-ionic hydrophilic surfactants (together with a combination of co-surfactants, as will be disclosed herein) is capable of both solubilizing the active agent when in concentrate form, and forming coronated swollen micelles that capture the active agent when mixed with an aqueous phase, while maintaining the structural stability of the swollen micelles.
  • the at least two non-ionic hydrophilic surfactants comprise at least one first non-ionic hydrophilic surfactant selected from ethoxylated castor oil, hydrogenated castor oil, pegylated-hydrogenated castor oil and derivatives thereof, and at least one second hydrophilic surfactant selected from polysorbates (i.e. polyoxyethylene sorbitan fatty acid esters), polyethoxylated fatty acids, and derivatives thereof.
  • first non-ionic hydrophilic surfactant selected from ethoxylated castor oil, hydrogenated castor oil, pegylated-hydrogenated castor oil and derivatives thereof
  • at least one second hydrophilic surfactant selected from polysorbates (i.e. polyoxyethylene sorbitan fatty acid esters), polyethoxylated fatty acids, and derivatives thereof.
  • the first non-ionic hydrophilic surfactant can be selected from saturated polyoxyethylene castor oil (polyoxyl 30 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 castor oil, polyoxyl 200 hydrogenated castor oil, etc.), unsaturated polyoxyethylene castor oils, and combinations thereof.
  • saturated polyoxyethylene castor oil polyoxyl 30 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 castor oil, polyoxyl 200 hydrogenated castor oil, etc.
  • unsaturated polyoxyethylene castor oils unsaturated polyoxyethylene castor oils, and combinations thereof.
  • the weight ratio between the total non-ionic hydrophilic surfactants and the total co-surfactants ranges between about 1 : 1 and about 3.5: 1, e.g. between about 1.25: 1 and about 3: 1.
  • the at least one solvent is selected from glycerol, ethanol, propanol, isopropanol, threose, and mixtures thereof.
  • said TKI is selected from axitinib, sunitinib, imatinib, nintedanib, dasatinib, nilotinib, erlotinib, and combinations thereof.
  • the total concentration of the non-ionic hydrophilic surfactants in the ophthalmic formulation ranges between about 5 wt% and about 8 wt%.
  • the total concentration of the co-surfactants in the ophthalmic formulation ranges between about 2 wt% and about 5 wt%.
  • the ophthalmic formulation comprises at least one solvent, typically in an amount ranging between about 0.1 wt% and about 1 wt%.
  • the ophthalmic formulation has an osmolality of between about 250 mOsm/kg and about 600 mOsm/kg, e.g. between about 250 mOsm/kg and about 400 mOsm/kg.
  • the ophthalmic formulation typically the aqueous phase, can comprise one or more electrolytes to obtain the desired osmolality, for example electrolytes such as NaCl.
  • the formulation further comprises at least one thickening agent in the aqueous phase.
  • thickening agent or body former refers to a substance that can increase the viscosity of the formulation over the external mucosal membrane of the eye to delay evacuation of the formulation from the eye by the lacrimal fluid.
  • said at least one thickening agent is selected from polyvinyl pyrrolidone, block copolymers of polyoxypropylene and polyoxyethylene (poloxamers), carboxymethyl cellulose and salts thereof, hydroxypropylmethylcellulose (HPMC), poly(vinyl alcohol), poly(acrylic acid), hydrocolloids such as xanthan gum, and combinations thereof.
  • the concentration of said at least one thickening agent in the formulation is up to about 0.2 wt%, e.g. between about 0.05 wt% and about 0. 1 wt%.
  • the ophthalmic formulation has a viscosity (at 25°C) of between about 1 and about 5 mP sec. According to some embodiments, the ophthalmic formulation has a zero shear viscosity (at 25°C) of at most 20 mPas, e.g. between about 8 mPas and about 20 mPas.
  • the formulations may further comprise various additives approved for ophthalmic uses, such as pH adjusting agents and buffers, neutralizing agents, emollients, humectants, preservatives, antioxidants, etc.
  • various additives approved for ophthalmic uses such as pH adjusting agents and buffers, neutralizing agents, emollients, humectants, preservatives, antioxidants, etc.
  • the formulation can further comprise at least one antioxidant, for example butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), tocopherol, tocopherol stearate, palmitoyl ascorbate, ascorbic acid, citric acid, etc.
  • BHT butylated hydroxytoluene
  • TBHQ tert-butylhydroquinone
  • tocopherol tocopherol stearate
  • palmitoyl ascorbate palmitoyl ascorbate
  • ascorbic acid citric acid
  • the formulation can further comprise at least one preservative, for example ethylenediaminetetraacetic acid (EDTA), sorbic acid, benzalkonium chloride, methyl paraben, propyl paraben, etc.
  • EDTA ethylenediaminetetraacetic acid
  • sorbic acid sorbic acid
  • benzalkonium chloride methyl paraben, propyl paraben, etc.
  • a further aspect of this disclosure provides a method of preparing the ophthalmic formulation as described herein, the method comprises mixing the concentrate composition described herein with an aqueous dispersing medium, thereby obtaining coronated swollen micelles formed from said concentrate composition and dispersed in an aqueous continuous phase formed from said aqueous dispersing medium.
  • said concentrate composition is mixed with said aqueous dispersing medium in a weight ratio ranging between about 1:8 and 1: 10.
  • said mixing is carried out under conditions using mechanical rotor or magnetic stirring applying only mild shear.
  • the mixture does not need to be subjected to high shears applied by homogenization, intense sonication, fluidizing techniques, etc.
  • the mixing is carried out under conditions preventing development of high shear forces in the mixture.
  • mixing is carried out by manually shaking the mixture of the concentrate composition and the aqueous medium.
  • the present disclosure provides a kit for preparing the ophthalmic formulation described herein, the kit comprises at least one first container containing the concentrate composition described herein, at least one second container containing an aqueous dispersing medium; and instructions for use.
  • the kit further comprises one or more applicators configured to permit topically applying of the ophthalmic formulation to the eye.
  • the first and second containers may be independently rigid, semi-rigid or flexible, and may have any suitable form.
  • the first and second containers may comprise the concentrate and the aqueous dispensing medium, respectively, in amounts suitable for preparation of a single dose of ophthalmic formulation or for multiple doses thereof.
  • the first and second containers are integrally formed and configured for mixing said concentrate composition and aqueous dispersing medium upon user demand (for example by having the content of one of the containers being introducible into the other container or by having a mixing zone in which the content of the containers can be conveniently mixed).
  • Mixing can be carried out by an active mixer, i.e. a movable mixing unit that permits mixing of the concentrate into the aqueous medium.
  • the first and second containers can be associated with one or more static mixing arrangements, which are configured to be fed concentrate and aqueous medium, and mix the concentrate and aqueous medium while flowing through the static mixing arrangement(s).
  • the concentrate composition can comprise between about 0.1wt% and about 1.25 wt% of said pharmaceutically active agent, e.g. between about 0.2 wt% and about 1 wt%.
  • kits for preparing the ophthalmic formulation described herein comprises at least one first container containing the concentrate composition described herein comprising between about 0. 1 wt% and about 1.25 wt% of said pharmaceutically active agent; at least one second container containing an aqueous dispersing medium; and instructions for use.
  • the ophthalmic formulation can be provided as a ready-for-use formulation, namely without requiring to carry out a dilution action of the concentrate prior to administration.
  • a ready for use ophthalmic formulation comprising coronated swollen micelles of the concentrate composition as disclosed herein dispersed in an aqueous continuous phase, the ophthalmic formulation comprising between about 0.01 wt% and about 0.025 wt% of said at least one pharmaceutically active agent.
  • an ophthalmic formulation as disclosed herein for use in treating a back of the eye disease or condition.
  • Figs. 6A-6D are time-lapsed pictures of a pig’s eye, onto which droplets of Form 2 were applied - immediately before application (Fig. 6A), upon application (Fig. 6B), O. lsec after application (Fig. 6C), and O. lsec after application (Fig. 6D)
  • Fig. 8 shows lesion area measurement in Pigs' eyes following various treatment protocols.
  • Empty concentrates were prepared by weighing all concentrate components and mixing them at 50-60°C. Axitinib (as an exemplary active compound) was then solubilized into the concentrate to obtain the loaded concentrates, as shown in Table 1- 1.
  • the aqueous phase was prepared separately, by mixing all ingredients to homogeneity, and then adjusting the pH to 7.2 ⁇ 0.2, if needed.
  • the loaded concentrates and the aqueous phase were then combined and mixed at a ratio of 1:9 (i.e. 10% concentrate and 90% aqueous phase) under mild mixing conditions to obtain the final formulations, as shown in Table 1-2.
  • Table 1-1 Exemplary concentrate compositions (all values in wt%)
  • Table 1-2 Exemplary formulations - after dilution in aqueous phase (all values in wt%)
  • FIG. 1A-1D Exemplary visualization of the appearance of the formulations of Tables 1-1 and 1-2 are shown in Figs. 1A-1D.
  • CNV laser-induced choroidal neovascularization
  • mice were euthanized and samples from the different part of the eye were collected from the vitreous humor, choroid, sclera, iris-ciliary body and aqueous humor matrices. Analysis of axitinib concentration in the various samples from Groups 4 and 5 was carried out by UC-MS/MS.
  • choroid, iris-ciliary and aqueous humor - 800 pU of water were added to the 2 mU Precellys lysing tubes containing the samples and homogenized using Precellys evolution set to 5 cycles of 15 sec at 5800 rpm with a pause of 30 sec between each cycle.
  • the sample was transferred to a 7 mU Precellys tube, with 1.2 mU of water, and homogenized using Precellys evolution set to 3 cycles of 15 sec at 6 800 rpm with a pause of 15 sec between each cycle. The concentrations were calculated based on the sample weight.
  • Table 9 A comparative axitinib concentration study in the different eye tissue samples for Groups 4 and 5 is shown in Table 9. As can be seen from Table 9, administration of the formulations of this disclosure provided effective delivery of axitinib to the choroid and iris-ciliary body, showing effective targeting to desired tissues. Table 9: Axitinib concentration in pig's different tissues (ng/g)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Dispersion Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
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Abstract

La présente invention concerne des formulations ophtalmiques pour l'administration topique de composés actifs au fond de l'œil, sur la base de compositions concentrées qui sont capables de former une pluralité de micelles gonflées à couronne portant au moins un agent pharmaceutiquement actif et ayant une tension interfaciale sensiblement nulle lorsqu'elles sont dispersées dans une phase continue aqueuse, ainsi que des procédés et des kits pour leur préparation, et leur utilisation dans le traitement de diverses maladies ou affections du fond de l'œil.
PCT/IL2025/050003 2024-01-03 2025-01-01 Formulations topiques pour l'administration d'un composé actif au fond de l'œil Pending WO2025146683A1 (fr)

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IL30992824 2024-01-03
IL309928 2024-01-03

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WO2025146683A1 true WO2025146683A1 (fr) 2025-07-10

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9456992B2 (en) 2012-01-13 2016-10-04 Xspray Microparticles Ab Pharmaceutical composition comprising stable, amorphous, hybrid nanoparticles of at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix forming component
WO2017201508A1 (fr) * 2016-05-20 2017-11-23 Azure Biotech, Inc. Systèmes destinés à une administration vaginale comportant un modulateur sélectif des récepteurs aux œstrogènes (serm) et leurs utilisations
US10010610B2 (en) 2014-01-16 2018-07-03 Retinal Therapies, LLC Compositions and methods for the treatment of intraocular neovascularization and/or leakage
WO2020047146A1 (fr) * 2018-08-28 2020-03-05 Cloudbreak Therapeutics, Llc Formulations d'émulsion d'inhibiteurs de multikinase
WO2020055713A1 (fr) 2018-09-10 2020-03-19 Taiwan Liposome Co., Ltd. Compositions pharmaceutiques ophtalmiques à libération prolongée et utilisations associées
US20200163877A1 (en) 2012-08-21 2020-05-28 Opko Pharmaceuticals, Llc Liposome formulations
US20200306182A1 (en) 2019-03-05 2020-10-01 Aerie Pharmaceuticals, Inc. Pharmaceutical compositions for treating ocular diseases or disorders
US20210052489A1 (en) 2012-05-03 2021-02-25 The Johns Hopkins University Particles, compositions and methods for ophthalmic and/or other applications
WO2021207486A1 (fr) * 2020-04-08 2021-10-14 Aerie Pharmaceuticals, Inc. Traitements
US20220023213A1 (en) 2018-11-19 2022-01-27 Chengdu Ruimu Pharmaceuticals Co., Ltd. Nanocrystalline eye drop, preparation method and use thereof

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9456992B2 (en) 2012-01-13 2016-10-04 Xspray Microparticles Ab Pharmaceutical composition comprising stable, amorphous, hybrid nanoparticles of at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix forming component
US20210052489A1 (en) 2012-05-03 2021-02-25 The Johns Hopkins University Particles, compositions and methods for ophthalmic and/or other applications
US20200163877A1 (en) 2012-08-21 2020-05-28 Opko Pharmaceuticals, Llc Liposome formulations
US10010610B2 (en) 2014-01-16 2018-07-03 Retinal Therapies, LLC Compositions and methods for the treatment of intraocular neovascularization and/or leakage
WO2017201508A1 (fr) * 2016-05-20 2017-11-23 Azure Biotech, Inc. Systèmes destinés à une administration vaginale comportant un modulateur sélectif des récepteurs aux œstrogènes (serm) et leurs utilisations
WO2020047146A1 (fr) * 2018-08-28 2020-03-05 Cloudbreak Therapeutics, Llc Formulations d'émulsion d'inhibiteurs de multikinase
WO2020055713A1 (fr) 2018-09-10 2020-03-19 Taiwan Liposome Co., Ltd. Compositions pharmaceutiques ophtalmiques à libération prolongée et utilisations associées
US20220023213A1 (en) 2018-11-19 2022-01-27 Chengdu Ruimu Pharmaceuticals Co., Ltd. Nanocrystalline eye drop, preparation method and use thereof
US20200306182A1 (en) 2019-03-05 2020-10-01 Aerie Pharmaceuticals, Inc. Pharmaceutical compositions for treating ocular diseases or disorders
WO2021207486A1 (fr) * 2020-04-08 2021-10-14 Aerie Pharmaceuticals, Inc. Traitements

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