Topical formulations for delivery of an active compound to the back of the eye

Abstract

The present disclosure concerns ophthalmic formulations for topical delivery of active compounds to the back of the eye, based on concentrate compositions that are capable of forming a plurality of coronated swollen micelles carrying at least one pharmaceutically active agent and having substantially zero interfacial tension when dispersed in an aqueous continuous phase, as well as methods and kits for their preparation, and uses thereof in treatment of various back of the eye diseases or conditions.

Description

[0001] Topical Formulations for Delivery of an Active Compound to the Back of the Eye

[0002] TECHNOLOGICAL FIELD

[0003] The present disclosure concerns ophthalmic formulations for topical delivery of active compounds to the back of the eye.

[0004] BACKGROUND ART

[0005] References considered to be relevant as background to the presently disclosed subject matter are listed below:

[0006] - US patent publication no. 10,010,610

[0007] - US patent publication no. 9,456,992

[0008] - US patent application publication no. 20200163877

[0009] - PCT patent application publication no. W02020055713

[0010] - US patent application publication no. 20210052489

[0011] - US patent application publication no. 2022023213

[0012] - US patent application publication no. 2020306182

[0013] Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.

[0014] BACKGROUND

[0015] 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.

[0016] GENERAL DESCRIPTION

[0017] 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.

[0018] 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.

[0019] The 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). 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).

[0020] Thus, in one of its aspects, 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.

[0021] In the context of this disclosure, the term composition will refer to the concentrate, namely a composition that is designed for dilution in an aqueous phase. By some embodiments, the concentrate composition is substantially devoid of water (i.e. comprising no more than 5 wt% of water). According to some embodiments, the concentrate composition is devoid of (i.e. free of) water.

[0022] The term formulation will refer to a liquid constituted by a continuous aqueous phase with swollen micelles of the concentrate dispersed therein.

[0023] 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.

[0024] 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. 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). Without wishing to be bound by theory, 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.

[0025] The term average size refers to the arithmetic mean of measured diameters of the swollen micelles (or coronated swollen micelles).

[0026] 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. In the compositions of this disclosure, 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.

[0027] 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.

[0028] Further, 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. As noted, once formulated by dispersing into the aqueous continuous phase, the micellar structure of the ophthalmic formulation is characterized by a substantially zero interfacial tension between the micelles and the continuous phase.

[0029] 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.

[0030] As noted, the concentrate composition comprises at least two non-ionic hydrophilic surfactants. The term 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. Unlike classic micelles, which are thermodynamically stable structures, the incorporation of active agents to form swollen micelles can cause destabilization of the micelles’ structure. By tailoring the combination of surfactants and co-surfactants, entrapment of active agent between the surfactants tails is obtained, thereby solubilizing it predominantly within the interface once mixed with an aqueous phase, integrating it into the interface and maintaining the structural stability of the coronated swollen micelles.

[0031] According to some embodiments, 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. According to some embodiments, 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.

[0032] According to some embodiments, the second non-ionic hydrophilic surfactant can be selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyethylene (40) stearate, polyoxyethylene (40) oleate, and mixtures thereof.

[0033] According to some embodiments, the weight ratio (w / w) of the first non-ionic hydrophilic surfactants to the second non-ionic hydrophilic surfactants in the concentrate composition ranges between about 3: 1 and about 1:3. According to other embodiments, the weight ratio (w / w) of the first non-ionic hydrophilic surfactants to the second non- ionic hydrophilic surfactants in the concentrate composition ranges between about 2: 1 and about 1:2. By some other embodiments, the weight ratio (w / w) of the first non-ionic hydrophilic surfactants to the second non-ionic hydrophilic surfactants in the concentrate composition ranges between about 1: 1.5 and about 2: 1. By yet other embodiments, the weight ratio (w / w) of the first non-ionic hydrophilic surfactants to the second non-ionic hydrophilic surfactants in the concentrate composition is about 1: 1.5, about 1: 1.4, about 1: 1.3, about 1: 1.2, about 1: 1.1, about 1: 1, about 1.1: 1, about 1.2: 1, about 1.3: 1, about 1.4: 1, about 1.5: 1, about 1.6: 1, about 1.7: 1, about 1.8: 1, about 1.9: 1 or about 2: l.

[0034] According to some embodiments, the total concentration of the non-ionic hydrophilic surfactants in the concentrate composition ranges between about 50 wt% and about 75 wt%.

[0035] As noted, the stable solubilization of the active agent in the concentrate composition and the spontaneous formation of swollen micelles thereof when mixed with an aqueous phase is due to a combination of surfactants and co-surfactants. Co-surfactant should be understood to encompass any lipophilic, hydrophilic or amphiphilic agent, different from said non-ionic hydrophilic surfactants, which contributes (together with the surfactants) to lowering of the interfacial tension between the surfactants’ phase and the aqueous phase to almost zero (or zero) allowing for the spontaneous formation of stable swollen micelles. According to some embodiments, the co-surfactants are hydrophilic cosurfactants or amphiphilic co-surfactants.

[0036] By some embodiments, at least two co-surfactants comprise at least one first cosurfactant that is a polyol and at least one second co-surfactant that is a polyether.

[0037] According to some embodiments, the first co-surfactant can be selected from propylene glycol, ethylene glycol, glycerol, a mixture of polyethylene glycol and polypropylene glycol, a copolymer of polyethylene glycol and polypropylene glycol, and mixtures thereof.

[0038] According to some embodiments, the second co-surfactant can be selected from polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600, and mixtures thereof.

[0039] The weight ratio of the first co-surfactant to the second co-surfactant can, by some embodiments, range between about 3: 1 to about 1:3. According to some embodiments, the weight ratio of the first co-surfactant to the second co-surfactant ranges between about 2: 1 and about 1:2.

[0040] According to some embodiments, the total concentration of the co-surfactants in the concentrate composition ranges between about 20 wt% and about 45 wt%.

[0041] According to other embodiments, 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.

[0042] By some embodiments, the concentrate composition further comprises at least one auxiliary surfactant, which is different from said first and second non-ionic hydrophilic surfactants. The auxiliary surfactant can be hydrophilic, amphiphilic or lipophilic, and can be ionic or non-ionic.

[0043] According to some embodiments, the auxiliary surfactant is selected from polyethylene glycol (15)-hydroxystearate (Solutol™ HS15), polypropylene glycol, propylene glycol, propylene glycol diacetate, and mixtures thereof.

[0044] By some embodiments, the concentrate composition comprises between about 1 wt% and about 18 wt% of said auxiliary surfactant.

[0045] By some embodiments, the concentrate composition also comprises at least one solvent. The solvent is an organic liquid, typically polar, that is water miscible and is suitable for assisting the solubilization of the active agent into the concentrate and / or swollen micelles and / or coronated swollen micelles formed therefrom, as well as for adjusting the osmolarity of the formulation. The introduction of at least one such solvent into the concentrate composition can facilitate full coverage of the interface by the hydrophilic surfactants when mixed into the aqueous medium. In other words, the use of at least one solvent alters the effective critical packing parameter (ECPP) of the interface, facilitating the control of the hydrophilicity / hydrophobicity of the surfactants, depending on the amount of water into which the concentrate composition is diluted to form the ophthalmic formulation, thus increasing stability of the formulation.

[0046] According to some embodiments, the at least one solvent is selected from glycerol, ethanol, propanol, isopropanol, threose, and mixtures thereof.

[0047] By some embodiments, the concentrate composition comprises said at least one solvent in an amount of at most about 8 wt%, e.g. between about 0.1 wt% and about 8 wt%. According to some embodiments, the concentrate composition comprises said at least one solvent in an amount of between about 1 wt% and about 6 wt%.

[0048] By some other embodiments, the weight ratio between the total non-ionic hydrophilic surfactants and the solvents ranges between about 10: 1 and about 15: 1.

[0049] According to some embodiments, the composition can comprise at least one oil, at an amount of no more than about 5 wt%, preferably no more than 3 wt%. According to some embodiments, the compositions are devoid of oil.

[0050] By some embodiments, the concentrate composition comprises at least one tyrosine kinase inhibitor (TKI) as the pharmaceutically active agent. A tyrosine kinase inhibitor is a molecule that effectively inhibits the activity of specific proteins termed “receptor tyrosine kinases”, including vascular endothelial growth factor receptors (VEGFRs). By blocking these receptors, a TKI helps to prevent the intracellular downstream signal transduction cascade of the angiogenic processes (the formation of new blood vessels), and as a result can also inhibit metastases. Vascular endothelial growth factor (VEGF) is widely recognized as the predominant factor driving angiogenesis. Of the VEGF family, VEGF-A stands out as the main mediator in pathological neovascularization. The interactions of VEGF-A with its tyrosine kinase receptor, VEGFR-1 and VEGFR-2, play pivotal roles in multiple facets of angiogenesis, including vascular permeability, endothelial cell survival, migration, proliferation and capillary formation. Additionally, vascular endothelial cells release platelet-derived growth factor B (PDGF-B), while surrounding structural cells, such as pericytes and vascular smooth muscular cells, express its receptor PDGFR-P, PDGF is crucial for recruiting pericytes, facilitating the maturation of newly formed vessels. As a result, concurrently inhibiting the signaling pathways of both VEGF and PDGF is suggested to offer an effective strategy for addressing diseases stemming from neovascularization and vascular leakage.

[0051] According to some embodiments, said TKI is selected from axitinib, sunitinib, imatinib, nintedanib, dasatinib, nilotinib, erlotinib, and combinations thereof.

[0052] According to some embodiments, the pharmaceutical active agent is axitinib.

[0053] According to some embodiments, the at least one pharmaceutically active agent is present in the concentrate composition in an amount of between about 0.1 wt% and about 1.25 wt%

[0054] As noted, the concentrate compositions of this disclosure are tailored for spontaneous formation of a transparent dispersion of coronated swollen micelles once mixed with an aqueous medium, in order to form ophthalmic formulations. Thus, by another aspect, the present disclosure provides an ophthalmic formulation comprising coronated swollen micelles of the concentrate composition as disclosed herein dispersed in an aqueous continuous phase.

[0055] According to some embodiments, the total concentration of the non-ionic hydrophilic surfactants in the ophthalmic formulation ranges between about 5 wt% and about 8 wt%.

[0056] According to some embodiments, the total concentration of the co-surfactants in the ophthalmic formulation ranges between about 2 wt% and about 5 wt%.

[0057] By some embodiments, the ophthalmic formulation comprises at least one solvent, typically in an amount ranging between about 0.1 wt% and about 1 wt%.

[0058] According to some embodiments, the at least one pharmaceutically active agent is present in the ophthalmic formulation in an amount of between about 0.01 wt% and about 0.12 wt%.

[0059] For forming the formulation, the concentrate is mixed into an aqueous phase, spontaneously forming the coronated swollen micelles. According to some embodiments, the coronated swollen micelles are substantially mono-disperse. The formulations are typically optically transparent (or substantially transparent) due to their mono-dispersed submicronic size. This permits easy detection of changes in the formulation's stability (as phase separation, bioactive precipitation, and / or coalescence of micelles that causes detectable clouding). According to some embodiments, the ophthalmic formulation is characterized by a substantially zero interfacial tension between the coronated swollen micelles and the continuous phase.

[0060] According to some other embodiments, the ophthalmic formulation is characterized by zero surface energy between the coronated swollen micelles and the aqueous phase.

[0061] By some embodiments, the ophthalmic formulation has a wetting angle of at most about 25°.

[0062] By some embodiments, the ophthalmic formulation has a shear viscosity of at most 25mPas at a shearing rate of 9000 1 / s, e.g. between about 8 mPas and about 20 mPas.

[0063] According to some embodiments, 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.

[0064] According to some embodiments, the ophthalmic formulation has a refractive index substantially the same as water, i.e. between about 1.34 and about 1.36.

[0065] In order to increase residence time of the formulation in the eye, the formulation, by some embodiments, further comprises at least one thickening agent in the aqueous phase. The term 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. According to some embodiments, 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.

[0066] By some embodiments, 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%.

[0067] According to some embodiments, 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.

[0068] In some embodiments, 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.

[0069] In some embodiments, 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.

[0070] In some embodiments, the formulation can further comprise at least one preservative, for example ethylenediaminetetraacetic acid (EDTA), sorbic acid, benzalkonium chloride, methyl paraben, propyl paraben, etc.

[0071] 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.

[0072] According to some embodiments, said concentrate composition is mixed with said aqueous dispersing medium in a weight ratio ranging between about 1:8 and 1: 10.

[0073] By some embodiments, 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. Hence, by some embodiments, the mixing is carried out under conditions preventing development of high shear forces in the mixture.

[0074] According to other embodiments, mixing is carried out by manually shaking the mixture of the concentrate composition and the aqueous medium.

[0075] By another aspect, 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. According to some embodiments, the kit further comprises one or more applicators configured to permit topically applying of the ophthalmic formulation to the eye.

[0076] 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.

[0077] By some embodiments, 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).

[0078] 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. Alternatively, 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).

[0079] In the kit embodiment, 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%.

[0080] By another aspect, there is provided a kit for preparing the ophthalmic formulation described herein, the kit 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.

[0081] Alternatively, 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. Hence, by another aspect, there is provided 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. By another aspect, there is provided an ophthalmic formulation as disclosed herein for use in treating a back of the eye disease or condition.

[0082] Another aspect provides a method of treating a back of the eye disease or condition, comprising administering an effective amount of an ophthalmic formulation described herein to a subject in need thereof.

[0083] A back of the eye disease (or a posterior segment ophthalmic disease) is a disorder or condition affecting posterior ocular tissues, such as the vitreous humor, the retina, the choroid, etc.

[0084] By some embodiments, the back of the eye disease or condition is selected from dry and wet age-related macular degradation (AMD), diabetic retinopathy and conditions associated therewith (such as non-proliferative diabetic retinopathy, proliferative retinopathy, maculopathy, vitreous hemorrhage, macular edema), retinal vascular occlusion, and malignant retinal diseases (such as ocular melanoma and retinoblastoma).

[0085] By some embodiments, the back of the eye disease or condition is selected from dry age-related macular degradation and wet age-related macular degradation.

[0086] As known, the effective amount for purposes herein may be determined by such considerations as known in the art. The amount must be effective to achieve the desired therapeutic effect, depending, inter alia, on the type and severity of the disease to be treated and the treatment regimen. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount. As generally known, the effective amount depends on a variety of factors including a variety of pharmacological parameters such as half-life in the body, undesired side effects, factors such as age and gender, and others.

[0087] The term treatment or any lingual variation thereof, as used herein, refers to the administering of a therapeutic amount of the formulations of the present disclosure which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease from occurring or a combination of two or more of the above.

[0088] As used herein, the term about is meant to encompass deviation of ± 10% from the specifically mentioned value of a parameter, such as temperature, concentration, etc.

[0089] Unless otherwise specifically indicated, all concentrations disclosed herein are provided as weight percentage, wt%, out of the weight of the ophthalmic formulation or the concentrate composition, as the case may be.

[0090] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases ranging / ranges between a first indicate number and a second indicate number and "ranging / ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0091] Unless the context requires otherwise, the word comprise, and variations such as “comprises” and "comprising" , will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any integer or step or group of integers and steps.

[0092] The term ... at least one... as applied to any component of a composition or a formulation should be read to encompass one, two, three, four, or even more different occurrences of said component in the composition or formulation.

[0093] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0095] Figs. 1A-1H are pictures of exemplary formulations according to this disclosure: Forml concentrate, lwt% axitinib (Fig. 1A), Forml diluted, 0.1wt% axitinib (Fig. IB), Form2 concentrate, lwt% axitinib (Fig. 1C), Form2 diluted, 0.1wt% axitinib (Fig. ID), Forml A 0.01wt% axitinib (Fig. IE), Form IB 0.01wt% axitinib (Fig. IF), Form2A 0.025wt% axitinib (Fig. 1G), and Form2B 0.025wt% axitinib (Fig. 1H).

[0096] Figs. 2A-2B show droplet-size distribution (by volume) for diluted Forml, 0.1% axitinib (Fig. 2A) and diluted Form2, 0.1wt% axitinib (Fig. 2B).

[0097] Figs. 3A-3B are pictures of Forml and Form2 samples, respectively, after shortterm chemical stability tests.

[0098] Figs. 4A-4D are LUMiFuge test results for Forml concentrate lwt% axitinib (Fig. 3A), Forml diluted, 0.1wt% axitinib (Fig. 3B), Form2 concentrate lwt% axitinib (Fig. 3C), and Form2 diluted, 0.1wt% axitinib (Fig. 3D).

[0099] Fig. 5 is a general art demonstration of a wetting angle.

[0100] 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)

[0101] Figs. 7A-7B show surface tension test results for Forml and Form2, respectively.

[0102] Fig. 8 shows lesion area measurement in Pigs' eyes following various treatment protocols.

[0103] DETAILED DESCRIPTION OF EMBODIMENTS

[0104] Exemplary formulations

[0105] 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.

[0106] Table 1-1: Exemplary concentrate compositions (all values in wt%)

[0107] * Polyoxyethylene (40) stearate

[0108] ** Polyoxyl 35 castor oil

[0109] *** Polyethylene glycol ( 15)-hydroxy stearate

[0110] Table 1-2: Exemplary formulations - after dilution in aqueous phase (all values in wt%)

[0111] Additional, ready-for-use formulations prepared out of concentrates having lower axitinib concentrations were also prepared, as shown in Tabel 1-3. Table 1-3: Exemplary formulations - after dilution in aqueous phase (all values in wt%)

[0112] Physical characterization

[0113] The physical properties of the formulations of Table 1-2 are shown in Table 2-1. The formulations were all in the form of a clear, transparent, homogenous dispersion of swollen micelles in a continuous aqueous phase, showing high transparency, homogeneity and have shown stability of at least 3 hours after mixing.

[0114] Exemplary visualization of the appearance of the formulations of Tables 1-1 and 1-2 are shown in Figs. 1A-1D.

[0115] The hydrodynamic radii of the droplets were measured at room temperature by dynamic light scattering (DLS) using Nano-ZS Zetasizer (Malvern, UK).

[0116] Table 2-1: Physical characterization of the formulations of Table 1-2 * Percent from label claim As clearly shown in Table 2-1, the formulations demonstrate full transparency, with a substantially mono-disperse size distribution (as can also be seen in Figs. 2A-2B) and uniform refractive index.

[0117] The physical properties of the formulations of Table 1-3 are shown in Table 2-2. Exemplary visualization of the appearance of the formulations of Table 1-3 are shown in Figs. 1E-1H

[0118] Table 2-2: Physical characterization of the formulations of Table 1-3

[0119] Formulations FormlA, FormlB, Form2A and Form2B were all in the form of a clear, transparent, homogenous dispersions of swollen micelles in a continuous aqueous phase, showing high transparency, homogeneity and have shown stability of at least 4 months after mixing. Hence, such formulations can be prepared well in advance before use, and do not require further dilution immediately prior to administration.

[0120] Chemical stability

[0121] The concentrate formulations were examined for short-term chemical stability during storage up to 90 days at different temperatures (4°C, 25°C and 40°C). The results for the concentrates of formulations 1 and 2 (i.e. the concentrates of Table 1-1) are provided in Tables 3-1 and 3-2, respectively, as well as Figs. 3A-3B.

[0122] The short-term chemical stability during storage up to 120 days at different temperatures was evaluated for the formulations of Table 1-3, and are provided in Table 3-3.

[0123] As can be seen, the formulation remains stable at the tested storage temperatures, without any evidence of change in physical and chemical properties. Table 3-1: Stability for Forml, 4°C

[0124] Table 3-1 (cont).: Stability for Forml. 25°C

[0125] Table 3-1 (cont.): Stability for Forml. 40°C Table 3-2: Stability for Form2, 4°C

[0126] Table 3-2 (cont).: Stability for Form2, 25°C

[0127] Table 3-2 (cont.): Stability for Form2, 40°C

[0128] Table 3-3: Stability for formulations of Table 1-3, 25°C, 4 months Table 3-3 (cont.): Stability for formulations of Table 1-3, 4 months

[0129] Long-term physical stability

[0130] To determine long term stability of formulations, a rapid measurement was carried out using LUMiSizer® analytical centrifugation. The results are shown in Figs. 4A-4D. LUMiSizer® analysis enables to predict the shelf-life of a formulation in its original concentration, even in cases of slow destabilization processes like sedimentation, flocculation, coalescence and fractionation. During LUMiSizer® measurements, parallel light illuminates the entire sample cell in a centrifugal field; the transmitted light is detected by sensors arranged linearly along the total length of the sample-cell. Local alterations of particles or droplets are detected due to changes in light transmission over time. The results are presented in a graph plotting the percentage of transmitted light (Transmission %) as a function of local position (mm), revealing the corresponding transmission profile over time.

[0131] The changes in transmission indicate the stability of the formulation - when the transmission profile remains constant, the samples are considered physically stable and their shelf-life can be extrapolated based on the measurement conditions.

[0132] For the tested formulation, the measurement conditions were 25°C, 3000rpm, 470m, 13.3hr duration, 800 profiles with 60-seconds interval, light factor of 1.0, and a 2.0mm PC cuvette.

[0133] As shown in Figs. 4A-4D, in all transmission profiles the lines overlap, suggesting that no changes in the transmission were observed, and all the systems are physically stable and expected, on the basis of this analysis, to be stable under storage conditions for at least 2 years. Surface behavior tests

[0134] As noted above, the formulations of this disclosure were found to provide beneficial surface behavior, with increased spreadability and improved wetting properties, that increase the contact area of the formulation with the surface of the eye and increase its residence time on the eye to permit enhanced penetration of the micelles carrying the active agent to the back of the eye. The formulations surface behavior of exemplary Formulations 1 and 2 was, thus, investigated.

[0135] Wetting angle

[0136] The wetting angle (or contact angle, a) between a liquid and a surface is the angle formed between the surface tangent on the liquid-vapor interface and the tangent on the solid-liquid interface at their intersection, as demonstrated in Fig. 5. A liquid is said to “wet” the surface, when the contact angle is <90°C - the smaller the angle, the liquid is considered to provide a better “wettability” onto the surface.

[0137] Glass slides were pre-washed by soaking them in 12wt% HC1 for 30 minutes, rinsed with denatured ethanol 96%, and then wiped dry with Kimwipes. 5pL droplets of Form2 were applied onto the glass slides by pipette, and the contact angle between the applied droplets and the glass surface were measured using a contact angle instrument (Dangguan Lonroy), according to ASTM 724. Measurements were carried out for samples at circa. 25°C immediately upon application of the droplet (to) and 180 seconds after application (tiso). The results are shown in Table 4.

[0138] Table 4: Contact angle measurements on glass slides

[0139] As can be seen, the measured contact angle of Form2 was significantly lower than water, indicating that Form2 has increased wettability compared to water.

[0140] In order to assess the behavior of Form2 on the eye, the formulation was applied onto fresh pig eyes. The tests were carried out immediately after harvesting (no more than 24 hours from harvesting), and kept in viable conditions until and during the tests were carried out. Figs. 6A-6D are time-lapsed pictures, taken at 0.1 sec intervals, showing immediate spreading of the applied droplet after application, and hence non-measurable contact angle. Thus, the formulation shows excellent spreadability and full wetting of the eye, providing an increased surface area between the formulation and the eye.

[0141] Surface tension

[0142] Surface tension is the tendency of a droplet of liquid to assume the minimal surface area possible, and is obtained by the balance of the inter-molecular cohesive forces (forces acting between molecules of the same type in the formulation) and the adhesive forces (forces acting between molecules of different types in the formulation).

[0143] In heathy eyes, the surface tension of lacrimal fluid on the eye is typically reduced within a few seconds from ca. 70mN / m to an equilibrium surface tension of ca. 45 mN / m - hence a surface tension of 45 mN / m is considered to provide good wettability of the eye and is considered the standard when examining lubrication properties of eye drops. In dry eyes, however, the surface tension of the lacrimal fluid is of at least 50mN / m at equilibrium, indicating a reduced wettability of the eye.

[0144] The surface tensions of Forml and Form2 were measured, as well as the time required to obtain an equilibrium surface tension. The tests were carried out in a DCAT tensiometer, at ca. 23°C, plate PT11.

[0145] Results of the surface tension measurements are provided in Table 5, as well as Figs. 7A-7B.

[0146] Table 5: Surface tension measurements

[0147] As can be seen, the surface tension at equilibrium of both Forml and Form2 are below 45 mN / m, indicating a lower surface tension than lacrimal fluid, and, hence, increased wetting and lubricating properties compared to lacrimal fluid. Zero shear viscosity and high shear (blinking) viscosity

[0148] Viscosity profiling enables the characterization of materials under a well-defined range of shear conditions. Under low shear conditions, or “zero shear” (i. e. at rest, without application of shear forces), higher viscosity can increase the residence time of the formulation on the eye. However, during high shear events, such as blinking, a high viscosity often leads to a ‘draggy’ feel, leading to blurry vision and “foreign body syndrome” (namely a feeling of a foreign body trapped in the eye).

[0149] In order to assess the viscosity of the formulations under zero shear and high shear conditions, Forml and Form2 were tested under different shearing conditions, using THERMO HAAKE RheosStress 6000. High (blinking) shear viscosity was measured at a shear rate of 9,000 1 / s. The results are provided in Table 6.

[0150] Table 6: Viscosity measurements

[0151] In both Forml and Form 2, the zero shear viscosity is higher than that of water, indicating that the formulation will be maintained over the eye for longer periods of time after application, compared to water.

[0152] Further, both Forml and Form 2, unlike water, show low viscosity values a decrease in viscosity at high shear rates compared to zero shear viscosity. Hence, the formulations demonstrate non-Newtonian, shear thinning behavior, indicating that no irritancy will be caused during blinking.

[0153] Pre-clinical studies in CNV model

[0154] Pre-clinical studies for Forml and Form2, compared to aflibercept ophthalmic injection, were carried out according to the following test protocol.

[0155] Study design

[0156] 31 female pigs, 4-6 weeks old, were tested in laser-induced choroidal neovascularization (CNV) model, namely subjected to laser injury to perforate Bruch's membrane, resulting in subretinal blood vessel recruitment from the choroid. The model is aimed at assessing treatment efficacy in lesion healing similar to wet- AMD disease.

[0157] The pigs were grouped in 6 test groups, as shown to Table 8. Ocular observation and fluorescein angiography testing was carried out at baseline and at 8- and 15-days. Study was ceased on Day 15, as the natural rate of lesion healing in pigs' eyes is typically about two weeks. On day 15 the eyes were frozen and stored at -80°C until the following tissues were dissected and collected: sclera, VH, retina, RPE / choroid, iris / ciliary body. Next the levels of axitinib at each compartment were tested.

[0158] Table 8: CNV model experimental design On day 1, all animals, except Group 1, underwent laser CNV induction OU. Animals in Group 2 received a 50pL dose of aflibercept intravitreally OU (currently considered the gold standard treatment), and animals in Groups 3-5 received a 50p topical dose of either saline (Group 3), formulations of this disclosure (Groups 4-5), BID in both eyes on Days 1-14 and SID on Day 15. Animals in Groups 6 received a 50p dose of balanced salt solution (BSS) intravitreally OU.

[0159] At Day 15, animals 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. For the retina, 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. For the vitreous humor and sclera - 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.

[0160] Results

[0161] Average lesion area assessment for the different treatments is shown on Fig. 8 for Day 8 and Day 15. Attention is first made to the results on Day 8. As can be seen, compared to aflibercept intravitreal injection, topically applied Form2 shows a decrease in lesion area, similar to aflibercept. On Day 15, both Forml and Form2 show a significant decrease in lesion area. Thus, topical application of formulations of this disclosure have been shown to provide at least comparable results aflibercept intravitreal injection. Therefore, formulations of this disclosure demonstrate significant delivery and efficacy of treatment by topical application, as compared to intravitreal injection.

[0162] 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)

Claims

CLAIMS:

1. A concentrate composition for preparing an ophthalmic formulation for topical administration, the concentrate composition comprising: 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.

2. The concentrate composition of claim 1, configured to have substantially zero surface energy when dispersed in the aqueous continuous phase.

3. The concentrate composition of claim 1 or 2, configured to provide said ophthalmic formulation with a wetting angle of at most about 25°.

4. The concentrate composition of any one of claims 1 to 3, configured to provide said ophthalmic formulation a surface tension of at most about 40 mN / m.

5. The concentrate composition of any one of claims 1 to 4, configured to provide said ophthalmic formulation a shear viscosity of at most 25 mP at a shearing rate of 9000 1 / s.

6. The concentrate composition of any one of claims 1 to 5, wherein the said 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, polyethoxylated fatty acids, and derivatives thereof.

7. The concentrate composition of claim 6, wherein the first non-ionic hydrophilic surfactant is 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.

8. The concentrate composition of claim 6 or 7, wherein the second non-ionic hydrophilic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, polyoxyethylene (40) stearate, polyoxyethylene (40) oleate, and mixtures thereof.

9. The concentrate composition of any one of claims 6 to 8, wherein the weight ratio of the first non-ionic hydrophilic surfactants to the second non-ionic hydrophilic surfactants ranges between about 3: 1 and about 1:3.

10. The concentrate composition of any one of claims 1 to 9, wherein the total concentration of the non-ionic hydrophilic surfactants in the composition ranges between about 50 wt% and about 75 wt%.

11. The concentrate composition of any one of claims 1 to 10, wherein said at least two co-surfactants comprise at least one first co-surfactant that is a polyol and at least one second co-surfactant that is a polyether.

12. The concentrate composition of claim 11, wherein said polyol is selected from propylene glycol, ethylene glycol, glycerol, a mixture of polyethylene glycol and polypropylene glycol, a copolymer of polyethylene glycol and polypropylene glycol, and mixtures thereof.

13. The concentrate composition of claim 11 or 12, wherein said polyether is selected from polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, and mixtures thereof.

14. The concentrate composition of any one of claims 11 to 13, wherein the weight ratio of the first co-surfactant to the second co-surfactant ranges between about 3: 1 and about 1:3.

15. The concentrate composition of any one of claims 1 to 14, wherein the total concentration of the co-surfactants in the composition ranges between about 20 wt% and about 45 wt%.

16. The concentrate composition of any one of claims 1 to 15, wherein 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.

17. The concentrate composition of any one of claims 1 to 16, further comprising at least one auxiliary surfactant.

18. The concentrate composition of claim 17, wherein said auxiliary surfactant is selected from polyethylene glycol (15)-hydroxystearate (Solutol HS15), polypropylene glycol, propylene glycol, propylene glycol diacetate, and mixtures thereof.

19. The concentrate composition of any one of claims 1 to 18, further comprising at least one solvent.

20. The concentrate composition of claim 19, wherein said at least one solvent is selected from glycerol, ethanol, propanol, isopropanol, threose, and mixtures thereof.

21. The concentrate composition of claim 19 or 20, comprising said at least one solvent in a concentration ranging between about 0.1 wt% and about 8 wt%.

22. The concentrate composition of any one of claims 1 to 21, further comprising at least one oil.

23. The concentrate composition of any one of claims 1 to 22, wherein said at least one pharmaceutically active agent is a tyrosine kinase inhibitor (TKI).

24. The concentrate composition of claim 23, wherein said TKI is selected from axitinib, axitinib, sunitinib, imatinib, nintedanib, dasatinib, nilotinib, erlotinib, and combinations thereof,25. The concentrate composition of any one of claims 1 to 24, wherein said at least one pharmaceutically active agent is present in the composition in an amount of between about 0. 1 wt% and about 1.25 wt%.

26. The concentrate composition of any one of claims 1 to 25, being devoid of water.

27. The concentrate composition of any one of claims 1 to 26, wherein the coronated swollen micelles have an average size of no more than about 50 nm.

28. An ophthalmic formulation comprising coronated swollen micelles of the concentrate composition of any one of claims 1 to 27 dispersed in an aqueous continuous phase.

29. The ophthalmic formulation of claim 28, having a wetting angle of at most about 25°.

30. The ophthalmic formulation of claim 28 or 29, having a surface tension of at most about 40 mN / m.

31. The ophthalmic formulation of any one of claims 28 to 30, having a shear viscosity of at most 25 mP at a shearing rate of 9000 1 / s.

32. The ophthalmic formulation of any one of claims 28 to 31, wherein said aqueous phase comprises at least one thickening agent.

33. The ophthalmic formulation of claim 32, wherein 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.

34. The ophthalmic formulation of claim 32 or 33, wherein the concentration of said at least one thickening agent in the formulation is up to about 0.2 wt%.

35. The ophthalmic formulation of any one of claims 28 to 34, further comprising at least one buffering agent.

36. The ophthalmic formulation of any one of claims 28 to 35, wherein the coronated swollen micelles are substantially mono-disperse.

37. A method of preparing the ophthalmic formulation of any one of claims 28 to 36, comprising mixing the concentrate of any one of claims 1 to 27 with an aqueous dispersing medium, thereby obtaining plurality of coronated swollen micelles formed from said concentrate and dispersed in an aqueous continuous phase formed from said aqueous dispersing medium.

38. The method of claim 37, wherein said aqueous dispersing medium comprises at least one thickening agent.

39. The method of claim 37 or 38, wherein said aqueous dispersing medium comprises at least one buffering agent.

40. The method of any one of claims 37 to 39, wherein said concentrate is mixed with said aqueous dispersing medium in a weight ratio ranging between about 1:8 and about 1: 10.

41. The method of any one of claims 37 to 40, wherein said mixing is carried out under conditions preventing development of high shear forces in the mixture.

42. A kit for preparing the ophthalmic formulation of any one of claims 28 to 36, comprising: at least one first container containing the concentrate composition of any one of claims 1 to 27; at least one second container containing an aqueous dispersing medium; and instructions for use.

43. The kit of claim 42, wherein said aqueous dispersing medium comprises at least one thickening agent.

44. The kit of claim 42 or 43, wherein said aqueous dispersing medium comprises at least one buffering agent.

45. The kit of any one of claims 42 to 44, wherein said first container and said second container are integrally formed and configured for mixing said concentrate and aqueous dispersing medium upon user demand.

46. An ophthalmic formulation according to any one of claims 28 to 36, for use in treating a back of the eye disease or condition.

47. The ophthalmic formulation for use of claim 46, wherein said back of the eye disease or condition is selected from dry age-related macular degradation, wet age-related macular degradation, diabetic retinopathy and conditions associated therewith (such as non-proliferative diabetic retinopathy, proliferative retinopathy, maculopathy, vitreous hemorrhage, macular edema), retinal vascular occlusion, and malignant retinal diseases (such as ocular melanoma and retinoblastoma).

48. A method of treating a back of the eye disease or condition, comprising administering an effective amount of an ophthalmic formulation according to any one of claims 28 to 36 to a subject in need thereof.

49. The method of claim 48, wherein said back of the eye disease or condition is selected from dry age-related macular degradation, wet age-related macular degradation, diabetic retinopathy and conditions associated therewith (such as non-proliferative diabetic retinopathy, proliferative retinopathy, maculopathy, vitreous hemorrhage, macular edema), retinal vascular occlusion, and malignant retinal diseases (such as ocular melanoma and retinoblastoma).

Images