Patent Description:
Laquinimod is a synthetic quinoline carboxamide with high oral bioavailability that has been suggested as an oral formulation for the treatment of e.g. multiple sclerosis (MS). Laquinimod and pharmaceutically acceptable salts thereof have been described in <CIT>.

The use of laquinimod in the treatment of eye diseases, such as glaucoma, inflammatory eye diseases and diseases associated with excessive vascularisation of the eye has been previously disclosed. Thus, laquinimod for use in the treatment of glaucoma was disclosed in the international application No. <CIT>, published as <CIT>. <CIT>, published as <CIT>, discloses the treatment of ocular inflammatory diseases by use of laquinimod. The use of laquinimod for the treatment of diseases associated with excessive vascularisation of the eye is disclosed in the international application No. <CIT>, published as <CIT>. For each type of ocular disease, laquinimod is proposed to be administered systemically or topically, and in the latter case, ocular or ophthalmic administration is mentioned.

However, several challenges must be overcome in connection with topical ocular formulations and their effective use in the treatment of an eye disorder, in particular a disorder affecting the posterior parts of the eye. Indeed, treatment of disorders where the drug must reach the posterior parts of the eye is often hampered by inefficient delivery of the active agent to the target site, largely due to the corneal barrier with its several compartments of opposite lipophilic or hydrophilic nature.

Provided herein is a pharmaceutical formulation as defined in the claims, comprising laquinimod or a pharmaceutically acceptable salt thereof for use in the treatment of an ocular disease.

The formulation provided herein is useful in a method of treating a subject suffering from an ocular disease, the method comprising local, preferably topical, administration to the eye of the subject of the formulation as described herein, containing a therapeutically effective amount laquinimod or a pharmaceutically acceptable salt thereof effective to treat the subject.

One aspect therefore relates to a pharmaceutical formulation as defined in the claims, for local, preferably topical, administration to the eye of a patient (local ocular use, or topical ocular use), comprising a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof, as a therapeutically active agent.

Thus, in one aspect, a pharmaceutical formulation for ocular administration is provided, said formulation comprising, in an aqueous phase:.

In a further aspect, a pharmaceutical formulation is provided, for ocular administration of laquinimod or a pharmaceutically acceptable salt of laquinimod, said formulation having a viscosity of <NUM> mPas to <NUM> mPas, as measured at <NUM>, an osmolality of <NUM> mOsm/kg to <NUM> mOsm/kg, and a pH of <NUM> to <NUM>.

In some embodiments, therefore, the pharmaceutical formulation for ocular administration comprises:.

In some embodiments, the formulation further comprises one or more components selected from (vii) a pharmaceutically acceptable preservative, (viii) a pharmaceutically acceptable surfactant (surface active agent), (ix) a pharmaceutically acceptable solubilizer, and (x) a pharmaceutically acceptable oil.

The formulation may be in the form of a gel or a water and oil containing emulsion (i.e. an oil-in-water emulsion, or a water-in-oil emulsion), containing laquinimod or a pharmaceutically acceptable salt of laquinimod in the form of solute and/or suspended particles.

Thus, in some embodiments, the formulation is an oil-in-water emulsion, comprising a pharmaceutically acceptable oil and an aqueous phase in the form of a suspension or solution of laquinimod or a pharmaceutically acceptable salt of laquinimod.

In some further embodiments, the formulation is a water-in-oil emulsion, comprising an aqueous phase in the form of a suspension or solution of laquinimod or a pharmaceutically acceptable salt of laquinimod, in a pharmaceutically acceptable oil phase. Preferably, the emulsion provided herein is an oil-in-water emulsion.

In some further embodiments, the formulation is a solution or suspension of laquinimod or a pharmaceutically acceptable salt of laquinimod, the formulation being a viscous gel.

The pharmaceutical formulation provided herein is useful for the treatment of various ocular diseases, e.g. glaucoma, ocular inflammatory diseases and diseases associated with excessive vascularisation of the eye.

In some embodiments, a pharmaceutical formulation is provided herein for the treatment of glaucoma. In some further embodiments, an ocular formulation is provided herein for the treatment an ocular inflammatory disease. In some further embodiments, an ocular formulation is provided herein for the treatment of a disease associated with excessive vascularisation of the eye.

In some embodiments, the ocular disease is one affecting the intermediary or posterior parts of the eye.

An advantageous feature of the formulation is a high stability against chemical degradation of laquinimod or the pharmaceutically acceptable salt of laquinimod present in the formulation.

A further advantageous feature of the formulation is a high homogeneity throughout the formulation.

A further advantageous feature is its capacity of containing a wide range of concentrations of laquinimod or a pharmaceutically acceptable salt of laquinimod.

A further advantageous feature of the formulation is a high delivery of the therapeutically active agent, across the cornea of the eye, advantageously allowing for local (e.g. topical) administration of laquinimod to the eye of a subject.

A further advantageous aspect is a high efficacy of laquinimod when administered locally, e.g. topically, to the eye of a patient, e.g. at a level comparable to that obtained by oral administration. Local administration of a drug may advantageously avoid unwanted systemic effects. Thus, one aspect is a pharmaceutical formulation for ocular use comprising, in an aqueous phase:.

A further aspect is a dosage container containing the pharmaceutical ocular formulation as provided herein. Thus, also provided herein is a dosage container containing a pharmaceutical formulation for ocular administration, comprising:.

The pharmaceutically acceptable pH regulating agent preferably is present in an amount providing a pH of at least <NUM> in the formulation.

A further aspect is a kit comprising a dosage container as mentioned herein, and instructions for use.

The inventive formulation is useful in the manufacture of a medicament for the treatment of an ocular disorder, e.g. an ocular disorder selected from glaucoma, an ocular inflammatory disease, and a disease associated with excessive vascularization of the eye.

Advantageously, a formulation as disclosed herein provides a means for local administration, preferably topical administration, of laquinimod to the eye of a patient (a mammal, such as an animal or human, preferably a human) with few or low (acceptable) side effects, such as stinging of the eye, temporarily blurred vision, and/or tearing of the eye.

Thus, a pharmaceutical, preferably topical, formulation of laquinimod or of a pharmaceutically acceptable salt of laquinimod is provided herein, allowing for the treatment of an eye disease by ocular administration, to a mammal, e.g. a human, in need of such treatment.

Further aspects and advantageous embodiments will become apparent from the following detailed description and examples.

Unless defined otherwise or clearly indicated by context, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the field of art to which this disclosure belongs. However, definitions of some of the terms used herein will be given herein below.

Unless otherwise specified or apparent from the context, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" generally means one element or more than one element.

As used herein, "API" stands for "active pharmaceutical ingredient", which in connection with the present disclosure is laquinimod or a pharmaceutically acceptable salt of laquinimod.

As used herein "autoimmune disease-associated ocular inflammation" is the inflammation affecting one or more parts of the eye or surrounding eye tissue secondary to an autoimmune disease.

The term "autoimmune disease" includes cell-mediated (e.g., T-cell) as well as antibody mediated (e.g., B-cell) disorders. Such disorders can be inter alia arthritic conditions, demyelinating diseases, and inflammatory diseases. For example, the autoimmune disease can be multiple sclerosis, autoimmune hemolytic anemia, autoimmune oophoritis, autoimmune thyroiditis, autoimmune uveoretinitis, Crohn's disease, chronic immune thrombocytopenic purpura, colitis, contact sensitivity disease, diabetes mellitus, Grave's disease, Guillain-Barré syndrome, Hashimoto's disease, idiopathic myxedema, myasthenia gravis, psoriasis, pemphigus vulgaris, rheumatoid arthritis, or systemic lupus erythematosus.

The term "carbomer copolymer type B" refers to a high molecular weight copolymer of acrylic acid and a long chain alkyl methacrylate cross-linked with allyl ethers of polyalcohols. It is typically used as a thickening agent, stabilizer and emulsifier in various pharmaceutical formulations.

The term "dosage container" as used herein refers to a container, such as a bottle, vial, tube, flask etc, suitable to contain a volume of the formulation as provided herein, either a volume corresponding to a unit (single), or a volume corresponding to more than one dose (multidose). The dosage container may include means allowing for application of a suitable amount of the formulation to an eye of a patient, or such means may be provided separately from the container.

As used herein, "effective" as in an amount effective to achieve an end, i.e., "therapeutically effective amount", means the quantity of a component that is sufficient to yield an indicated therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this disclosure. An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated.

The term "excipient" refers to a pharmaceutically acceptable chemical, such as known to those of ordinary skill in the art of pharmacy to aid in the administration of the medicinal agent. It is a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.

The term "extent" as used in relation to vascularization, is taken to mean the severity of the vascularisation. Such extent of vascularisation can be assessed using several different measurable parameters, such as the area of vascularisation, the number of vessels in the vascularised area, the length of the vessels in the vascularised area, or the thickness of the vessels in the vascularised area.

The term "humectant" refers to a hydrophilic compound capable of retaining moisture in a formulation.

The term "laquinimod" refers to the compound <NUM>-chloro-N-ethyl-<NUM>-hydroxy-<NUM>-methyl-<NUM>-oxo-N-phenyl-<NUM>,<NUM>-dihydroquinoline-<NUM>-carboxamide, having the structural formula:
<CHM>.

Unless otherwise specified or apparent from the context, the term laquinimod includes the free base form of the compound as well as its salt form.

The term "macrogol <NUM> hydroxystearate" refers to a mixture of mainly monoesters and diesters of <NUM>-hydroxystearic acid and macrogols obtained by the ethoxylation of <NUM>-hydroxystearic acid. Macrogol <NUM> hydroxystearate is also known as <NUM>-hydroxyoctadecanoic acid polymer with α-hydro-ω-hydroxypoly(oxy-<NUM>,<NUM>-ethanediyl); <NUM>-hydroxystearic acid polyethylene glycol copolymer; macrogol <NUM> hydroxystearate; polyethylene glycol-<NUM>-hydroxystearate; and polyethylene glycol <NUM><NUM>-hydroxystearate. In some embodiments, the macrogol <NUM> hydroxystearate is Kolliphor® HS <NUM> (BASF AG, Germany). Kolliphor® HS <NUM> consists of polyglycol mono- and di-esters of <NUM>-hydroxystearic acid and about <NUM>% free polyethylene glycol.

The term "mammal" refers to a human or any mammalian animal, e.g. a primate, a farm animal, a pet animal, or a laboratory animal. Examples of such animals are monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice, rats etc. Preferably, the mammal is a human.

The term "surfactant" refers to an organic chemical compound capable of lowering the surface tension (or interfacial tension) between two liquids, between a gas and a liquid, or between a liquid and a solid. A surfactant is an amphiphilic compound, i.e. a compound that contains a hydrophobic moiety ("the hydrophobic tail") as well as a hydrophilic moiety (the "hydrophilic head" or "polar head"). Most commonly, surfactants are classified according to the hydrophilic head. A "non-ionic surfactant" has no electrically charged groups in its head; the hydrophilic head of a "cationic surfactant" carries a net positive electrical charge, and the hydrophilic head of an "anionic surfactant" carries a net negative electrical charge.

The term "tonicity adjusting agent" (or alternatively "tonicity agent"), as used herein, refers to a compound that contributes to the osmolality of a solution. The osmolality of an ocular formulation is preferably adjusted to minimize discomfort to the patient upon ocular administration.

As used herein, the expression "ocular administration" or "ophthalmic administration" etc, of a formulation refers to application of a formulation to the eye of a subject.

The expression "ocular formulation", "ophthalmic formulation" etc as used herein refers to a pharmaceutical composition formulated for administration to the eye of a subject.

As used herein, the term "ocular disease" (which term is considered herein to be synonymous with "ocular disorder", "eye disease", or "eye disorder") refers to a disease affecting the eye of a mammal subject, i.e. an animal or a human, preferably a human.

"Ocular inflammatory disease" or "OID" as used herein means the inflammation affecting one or more parts of the eye or surrounding eye tissue. OlD may include, but is not limited to, inflammation of the orbital tissues, the lacrimal apparatus, the eyelid, the conjunctiva (conjunctivitis), the cornea, the retina, a component of the optic pathway, e.g., the optic nerve, and a component of the uveal tract (uveitis), i.e., the iris, ciliary body and choroid. Specific examples of OlD include uveitis, acute conjunctivitis, viral conjunctivitis, nongonococcal bacterial conjunctivitis, adult gonococcal conjunctivitis, inclusion conjunctivitis, seasonal allergic conjunctivitis, chronic conjunctivitis, granular conjunctivitis, perennial allergic conjunctivitis, episcleritis, scleritis, atopic keratoconjunctivitis, and vernal keratoconjunctivitis.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

The term "pH regulating agent" refers generally to a compound or mixture of compounds, capable of changing and/or maintaining the pH of an aqueous phase. A common example of a pH regulating agent is a pH buffer (or buffering agent).

By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.

The term "polyoxyethylene-polyoxypropylene block copolymer" refers to poloxamers of <NPL>, including salts and known equivalents thereof. Examples of poloxamers are poloxamer <NUM> and poloxamer <NUM>.

The term "polyoxyl castor oil", (also sometimes referred to as ethoxylated castor oil, or polyethylene glycol castor oil) of <NPL>, mixture of triricinoleate esters of ethoxylated glycerol with small amounts of polyethylene glycol ricinoleate and the corresponding free glycols. It is a nonionic surfactant, which may be used as emulsifying agent or solubilising agent. The mixture may also be referred to as polyoxyl n castor oil, where n represents the number of oxyethylene units in the compound. An example of a commercially available product is Kolliphor® EL, which is polyoxyl <NUM> castor oil.

The term "polysorbate <NUM>" refers to the compound of <NPL>, also known as polyoxyethylene (<NUM>) sorbitan monooleate, sorbitan monooleate ethoxylate, and the like, as well as salts and known equivalents thereof.

A "preservative", as used herein, refers to an additive which inhibits both microbial growth and kills microorganisms that contaminate a formulation exposed to the surroundings.

The term "solubilizing agent" (or alternatively "solubilizer") refers to a compound that, when added to a solvent phase or formulation, is capable of increasing the solubility of another compound in said solvent phase or formulation.

The term "solubilizing effective amount" of a substance ("solubilizer") within a formulation refers to an amount of the substance sufficient to solubilize another component of the composition. For example, an "API-solubilizing effective amount" is an amount sufficient to solubilize an API (which in the present case is laquinimod or a pharmaceutically acceptable salt thereof) such that the API is more therapeutically effective as compared to the absence of the solubilizer. In some embodiments an "API-solubilizing effective amount" is an amount sufficient to solubilize an API such that the API is more therapeutically effective as compared to the absence of the solubilizer in an ocular (ophthalmic) formulation, e.g. a topical ocular formulation.

As used herein, "treating" encompasses, e.g., inducing inhibition, regression, or stasis of a disease, disorder or condition, or ameliorating or alleviating a symptom of a disease, disorder or condition. "Ameliorating" or "alleviating" a condition or state as used herein shall mean to relieve or lessen the symptoms of that condition or state. "Inhibition" of disease progression or disease complication in a subject as used herein means preventing or reducing the disease progression and/or disease complication in the subject.

The term "unit dose" as used herein is the amount of the inventive formulation to be administered to the subject in a single administration, or the amount of laquinimod, or salt of laquinimod contained in said amount of the inventive formulation. The unit dose disclosed herein can be administered once daily, twice daily, three times daily, four times daily, five times daily, every other day, weekly, twice weekly, three times weekly, four times weekly, five times weekly or six times weekly.

By "vascularisation" and "neovascularisation" is meant a process by which new blood vessels form. The terms "vascularisation" and "neovascularisation" are used interchangeably herein.

As used herein, the expression "vascularisation of the eye" is synonymous to ocular neovascularisation.

By "excessive vascularisation" is meant an event wherein vascularisation occurs to an extent that is deleterious to the normal functioning of the affected tissue. Such excessive vascularisation occurs during or as an effect of eye diseases or eye disorders such as corneal neovascularisation, neovascularisation of the iris, neovascularisation of the ciliary body, corneal pannus, choroidal neovascularisation, proliferative diabetic retinopathy, retinopathy of prematurity, ischemic retinopathy, retinal neovascularisation, hypertensive retinopathy, and wet age-related macular degeneration.

In the context of the present disclosure, the terms "an ocular disease or ocular disorder associated with excessive vascularisation of the eye" and "an ocular disease or ocular disorder associated with vascularisation of the eye" are taken to mean any ocular disease or ocular disorder which is considered by those of skill in the art to be caused by, and/or affect vascularisation of one or more tissues of the eye, e.g. in which said vascularisation is deleterious to the normal functioning of the affected tissue. Such diseases or disorders can lead to loss of vision.

The term "viscosity" as used herein refers to the dynamic viscosity.

The term "viscosity agent" (which in the technical field of the invention may also be referred to as viscosity enhancing agent, viscosity enhancer, viscosity modifying agent, viscosity imparting agent, thickening agent, thickener etc.) refers to an agent capable of increasing the viscosity of a liquid when admixed with the liquid.

Provided herein is a pharmaceutical formulation for ocular administration comprising, in an aqueous phase:.

The ocular (e.g. topical ocular) formulation provided herein is a pharmaceutical formulation and comprises laquinimod or a pharmaceutically acceptable salt thereof at a concentration suitable to provide a therapeutically effective amount of laquinimod or pharmaceutically effective amount by administration to the eye (ocular administration), preferably by topical adminstration to the eye, e.g. as an eye drop formulation.

In some embodiments, laquinimod is present in the free base form (i.e. non-salt form). In other embodiments, the formulation comprises a pharmaceutically acceptable salt of laquinimod, e.g. a metal salt, e.g. a salt comprising a metal selected from lithium, sodium, potassium, magnesium, calcium, manganese, copper, zinc, aluminum and iron. In some embodiments, the pharmaceutically acceptable salt of laquinimod is laquinimod sodium.

In some embodiments, the concentration of laquinimod in the formulation is about <NUM>/l to about <NUM>/l (or a corresponding concentration of a pharmaceutically acceptable salt of laquinimod), e.g. about <NUM> to about <NUM>/l, or about <NUM> to about <NUM>/l, or about <NUM> to about <NUM>/l.

In some embodiments, the concentration of laquinimod in the formulation is within the range of <NUM> to <NUM>/l, <NUM>/l to <NUM>/l, or <NUM> to <NUM>/l. In some embodiments, the concentration of laquinimod in the formulation is within the range of <NUM> to <NUM>/l, <NUM> to <NUM>/l, or <NUM> to <NUM>/l. In some embodiments, the concentration of laquinimod in the formulation is within the range of <NUM> to <NUM>/l, e.g. <NUM> to <NUM>/l, or <NUM> to <NUM>/l.

In some embodiments, the concentration of laquinimod in the formulation is within the range of <NUM> to <NUM>/l, <NUM> to <NUM>/l, or <NUM> to <NUM>/l.

In some embodiments, the concentration of laquinimod in the formulation is within the range of <NUM> to <NUM>/l, <NUM> to <NUM>/l, <NUM> to <NUM>/l, <NUM> to <NUM>/l, <NUM> to <NUM>/l, <NUM> to <NUM>/l, <NUM> to <NUM>/l, <NUM> to <NUM>/l, <NUM> to <NUM>/l, or <NUM> to <NUM>/l.

In some embodiments, the concentration of laquinimod in the formulation is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l. In some embodiments, the concentration of laquinimod is <NUM>/l.

As used herein "g/l" designates the amount (g) of laquinimod (as a free base or in the form of a pharmaceutically acceptable salt), per volume (I) of formulation. It is noted that the concentration may also be expressed in mg/ml, <NUM>/l being equivalent to <NUM>/ml. Unless otherwise specified or apparent from the context, the indicated amount refers to the free base form, and the person of ordinary skill will be well capable of calculating the corresponding concentration or amount of a salt of laquinimod, if such is used.

In the pharmaceutical formulation provided herein, laquinimod will have a high stability against chemical decomposition (or "degradation"), e.g. by oxidation, which advantageously allows for a long shelf life. Thus, in some advantageous embodiments, the amount of oxidation decomposition product present in the composition is not more than <NUM>% w/w relative to the amount of laquinimod or, more preferably is not more than <NUM>% w/w even more preferably is not more than <NUM>% w/w, or is undetectable, e.g. after a period of at least <NUM> months, preferably at least <NUM> months, more preferably at least <NUM> year, even more preferably at least <NUM> years, e.g. when kept at room temperature (about <NUM>-<NUM>) in a sealed container suitable for pharmaceutical formulations.

The formulation provided herein has a (dynamic) viscosity of from about <NUM> mPas to about <NUM> mPas when measured at a temperature of <NUM> using a method as described herein, (the falling ball method). In some embodiments, the viscosity ranges from about <NUM> mPas to about <NUM> mPas, from about <NUM> mPas to about <NUM> mPas, from about <NUM> mPas to about <NUM> mPas, from about <NUM> mPas to about <NUM> mPas, from about <NUM> mPas to about <NUM> mPas, from about <NUM> mPas to about <NUM> mPas, from about <NUM> mPas to about <NUM> mPas, from about <NUM> mPas to about <NUM> mPas, from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, e.g. from about <NUM> mPas to about <NUM> mPas.

In some of these embodiments, the viscosity is at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, or at least <NUM> mPas.

In some of these embodiments, the viscosity is at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, at most <NUM> mPas, or at most <NUM> mPas.

For example, in some embodiments, the viscosity is within a range of from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas. In some of these embodiments, the viscosity is at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, or at least <NUM> mPas.

Thus, in some embodiments, the viscosity of the formulation is within a range of from about <NUM> mPas to about <NUM> mPas, or about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas.

In some further embodiments, the viscosity of the formulation is within a range of from about <NUM> mPas to about <NUM> mPas, or about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas. In some of these embodiments, the viscosity is at least <NUM> mPas, at least <NUM> mPas, at least <NUM> mPas, or at least <NUM> mPas.

Thus, in some further embodiments, the viscosity of the formulation is within a range of from about <NUM> mPas to about <NUM> mPas, or about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas.

In some further embodiments, the viscosity of the formulation is within a range of from about <NUM> mPas to about <NUM> mPas, or about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas, or from about <NUM> mPas to about <NUM> mPas.

The herein indicated viscosity is the dynamic viscosity as measured at a temperature of <NUM>, e.g. using a falling ball viscometer as described herein.

The formulation comprises one or more pharmaceutically acceptable viscosity agents.

Suitable viscosity agents for use herein include polyvinyl alcohol, poly(acrylic acid) homo- or copolymers (carbomers), and various cellulose-based polymers, e.g. hydroxypropylmethylcellulose and sodium carboxymethyl cellulose.

In some embodiments, the pharmaceutically acceptable viscosity agent comprises one or more of the group consisting of polyvinyl alcohol, poly(acrylic acid) homo- or copolymers (carbomers), polyvinylpyrrolidone, and cellulose derivatives, such as hydroxypropylmethylcellulose and sodium carboxymethyl cellulose.

In some embodiments, the viscosity agent is selected from cellulose-based polymers, polyvinyl alcohol, and poly(acrylic acid) homo- and copolymers, and combinations thereof.

In some embodiments, the viscosity agent comprises a cellulose-based polymer (or cellulose derivative), such as hydroxypropylmethylcellulose or sodium carboxymethyl cellulose, e.g. the viscosity agent comprises sodium carboxymethyl cellulose. In some embodiments, the viscosity agent comprises a polyvinyl alcohol. In some embodiments, the viscosity agent comprises a poly(acrylic acid) homopolymer. In some embodiments, the viscosity agent comprises a poly(acrylic acid) copolymer.

In a carbomer as used herein, the polymer may be a homopolymer of acrylic acid, or may be crosslinked with an allyl ether of pentaerythritol, allyl ether of sucrose, or allyl ether of propylene. In some embodiments, the carbomer is a homopolymer of acrylic acid, (a carbomer homopolymer, e.g. carbomer homopolymer type B). In some other embodiments, the carbomer is a crosslinked copolymer.

The viscosity agent (which term may refer to either one particular viscosity agent or a mixture of such agents) is present in a total amount sufficient to provide the desired viscosity in the formulation, i.e. a viscosity within the ranges as mentioned herein above. As will be apparent to the person of ordinary skill in the art, the exact amount will vary as a function of the particular viscosity agent(s) selected, and furthermore will depend on the other ingredients in the formulation, and the concentrations of these other ingredients. The person of ordinary skill in the art will be able to determine the required amount of viscosity agent in light of the present description and illustrating examples provided herein.

It has been noted that the viscosity of the formulation has a tendency to decrease when the concentration of laquinimod is increased, and the amount of any given viscosity agent will generally have to be determined and adjusted depending on in particular the laquinimod concentration of the formulation.

Lachrymal fluid is isotonic with blood having an isotonicity value corresponding to that of a <NUM>% NaCl solution. Ideally, therefore, an ophthalmic formulation will be isotonic with lachrymal fluid, though a tonicity ranging from about that of a <NUM>% NaCl solution to a <NUM>% NaCl solution is generally tolerable to the eye. In case a small volume of an ocular formulation is administered, the tonicity may deviate from within this range, because dilution with lachrymal fluid may quickly reduce discomfort. Preferably, though the formulation should be approximately isotonic. The formulation provided herein comprises a pharmaceutically acceptable tonicity adjusting agent, preferably a non-ionic tonicity adjusting agent, e.g. one or more compounds selected from mannitol, sorbitol, glycerol, polyethylene glycol (PEG), polypropylene glycol (PPG), and sorbitol, although the tonicity agent is not limited to this selection, as other alternative tonicity agents are well-known within the technical field. A preferred non-ionic tonicity adjusting agent is mannitol.

In some embodiments, the tonicity adjusting agent comprises mannitol. In some embodiments, the tonicity adjusting agent is mannitol.

In some embodiments, the tonicity adjusting agent (e.g. mannitol), is present in the formulation at a concentration of about <NUM> to about <NUM>/l of formulation, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, or about <NUM> to about <NUM>/l.

In some embodiments, the tonicity adjusting agent (e.g. mannitol), is present in the formulation at a concentration of about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, or about <NUM> to about <NUM>/l.

Ideally, a pharmaceutical formulation for ocular administration should preferably have an osmolality within a range of <NUM> to <NUM> mOsm/kg, in order not to cause discomfort on application to the eye, though values somewhat outside this range may be tolerated in case the amount of formulation applied to the eye is small.

In some embodiments, the formulation of the invention has an osmolality within a range of about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg.

In some embodiments, the formulation of the invention has an osmolality within a range of about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg.

In some embodiments, the formulation of the invention has an osmolality within a range of about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg.

In some embodiments, the formulation of the invention has an osmolality within a range of about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg.

In some embodiments, the formulation of the invention has an osmolality within a range of about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg.

In some embodiments, the formulation of the invention has an osmolality within a range of about <NUM> to about <NUM> mOsm/kg, about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg, or about <NUM> to about <NUM> mOsm/kg, e.g. about <NUM> mOsm/kg.

The formulation of the invention comprises a humectant (within the technical field also sometimes referred to as "wetting agent"), e.g. a polyol, such as a C3-C6 polyol, e.g. a C3-C5 polyol, or a C3-C4 polyol, such as sorbitol, xylitol, or glycerol, or a mixture of one or more such polyols. Preferably, the humectant comprises glycerol. In some embodiments, the humectant is glycerol.

In some embodiments, the humectant (e.g. glycerol), is present in the formulation at a concentration of about <NUM> to about <NUM>/l of formulation, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, or about <NUM> to about <NUM>/l. In some embodiments, the humectant (e.g. glycerol), is present in the formulation at a concentration of about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to <NUM>/l, or about <NUM> to <NUM>/l. In some embodiments, the humectant (e.g. glycerol), is present in the formulation at a concentration of about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to <NUM>/l, or about <NUM> to <NUM>/l. In some embodiments, the humectant is present in the formulation at a concentration of about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, or about <NUM> to about <NUM>/l, e.g. about <NUM>/l. In some embodiments, the humectant (e.g. glycerol), is present in the formulation at a concentration of about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, about <NUM> to about <NUM>/l, or about <NUM> to about <NUM>/l.

In order to protect in particular laquinimod from chemical degradation, the formulation contains a pharmaceutically acceptable antioxidant, such as the disodium salt of ethylenediaminetetraacetic acid (EDTA).

In some embodiments, the pharmaceutically acceptable antioxidant comprises disodium salt of ethylenediaminetetraacetic acid (EDTA). In some embodiments, the pharmaceutically acceptable antioxidant is disodium salt of ethylenediaminetetraacetic acid (EDTA).

In some embodiments, the concentration of the antioxidant in the formulation is withing the range of about <NUM>/l to about <NUM>/l, about <NUM>/l to about <NUM>/l, or about <NUM>/l to about <NUM>/l. In some embodiments, the concentration of the antioxidant is withing the range of about <NUM>/l to about <NUM>/l, about <NUM>/l to about <NUM>/l, or about <NUM>/l to about <NUM>/l. In some embodiments, the concentration of the antioxidant is withing the range of about <NUM>/l to about <NUM>/l, about <NUM>/l to about <NUM>/l, or about <NUM>/l to about <NUM>/l.

The amount of antioxidant present in the formulation will generally depend on the amount of laquinimod contained therein. In some embodiments, the formulation may contain antioxidant in a weight ratio to laquinimod (weight of antixodiant : weight of laquinimod) in a range of about <NUM>:<NUM> to about <NUM>:<NUM>, about <NUM>:<NUM> to about <NUM>:<NUM>, about <NUM>:<NUM> to about <NUM>:<NUM>, or about <NUM>:<NUM> to about <NUM>:<NUM>; e.g. about <NUM>:<NUM> to about <NUM>:<NUM>, about <NUM>:<NUM> to about <NUM>:<NUM>, about <NUM>:<NUM> to about <NUM>:<NUM>, about <NUM>:<NUM> to about <NUM>:<NUM>, or about <NUM>:<NUM> to about <NUM>:<NUM>, such as about <NUM>:<NUM>.

It is preferred that the pH regulation agent be present in the formulation in an amount sufficient to provide a pH of at least <NUM> in the formulation. Preferably, the formulation provided herein has a pH of from about <NUM> to about <NUM>, e.g. a pH of from <NUM> to <NUM>, or a pH of from <NUM> to <NUM> (when measured at a temperature of <NUM>). In some embodiments, the pH is at most <NUM>. For example, in some embodiments the formulation has a pH of from <NUM> to <NUM>, e.g. from <NUM> to <NUM>, or from <NUM> to <NUM>. In some embodiments, the pH is at most <NUM>. For example, in some embodiments the formulation has a pH of from <NUM> to <NUM>, e.g. from <NUM> to <NUM>. In some further embodiments, the formulation has a pH in the range of <NUM> to <NUM>, e.g. <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>. In some further embodiments, the formulation has a pH in the range of <NUM> to <NUM>, e.g. <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>. In some further embodiments, the formulation has a pH in the range of <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>. In some further embodiments, the formulation has a pH in the range of <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>. In some further embodiments, the formulation has a pH in the range of <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>. In some further embodiments, the formulation has a pH in the range of <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>. In some embodiments, the formulation has a pH of about <NUM>.

The formulation contains a pH regulating agent to provide a pH within the above-mentioned ranges. For example, the formulation may contain from about <NUM> to about <NUM>/l of pH regulating agent, e.g. about <NUM> to about <NUM>/l of pH regulating agent.

In some embodiments, the pH regulating agent comprises one or more pH buffering agents, e.g. selected from TRIS (tris(hydroxymethyl)aminomethane, IUPAC name: <NUM>-amino-<NUM>-(hydroxymethyl)propane-<NUM>,<NUM>-diol) and disodium hydrogen phosphate dihydrate. In some embodiments, the pH regulating agent comprises TRIS. In some embodiments, the pH regulating agent comprises disodium hydrogen phosphate dihydrate. In some embodiments, the pH regulating agent is TRIS. In some embodiments, the pH regulating agent is disodium hydrogen phosphate dihydrate.

If necessary, the pH of the formulation may also be adjusted by addition of a base or an acid, e.g. a strong base such as sodium hydroxide, or a strong acid, such as a hydrochloric acid, and optionally maintained at the desired pH by use of a suitable buffering agent, e.g. as mentioned herein above.

In some embodiments, the formulation comprises an API-preserving effective amount of a pharmaceutically acceptable preservative. In some embodiments, the formulation comprises a preservative selected from benzalkonium chloride and benzethonium chloride (IUPAC name: N-benzyl-N,N-dimethyl-<NUM>-{<NUM>-[<NUM>-(<NUM>,<NUM>,<NUM>-trimethylpentan-<NUM>-yl)phenoxy]ethoxy}ethanaminium chloride). In some embodiments, the preservative comprises is benzalkonium chloride. In some embodiments, the preservative comprises is benzalkonium chloride. Benzalkonium chloride (<NPL>) is a mixture of alkylbenzyldimethylammonium chlorides of the general formula
<CHM>
wherein n is an integer in the range of <NUM> to <NUM>.

The concentration of preservative may typically range from about <NUM>/l to about <NUM>/l, from about <NUM>/l to about <NUM>/l, from about <NUM>/l to about <NUM>/l, or from about <NUM>/l to about <NUM>/l. In some embodiments, the concentration of preservative is at most <NUM>/l. Thus, in some embodiments, the concentration of preservative is within the range from about <NUM>/l to about <NUM>/l, from about <NUM>/l to about <NUM>/l, from about <NUM>/l to about <NUM>/l, or from about <NUM>/l to about <NUM>/l.

In some embodiments, the formulation provided herein does not contain any preservative. For example, in some embodiments, when the formulation is provided in a single-use container (i.e. used at only one occasion), or a single-dose container (i.e. containing only one dose), a preservative may be omitted. In some of these embodiments, the formulation contains no preservative.

There are also multidose containers that obviate the need for a preservative, such as the Novelia® PFMD bottle sold by Nemera (France), and similar devices, such as a multidose container as described e.g. in the article "<NPL>). Thus, in some further embodiments, the formulation is a preservative-free formulation provided in a multidose container suitable for dispensing preservative-free formulations to the eye.

In some embodiments, the formulation additionally comprises a surfactant (surface active agent), preferably a nonionic surfactant. For example, the formulation may comprise a nonionic surfactant selected from a polysorbate, such as polysorbate <NUM>, and a poloxamer, such as poloxamer <NUM> or poloxamer <NUM>. In some embodiments, the formulation comprises polysorbate <NUM> as a surfactant.

In a formulation, e.g. a gel form formulation, as described herein, a suitable concentration of surfactant may range from e.g. <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l; from <NUM> to <NUM>/l, from <NUM> to <NUM>/l or from <NUM> to <NUM>/l. In some embodiments, in a formulation, e.g. a gel formulation, as described herein, a suitable concentration of surfactant is within the range of <NUM> to <NUM>/l, <NUM> to <NUM>/l, <NUM> to <NUM>/l or <NUM> to <NUM>/l; e.g. within the range of from <NUM> to <NUM>/l, <NUM> to <NUM>/l, <NUM> to <NUM>/l, or <NUM> to <NUM>/l. In some embodiments, a suitable concentration of surfactant in a gel formulation as described herein is within the range of from <NUM> to <NUM>/l, e.g. about <NUM>/l. In some of these embodiments, the surfactant is polysorbate <NUM>.

In an emulsion form formulation as described herein, the concentration of surfactant will generally be higher than in a gel formulation, and a suitable concentration of surfactant may range from e.g. <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, from <NUM> to <NUM>/l, or from <NUM> to <NUM>/l.

In some embodiments, the formulation provided herein does not contain any surfactant. In some embodiments, the formulation is a gel formulation that does not contain any surfactant.

In some embodiments, the formulation provided herein comprises a solubilizing effective amount of a pharmaceutically acceptable solubilizer (or solubilizing agent), such as macrogol <NUM> hydroxystearate, polyoxyl castor oil, polyvinylpyrrolidone or cyclodextrin (e.g. beta-cyclodextrin).

In some embodiments, the formulation contains cyclodextrin, e.g. beta-cyclodextrin, e.g. at a concentration in the range of from about <NUM> to about <NUM>/l, e.g. from <NUM> to <NUM>/l, or from <NUM> to <NUM>/l, for example from <NUM> to <NUM>/l, or from <NUM> to <NUM>/l.

In some embodiments, the formulation contains macrogol <NUM> hydroxystearate, e.g. at a concentration in in the range of from about <NUM> to <NUM>/l, e.g. from <NUM> to <NUM>/l, or from <NUM> to <NUM>/l, for example from <NUM> to <NUM>/l.

In some embodiments, the formulation contains polyoxyl castor oil, e.g. at a concentration in the range of from about <NUM> to about <NUM>/l, e.g. from <NUM> to <NUM>/l, or from <NUM> to <NUM>/l, for example from <NUM> to <NUM>/l.

In some embodiments, the formulation provided herein does not contain any solubilizing agent.

Finally, it is noted that that some constituents possess several functional attributes, and therefore may be present in the formulation of the invention in different capacities. For example, the person of ordinary skill in the art will know that carbomer copolymer (Type B) has been used in the field of pharmaceutical formulations as a thickening agent, as a gel-forming agent, as a stabilizer, and as an emulsifier. Likewise, polyoxyl castor oil has been applied as a nonionic solubilizer, but also as an oil-in-water emulsifier. Other components mentioned herein that have multiple applications are, for example macrogol <NUM> hydroxystearate (nonionic solubilizer, emulsifier), polyvinylpyrrolidone (solubilizer, viscosity enhancer) etc..

It is also noted that any functional agent as referred to herein (e.g. viscosity agent, tonicity agent, humectant etc) generally may comprise one or more compounds having the required functionality, i.e. unless otherwise specified or apparent from the context, the functional agent may consist of one such compound only, or may comprise a mixture of two or more such compounds.

In some embodiments, the formulation provided herein does not contain any of the optional components (vii) to (ix) or, if a gel formulation, does not contain any of the optional components (vii) to (x).

In some further embodiments, the formulation provided herein comprises:.

In some embodiments, the formulation for ocular administration comprises:.

In some embodiments, the formulation provided herein has a viscosity of about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, about <NUM> to <NUM> mPas, or about <NUM> to <NUM> mPas; an osmolality of about <NUM> to <NUM> mOsm/kg, about <NUM> to <NUM> mOsm/kg, about <NUM> to <NUM> mOsm/kg, or about <NUM> to <NUM> mOsm/kg; and a pH of about <NUM> to <NUM>, about <NUM> to <NUM>, about <NUM> to <NUM>, about <NUM> to about <NUM>, e. g about <NUM> to <NUM>.

In some embodiments, the formulation provided herein has a viscosity of about about <NUM> to <NUM> mPas; an osmolality of about <NUM> to <NUM> mOsm/kg; and a pH of about <NUM> to about <NUM>.

In some embodiments, the formulation provided herein has a viscosity of about <NUM> to <NUM> mPas; an osmolality of about <NUM> to <NUM> mOsm/kg; and a pH of about <NUM> to about <NUM>, e.g. about <NUM>.

In some embodiments, the formulation comprises:.

The formulation provided herein is either a gel formulation or a water and oil containing emulsion formulation. In some embodiments, the water and oil containing emulsion formulation is an oil-in-water emulsion. The water present in the formulation should be suitable for pharmaceutical use, such as distilled water, purified water, or water for injection.

In some embodiments, the water and oil containing emulsion formulation, e.g. an oil-in-water emulsion.

In a water and oil containing emulsion formulation, the oil is a pharmaceutically acceptable oil, e.g. an oil selected from vegetable oils, such as castor oil, maize oil, olive oil or camelina oil. In some embodiments, the oil is castor oil. Depending on whether the oil forms the outer phase or the inner phase, the proportion of the oil and the water phase will vary, as readily understood by the person of ordinary skill in the art. Thus, in a water-in-oil emulsion, the volume of oil will normally be higher than the volume of the aqueous phase, and vice versa for an oil-in water emulsion. It is considered that in an emulsion the inner phase (e.g. the oil phase) may be present in an amount of e.g. <NUM>-<NUM>/l, or from <NUM> to <NUM>/l, e.g. from <NUM> to <NUM>/l, such as about <NUM> to <NUM>/l.

In some embodiments, the formulation provided herein is a water and oil containing emulsion, preferably an oil-in-water emulsion, comprising:.

In some embodiments, the water and oil containing emulsion (preferably oil-in-water emulsion) comprises:.

In some embodiments, the water and oil containing emulsion (preferably oil-in-water emulsion), comprises:.

Some further emulsion formulations provided herein are as indicated in TABLES <NUM> to <NUM>.

In some embodiments, the formulation is a gel formulation. In some embodiments, the gel formulation comprises:.

In some embodiments, the gel formulation comprises:.

and optionally one or more components selected from:.

In some further embodiments, the gel formulation comprises:.

In some embodiments, the gel formulation for ocular administration, e.g. topical ocular administration, comprises:.

In some embodiments, the gel formulation, in addition to components (i) to (vi), further comprises:.

In some embodiments, the gel formulation provided herein does not contain any surfactant. In some embodiments, the gel formulation provided herein does not contain any solubilizing agent. In some embodiments, the gel formulation provided herein does not contain any preservative. In some embodiments, the gel formulation provided herein does not contain any of the optional components (vii) to (ix).

Some further gel formulations provided herein are as indicated in TABLES <NUM> to <NUM>.

Also provided herein is a process for preparing the formulations of the invention, comprising the general steps of:.

The formulation provided herein will be administered locally, preferably topically, to the eye of a patient, e.g. from a dosage container allowing for applying a small volume of the formulation to the eye, to allow for administration to an eye of e.g. <NUM>-<NUM> droplets having a droplet volume of <NUM>-<NUM>µl or <NUM>-<NUM>µl, or <NUM>-<NUM>µl e.g. <NUM>-<NUM>µl. In some embodiments, the formulation is applied from a single-dose container, or a single-use container. In some embodiments, the formulation is applied from a multidose container including the PureFlow® technology, as in the Novelia® multidose eye dropper, sold by Nemera (France).

Thus, in some embodiments, the formulation of the invention, advantageously free from any preservative, is provided in a multidose container having a valve construction allowing for effective protection of the formulation from microbial contamination, e.g. Novelia® multidose eye dropper.

The therapeutically effective amount of laquinimod may lie within the range of from <NUM>-<NUM> per administration (or an equivalent amount of a pharmaceutically acceptable salt of laquinimod). In some embodiments, the therapeutically effective amount of laquinimod is <NUM>-<NUM> per administration. In some embodiments, the therapeutically effective amount of laquinimod is about <NUM> per administration. In some embodiments, the therapeutically effective amount of laquinimod is about <NUM> per administration. In some embodiments, the therapeutically effective amount of is about <NUM> per administration. In some embodiments, the therapeutically effective amount of laquinimod is at least <NUM>/day. Preferably, the formulation provided herein will be periodically administered <NUM>-<NUM> times a day, e.g. <NUM>-<NUM> times a day, <NUM>-<NUM> times a day, or <NUM>-<NUM> times a day. In some embodiments, the periodic administration is once a day. In some embodiments, the periodic administration is twice a day. In some embodiments, the periodic administration is three times a day. In some embodiments, the periodic administration is once every <NUM> days. In some embodiments, the formulation is administered once a week.

In some embodiments, the formulation is administered once daily for a period of <NUM> to <NUM> days, or for a longer period, e.g. for a period of <NUM> month to <NUM> months, <NUM>-<NUM> months, or <NUM>-<NUM> months. In some embodiments, the formulation is administered once a day for a period of <NUM> days. In some embodiments, the formulation is administered once daily for a period of <NUM> to <NUM> days. In some embodiments, the formulation is administered once daily for a period of <NUM> to <NUM> days. In some embodiments, the formulation is administered once daily for about <NUM> days. In some embodiments, the formulation is administered for a period of <NUM>-<NUM> months, or for a period of <NUM>-<NUM> months, or for a period of <NUM>-<NUM> months, e.g. once a week for a period of <NUM>-<NUM> months. The precise dosage regiment and length of the treatment period however will normally be decided upon by the treating physician.

A further aspect is a dosage container, containing the laquinimod formulation as provided herein. The dosage container may be such as to include integral means to allow for administering a suitable dosage of the formulation to the eye of a patient, or such means may be provided separately. In some embodiments, the dosage container is a multidose container, allowing for the application of appropriate doses of the formulation to the eye of a patient. For example, in some embodiments, the dosage container is a bottle of the type sold by Nemera. In some embodiments, the dosage container is a Novelia® PFMD bottle or a bottle of similar type. In some of these embodiments, the formulation provided herein is preservative-free.

A further aspect is a kit (which may also be referred to as a kit-of-parts), comprising a dosage container as disclosed herein, and instructions for use. In some embodiments, such a kit also includes one or more additional containers, containing further appliances or materials useful in connection with the administration of the formulation, such as rinses, wipes, separate dosage means etc..

The ocular formulation disclosed herein is useful for the treatment of ocular diseases for which laquinimod provides a therapeutically beneficial effect, such as glaucoma, an ocular inflammatory disease, and a disease associated with excessive vascularization of the eye. In some embodiments, the OID is a disease affecting the intermediary or posterior parts of the eye.

The therapeutic activity of laquinimod in the treatment of such diseases has been described in patent documents referred to herein above.

In some embodiments, the ocular disease is an inflammatory ocular disease (OID). In some embodiments, the OID is selected from uveitis, bacterial conjunctivitis, viral conjunctivitis, or an inflammation of the orbital tissue, the lacrimal apparatus, the eyelid, the cornea, the retina or the optic pathway.

In some embodiments, the OID is selected from uveitis, acute conjunctivitis, viral conjunctivitis, nongonococcal bacterial conjunctivitis, adult gonococcal conjunctivitis, inclusion conjunctivitis, seasonal allergic conjunctivitis, chronic conjunctivitis, granular conjunctivitis, perennial allergic conjunctivitis, episcleritis, scleritis, atopic keratoconjunctivitis, and vernal keratoconjunctivitis.

In some embodiments, the OID is uveitis. Uveitis is the inflammation of the uvea or the uveal tract, which includes the iris, the ciliary body and the choroid portions of the eye. Inflammation of the overlying retina, called retinitis, or of the optic nerve, called optic neuritis, may occur with or without accompanying uveitis. Anatomically, uveitis may be classified as anterior, intermediate, posterior or diffuse, depending on the portion of the uveal tract that is affected. Anterior uveitis is localized primarily to the anterior segment of the eye and includes iritis and iridocyclitis. Intermediate uveitis, also called peripheral uveitis, is centered in the area immediately behind the iris and lens in the region of the ciliary body and pars plana, hence the alternate terms "cyclitis" and "pars planitis". Posterior uveitis signifies any of a number of forms of retinitis, choroiditis, or optic neuritis. Diffuse uveitis implies inflammation involving all parts of the eye, including anterior, intermediate, and posterior structures (<NPL>). Inflammation from uveitis may result in a variety of other eye conditions, including glaucoma, cataracts, and cystoid macular edema, and ultimately may lead to permanent vision loss.

In some embodiments, the uveitis is intermediate, posterior or diffuse uveitis. In some embodiments, the uveitis is posterior or diffuse uveitis. In some embodiments, the uveitis includes posterior uveitis. In some embodiments, the uveitis is posterior uveitis. In some embodiments, the uveitis is diffuse uveitis.

In some embodiments, the OID is a conjunctivitis. In some embodiments, the OID is associated with an autoimmune disease, such as multiple sclerosis, autoimmune hemolytic anemia, autoimmune oophoritis, autoimmune thyroiditis, autoimmune uveoretinitis, Crohn's disease, chronic immune thrombocytopenic purpura, colitis, contact sensitivity disease, diabetes mellitus, Grave's disease, Guillain-Barre's syndrome, Hashimoto's disease, idiopathic myxedema, myasthenia gravis, psoriasis, pemphigus vulgaris, rheumatoid arthritis, or systemic lupus erythematosus. In some embodiments, the OID is associated with Crohn's disease.

In some embodiments, the ocular disease is associated with excessive (or deleterious) vascularisation of the eye, e.g. in response to external stimuli to the eye, or as a natural result of age. The eye consists of many different tissues, such as the cornea, the iris, the ciliary body, the choroid, the retina, and the macula, which tissues may be subject to deleterious vascularisation. In some embodiments, the ocular disease is associated with excessive vascularisation of the cornea, the iris, the ciliary body, the choroid, the retina, and/or the macula. In some embodiments, the ocular disease is associated with excessive vascularisation of a tissue in an anterior part of the eye, such as the cornea, the iris, or the ciliary body.

In some embodiments the ocular disease is selected from the group consisting of corneal neovascularisation, neovascularisation of the iris, neovascularisation of the ciliary body, corneal pannus, choroidal neovascularisation, retinal neovascularisation, hypertensive retinopathy, wet age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic retinopathy.

In some further embodiments the ocular disease is associated with excessive vascularisation of a tissue in a posterior part of the eye, such as the choroid, the retina, or the macula.

In some embodiments, the ocular disease associated with excessive vascularisation is retinal neovascularisation. In some further embodiments, the ocular disease associated with excessive vascularisation is vascularisation of the macula, also known as wet age-related macular degeneration.

The following abbreviations may be used herein below:.

All excipients used for the formulations were sourced in a quality compliant with Unites States Pharmacopoeia (USP) and/or European Pharmacopeia (EP). The excipients were selected for ophthalmic administration. All chemicals used for analytical methods were sourced in a quality adequate for the individual method (e.g. pro analysis).

The formulations were prepared as follows: weighing of excipients, dissolution in water for injection (WFI) overnight at <NUM>-<NUM> on magnetic stirrer in about <NUM>% of final volume, adjustment of pH in formulations tempered to <NUM>-<NUM>, filling to final volume and dissolving of laquinimod. The pH adjustment in highly viscous formulations was carried out on day <NUM> and aliquotation of formulations and start of accelerated aging study was carried out on day <NUM>.

The weighing of excipients was done in a solubility-dependent order, meaning readily solubilized excipients were introduced first to the formulation preparation and excipients of low solubility, i.e. gelling agents were added last. In detail this process looked as follows: Providing of -<NUM>% of final volume with water (Aqua B. Braun, Braun) in non-sterile <NUM> PP-beakers (Sarstedt), stepwise supplementation of excipients as described above with stirring of formulation preparation in between steps with magnetic bar on stirrer (CIMARECi Poly, Thermo Scientific).

The adjustment of pH required the complete dissolving of all excipients, which was not readily achieved for every formulation even after overnight stirring due to excipients of low-solubility like Carbomer Type B being present in some of the formulations. Therefore, the formulations were inspected by eye after overnight stirring and if incomplete dissolution of excipients was detected a high-performance rod disperser (T <NUM> digital ULTRA-TURRAX®, IKA) fitted with dispersion tool (S <NUM> N - <NUM>, IKA) was applied to the formulation.

A sufficient volume of formulation was saved for placebo samples and laquinimod was dissolved in the gel formulations at <NUM>/ml using a vessel-fitted disperser (ULTRA-TURRAX® Tube Drive P control, IKA) equipped with single-use mixing vessels (DIS-<NUM>-S-M. <NUM>, IKA). Laquinimod and formulation were combined in the mixing vessel, the disperser set to <NUM> rpm and the formulation stirred for at least <NUM> or until laquinimod was completely dissolved as judged by eye.

In the case of emulsion formulations, the aqueous phase of the formulation was blended with the oil phase, i.e. castor oil was added after dissolving laquinimod in the aqueous phase. Hence, the volume of the aqueous phase was corrected for the volume of oil before laquinimod was dissolved like described before. Emulsification was achieved with the disperser set to stirring speeds yielding a vortex between stirrer and surface of the liquid (<NUM> rpm for <NUM> formulation, <NUM> rpm for <NUM> placebo). Stirring took place for <NUM> while the oil was added slowly to the aqueous solution over a period of -<NUM> seconds utilizing reverse-pipetting technique to account for the high viscosity of oil (<NUM>-<NUM>µl pipette, Eppendorf).

The adjustment of the final pH of all formulations and buffers as well as the pH measurement of the obtained formulations were performed with calibrated pH-electrode (VWR) connected to a SevenEasy pH-Meter (Mettler Toledo) at a temperature between <NUM> and <NUM> (compliant with both, EP and USP).

A manual filling procedure was performed using standard laboratory pipettes and sterile tips. Prior to filling, the formulations were mixed and emulsified, to ensure that the formulations were homogenous, and <NUM> of each formulation was transferred into sterile, particle-free 2R-vials (Adelphi) under a laminar air flow cabinet. The vials were closed with sterile FluroTec-coated (ethylene tetrafluoroethylene; ETFE) chlorobutyl stoppers (<NUM>; Adelphi) and crimped with suitable aluminum caps.

The analysis by RP-HPLC was externalized to EpiQMmax with the parameters shown in TABLE <NUM>.

Determination of osmolality was performed by freezing point depression in an osmometer (Osmomat <NUM>, Gonotec). The total osmolality of aqueous solutions is determined by comparative measurements of the freezing points of pure water and of solutions. Each measurement was performed in <NUM>µl aliquots after calibration with sodium chloride standard (<NUM> mOsm/kg) and purified water. The gels and emulsions were measured in <NUM> replicates, and <NUM> replicates if the deviation between duplicate measurements was ><NUM>%. Thereafter, the arithmetic mean and SD were calculated.

The particle sizes were determined by flow imaging analysis using a FlowCam <NUM> system, 10x Objective (ANASYSTA) with manual loading of samples. Particle size measurement was performed for formulations containing laquinimod (as API) at a concentration of <NUM>/ml. The acceptance criteria for sub-visible particle (SVP) determination are defined as follows: for every <NUM>µg of laquinimod, no more than <NUM> particles > <NUM>; no more than <NUM> particles > <NUM>; no particle > <NUM> (PhEur monograph "Eye preparations", dosage form monograph no. <NUM>, version <NUM>/<NUM>). The results were reported as particles/<NUM>µg laquinimod for each of the described particle filter groups.

Sample preparation for particle size measurement encompassed <NUM>:<NUM> dilution of samples with buffer solution of same pH, supersaturated with laquinimod. Sodium phosphate buffers with pH values of <NUM> and <NUM> and Tris buffers with pH values of <NUM> and <NUM> were prepared and laquinimod was added to the point of supersaturation before centrifuging at 2000xg for <NUM> and using the supernatant for sample dilution. Prior to diluting samples, a suitable amount of buffer was filtrated with syringe filter (<NUM> alumina membrane). The FlowCam <NUM> system was rinsed with water (Aqua B Braun) between replicate measurements and additionally with <NUM>% surfactant (Hellmanex®, Hellma Analytics) to prevent cross-contamination and ensure reproducibility between measurements.

Samples were visually controlled on changes during storage. Assessment was performed using an inspection light box equipped with non-flickering fluorescent lamps and a black and a white background plate. The samples were evaluated for <NUM> sec without magnification.

During characterization all samples (duplicates) were stored for up to two weeks at <NUM>, <NUM>, <NUM>, and <NUM> and protected from light and, in a follow-up experiment, at <NUM>, <NUM>, and <NUM>. The samples stored at <NUM> ± <NUM> were kept in refrigerator with external monitoring of the temperature. Samples subjected to an accelerated aging were stored in cabinets (Memmert) with controlled humidity at <NUM> ± <NUM> / <NUM> ± <NUM> % relative humidity (RH), at <NUM> ± <NUM> / <NUM> ± <NUM> % RH and at <NUM> ± <NUM> / <NUM> ± <NUM> % RH (ICH Q1 guideline), respectively. The temperature was monitored throughout the storage period.

Sample density was measured with a Gay-Lussac Pycnometer (Carl Roth) and a sample volume of <NUM> at room temperature (RT). The pycnometer was weighed using an analytical balance (SECURA <NUM>-<NUM>, Sartorius).

The dynamic viscosity of samples was measured with a falling ball viscometer Microviscometer Lovis <NUM> ME (Anton Paar) at <NUM>, or at both <NUM> and <NUM>, respectively, using capillaries of different diameters. The dynamic viscosity η of the respective samples was calculated based on the known density of the ball (ρb = <NUM>/cm<NUM>) and the measured sample density (ρs) as well as the characteristic constant of the capillary (C1), according to the equation: <MAT>.

The falling time (t1) was averaged from the last six individual measurements at an angle of the capillary of <NUM>°. In total, twelve measurements were taken, with the individual falling times reaching an equilibrium within the first six measurement cycles due to the polymeric nature of the samples.

The materials used in EXAMPLES <NUM>-<NUM>, as well as the supplier and article number of each material are listed in TABLE <NUM>.

Ten different formulations, viz. <NUM> emulsions (E1 and E2) and <NUM> gels (S1 to S8), were prepared using the method described herein above. The ingredients of the formulations are shown in TABLE <NUM>.

RP-HPLC analysis was performed after one and two weeks of storage at <NUM> and after <NUM> weeks at <NUM>, respectively. After two weeks at <NUM>, very low degradation of <NUM>% (in average) was observed, while at <NUM> the degradation was slightly higher (<NUM>% in average). The highest degradation (based on RP-HPLC peak area) was observed in emulsion formulations E1 and E2, with a decrease of relative area of the main peak of <NUM>% or higher compared to the initial concentration (t=<NUM>) (TABLE <NUM>).

For some of the formulations, some sedimentation was observed, and a sedimentation profile was determined by RP-HPLC. For this purpose, samples were taken at different height (<FIG>) before and after re-suspension. The absolute peak area of samples (after identical dilution) was compared (TABLE <NUM>).

As may be seen from TABLE <NUM>, the absolute peak areas of the main peak of all samples were similar before and after re-suspension. This indicates that visible particles represented only a very small portion of the total amount of laquinimod in the formulations. Therefore, it was concluded that laquinimod in supernatant must either be dissolved, or else suspended particles of laquinimod are small enough not to undergo sedimentation. The sediment was assumed to be an interaction between carbomer and laquinimod and to be influenced by pH. After the titration of formulation S1 from pH <NUM> to pH <NUM>, the sediment was cleared, which supported the assumption of a pH-dependent interaction between carbomer and laquinimod.

The samples were visually checked at each time point (<FIG>). At t = <NUM>, all gel formulations without laquinimod were optically clear, while the emulsion formulations were slightly turbid. After adding laquinimod, all gel formulations except S3 were turbid. The pH of formulation S3 was <NUM> which resulted in the complete dissolution of laquinimod. In formulation S8, even at t = <NUM> a slight sedimentation was observed.

During storage the emulsion formulations showed creaming at <NUM> and <NUM>, while at <NUM> and at <NUM> the emulsions broke (<NUM>: formulation E1; <NUM>: both, formulation E1 and E2). After re-suspension, all emulsions were visually homogenous again.

In all gel formulations, except in S3, sedimentation was observed. S1 showed the largest sediment, followed by S2 and S8. Only little sediment was observed in formulations S4, S5, S6 and S7. In formulations S5 and S6 the sediment could not be re-suspended completely, while the other gel formulations were homogenous after re-suspension. In formulations S4 and S7 almost no sediment was observed, which suggests that the beta-cyclodextrin in formulation S4 and the Polysorbate in formulation S7 seem to have the stabilizing effect on laquinimod.

In accordance with Ph Eur <NUM> "Eye preparations", the particle size was measured in classes > <NUM>, > <NUM> and > <NUM>. In each class, the particle number was calculated per <NUM>µg of laquinimod. Particles were found in formulations E1, E2, S1, S2, and S8. In the suspensions (gels), cylindrical particles were detected, while in emulsions mostly oil droplet were detected (<FIG>). An increase in pH was observed to lead to a lower number of particles.

The osmolality of formulations E1, E2 and S1-S8 was measured, and, as a comparison, of similar formulations, except for not containing any laquinimod ("empty" formulations). The theoretical and measured osmolality of these formulations and of "empty" formulations, containing no laquinimod are shown in TABLE <NUM>.

In order to assess the optimum concentration of viscosity agents, different concentrations were tested in "placebo" formulations (viz. not containing laquinimod) with target viscosity of <NUM> mPas. After the addition of laquinimod, the viscosity decreased strongly. This indicates an interaction between laquinimod and viscosity agents. All formulations were in a similar range of viscosity besides formulation S5, which contained HPMC. The viscosity of the different formulations was adjusted using different viscosity agents. The amount of the viscosity agents was determined by placebo formulations. The viscosities of formulations E1-S8, measured at <NUM>, are indicated in TABLE <NUM>, which also lists the type and concentration of the viscosity agent used.

Formulations E2 (renamed E2-<NUM>) and S3 (renamed S3-<NUM>) were selected as a starting point for further formulations, viz. emulsion formulations E2-<NUM> to E2-<NUM> and gel formulations S3-<NUM> to S3-<NUM>. In both types of formulations, having a pH of at least <NUM>, laquinimod was completely dissolved.

As there was a substantial difference in viscosity of placebo formulations and those containing laquinimod, the viscosity of laquinimod-containing formulations E2-<NUM> to E2-<NUM> and S3-<NUM> to S3-<NUM> was adjusted by addition of sodium carboxymethyl cellulose.

The ingredients in the emulsion formulations are shown in TABLE <NUM>, and the ingredients in the gel formulations are shown in TABLE <NUM>.

Samples of all formulations were stored for up to <NUM> weeks at <NUM>, <NUM>, and <NUM> and subsequently analysed by RP-HPLC. During <NUM> and <NUM> storage no substantial decrease of relative area of main peak was detected, but there was a small decrease after <NUM> weeks of storage at <NUM>. The results of the RP-HPLC analyses are shown in TABLES <NUM> and <NUM>.

The visual appearance of samples of all formulations after aging was examined in the same way as described for EXAMPLE <NUM> and similar results were obtained.

The osmolality of formulations E2-<NUM> to E2-<NUM> and S3-<NUM> to S3-<NUM> was measured, as was that of similar formulations, except for not containing any laquinimod ("empty" formulations).

The theoretical and measured osmolality of these formulations are shown in TABLE <NUM>.

The viscosity of some formulations containing laquinimod and carbomer was adjusted with sodium carboxymethyl cellulose. The formulations containing Kolliphor® HS15, Kolliphor® ELP, or Kollidon® 17PF had a lower viscosity.

In addition to the measurement at <NUM>, the viscosity was measured at <NUM> to mimic the conditions in the eye. The results are shown in TABLE <NUM>.

A further gel formulation, formulation S7-<NUM>, was prepared, starting from the formulation S7, but with addition of a further viscosity agent. The contents of formulation S7 (for comparison) and S7-<NUM> are shown in TABLE <NUM>.

Using the same system for determining viscosity as described herein above, the viscosity of formulation S7-<NUM> at <NUM> was <NUM> mPas.

The ocular permeation of laquinimod in formulations of the invention was investigated, using bovine cornea.

Three formulations of the invention (S3, S4 and S7), containing laquinimod at a concentration of <NUM>/ml, were used in the assay. As a reference, a formulation of laquinimod (<NUM>/ml) in saline (<NUM>% w/v) was used. The formulations were stored in a refrigerator set to maintain +<NUM>.

Bovine eyes were supplied by ABP, Ruthvenfield Road, Inveralmond Industrial Estate, Perth, PH1 3XB, UK. The eyes had been collected from freshly slaughtered cattle and placed into a container containing cold Hank's balanced salt solution (HBSS). Eyes were kept cold using cool packs during transport to the test facility.

The receptor fluid for drug permeation assays was HEPES solution (<NUM>, pH <NUM>±<NUM>, containing <NUM>% w/v EDTA).

Six (<NUM>) replicates were treated with each formulation for a <NUM> exposure period. Permeability samples were collected test item treated corneas only, immediately prior to dosing and at half hour intervals following dosing. The final sample was collected at <NUM> post dose (in total <NUM> samples were collected per cornea). Opacity of corneas was measured prior to dosing and following the final permeability sample collection. The concentration of laquinimod in the permeation samples was measured throughout the exposure period.

Corneas were dissected from freshly obtained eyes. On arrival, eyes were rinsed with HBSS then examined for obvious defects or signs of damage (e.g. scratches, opacity or neovascularisation). Corneas from undamaged eyes were removed, leaving a sclera margin of ca <NUM>. Collected corneas were placed epithelial side down in HBSS at ambient temperature until required. Corneas were then be mounted epithelial side forward in specially designed corneal holders obtained from Duratec Analysentechnik GmbH, Rheinauer Strasse <NUM>, D-<NUM> Hockenheim, Germany. These holders consist of anterior and posterior compartments, which allow access to the epithelial and endothelial sides of the cornea, respectively.

Once mounted, both chambers of each corneal holder were filled with pre-warmed Minimum Essential Medium (MEM) without phenol red. The posterior chamber was filled first to encourage the cornea to return to its original curvature and care was taken to avoid the introduction of bubbles into the media. Holders were then equilibrated for ≥<NUM> in an incubator set to maintain a temperature of <NUM> prior to dosing.

At the end of the equilibration period, the media in both chambers were replaced with fresh pre-warmed MEM without phenol red. Baseline opacity readings was then taken and damaged corneas or corneas with opacity ><NUM> opacity units were rejected from further use. Corneas that passed these checks were assigned to study treatment groups. The MEM in the posterior chamber was replaced with pre-warmed receptor fluid using a syringe to allow measurement of the volume of fluid added to the chamber. The volume of the posterior chamber was recorded.

MEM in the anterior chamber was removed immediately prior to dosing. A pre-dose sample of receptor fluid was collected from each test item treated cornea. No receptor fluid samples were collected from corneas to be treated with the vehicle control. The access ports for the posterior chamber were sealed with tape to prevent leakage during the incubation period.

The laquinimod formulations and the saline control were applied undiluted. Prior to dosing, cornea holders were tipped forward to avoid contact between dosing solution and the corneal epithelium. The dose (ca <NUM>µl) was applied via the anterior chamber access ports using a syringe. Each dose was applied to six (<NUM>) replicate corneas for a <NUM> exposure. Before collecting the dose from the vial, the formulation was resuspended by gentle turning of the vial.

After dosing, corneal holders were tilted into the horizontal position to begin exposure, taking care to cover the epithelial surface of each cornea with test item. Corneas were exposed to test items or vehicle control for <NUM> in an incubator set to maintain a temperature of <NUM>.

Receptor fluid samples (ca <NUM>) were collected from the posterior chamber of each test item treated cornea before dosing and at half hour intervals post dose. A final receptor fluid sample was taken <NUM> post dose. Immediately following sampling, the removed receptor fluid was replaced with fresh, pre-warmed receptor fluid and the posterior chamber re-sealed taking care not to lose any sample or introduce air bubbles. Collected samples of receptor fluid were stored in a freezer set to maintain a temperature of -<NUM> until analysis.

Following the final receptor fluid collection, dosing solutions were removed from anterior chambers and corneas were rinsed with MEM with phenol red (ca <NUM> per rinse). Corneas were rinsed at least <NUM> times for both the anterior and posterior chambers, or until no there was no visual evidence of residual test item. Once rinsing was complete, one additional rinse with MEM without phenol red was performed to remove phenol red, to avoid any interference with subsequent optical measurements. Both chambers were then refilled with MEM without phenol red before proceeding.

Following rinsing, opacity of all corneas was measured using an opacitometer supplied by Duratec Analysentechnik GmbH, by placing each corneal holder into the opacitometer and recording the subsequent lux reading.

Samples were stored in a freezer set to maintain -<NUM> until analysis. A <NUM>µl aliquot of calibration standards (in the range <NUM> - <NUM> ng/ml), quality control or test samples was transferred in to a <NUM> round well plate and to each well <NUM>µl internal standard was added. This was then diluted with <NUM>µl methanol and <NUM>µl <NUM>% trifluoroacetic acid. The <NUM> round well plate was then capped, vortex mixed and centrifuged at a temperature of <NUM> for <NUM> minutes at <NUM>. Samples were then injected on a Sciex API4000™ mass spectrometer coupled with a Waters Acquity UPLC® system to generate known concentrations of laquinimod.

Study samples were extracted and analysed in batches together with calibration standards and quality check (QC) samples using the established method. The calibration samples were extracted in duplicate.

The detector responses were plotted against the concentration of laquinimod to produce a calibration curve, excluding the origin from the regression analysis. The determined concentration for each prepared standard used to construct the calibration curve should be within <NUM> ± <NUM> % of the nominal concentration. At least <NUM>% (and a minimum of <NUM>) of the calibration standards should meet the above criteria. The determined concentrations of at least <NUM>% of the bracketing QC samples must be within <NUM> ± <NUM> % of the nominal concentrations and at least <NUM>% at each concentration level should fulfil this criterion.

Study samples where the determined concentration was above the analytical range of the assay were re-assayed following dilution. Study samples where the determined concentration was below the analytical range were reported as <LLOQ (not quantifiable).

Data collection was performed using Analyst® Software from Applied Biosystems. Statistical analyses including regression analysis and descriptive statistics including arithmetic means and standard deviations, accuracy and precision were performed using Watson Laboratory Information Management System (Watson LIMS™) and Microsoft® Excel®.

Receptor fluid samples were stored in a freezer at a temperature of -<NUM> until analysis.

The computerised systems used in the study and the data collected and/or analysed by these systems are indicated in TABLE <NUM>.

Statistical analyses were limited to derivation of means, standard deviations and coefficients of variation where appropriate.

Opacity was calculated using the following formula: <MAT> where:.

The opacity change and corrected opacity change were calculated as:.

In TABLE <NUM> the results of the pre-dose and post-dose opacity measurements are listed.

Treatment with formulations S3 or S4 caused little to no change in opacity, while treatment with Formulation S7 caused some increase in opacity.

The total permeation of laquinimod was calculated from the results provided from LC-MS/MS analysis.

The permeability results, in terms of cumulative absorption of laquinimod (µg/cm<NUM>) across the bovine cornea (n = <NUM>) following exposure to formulations S3, S4 and S7, respectively, are listed in TABLES <NUM> to <NUM> and illustrated in <FIG>.

Laquinimod cumulative absorption increased throughout the exposure period for each inventive formulation. The results from all three formulation treatments were of the same magnitude and followed the same general pattern. Formulation S4 resulted in the least laquinimod permeation and was the most consistent between different corneas. Formulation S3 and Formulation S7 resulted in higher laquinimod permeability but the results were more variable between corneas.

Formulations E2-2A, S3-3A, and S3-8A were prepared, having the pH values and compositions as described in TABLE <NUM>.

The viscosity of formulations E2-2A, S3-3A, and S3-8A, measured at <NUM> using the method as described herein above, were found to be <NUM> mPa. s, <NUM> mPa. s, and <NUM> mPa. s, respectively.

Using the same test system and protocol as in EXAMPLE <NUM>, corneal opacity change and permeability were determined for formulations E2-2A, S3-<NUM>, S3-3A, S3-<NUM>, S3-<NUM>, and S3-8A. In TABLE <NUM> the results of the pre-dose and post-dose opacity measurements are listed for the different formulations and for a saline control.

As may be seen from the data in TABLE <NUM>, all treatments caused little to no change in opacity; the results were similar to those of the control group. There was little to no evidence of damage detected in corneas treated with any of these formulations. Formulation S3-<NUM> had the highest increase in opacity (<NUM> ± <NUM>), however this treatment group also showed the most variation with post dose opacity change ranging from <NUM> to <NUM>.

The permeability results, in terms of cumulative absorption of laquinimod (µg/cm<NUM>) across the bovine cornea (n = <NUM>) following exposure to formulations E2-2A, S3-<NUM>, S3-3A, S3-<NUM>, S3-<NUM>, and S3-8A, respectively, are listed in TABLES <NUM> to <NUM> and represented in <FIG>.

Using the same test system and protocol as in EXAMPLE <NUM>, corneal opacity change and permeability across bovine corneas were determined for formulations S3-3A and S7-<NUM>, and for laquinimod <NUM>/ml in saline (PBS) at pH <NUM>, in vitro, after a single <NUM> exposure.

Six replicate corneas were treated with each formulation or saline (negative control) for a <NUM> exposure period. Permeability samples were collected from test item treated corneas only, immediately prior to dosing and at half hourly intervals following dosing. The final sample was collected at <NUM> post dose (<NUM> samples were collected per cornea in total). The opacity of corneas was measured prior to dosing and following the final permeability sample collection. The concentration of the active ingredient was measured in the permeation samples collected throughout the exposure period by LC-MS/MS. The results of opacity measurements pre- and post-dose are shown in TABLE <NUM>.

The results presented in TABLE <NUM> show that all treatments caused little to no change in opacity.

The permeability results, in terms of cumulative absorption of laquinimod (µg/cm<NUM>) across the bovine cornea (n = <NUM>) following exposure to formulations S3-3A and S71, and to laquinimod in saline, respectively, are listed in TABLES <NUM> to <NUM> and illustrated in <FIG>.

The results presented in TABLES <NUM>-<NUM> show that laquinimod cumulative absorption increased throughout the exposure period for each formulation. At <NUM> post dose, the formulations could be ranked in the following order from greatest to least permeability: Formulation S7-<NUM> > Formulation S3-3A > Laquinimod in PBS.

The efficacy of the inventive formulation was tested in vivo in a mouse model of uveitis.

Female B10. RIII mice (-<NUM> weeks of age at the beginning of the study) were immunised with an emulsion containing the interphotoreceptor retinoid binding protein peptide <NUM>-<NUM> (IRBP <NUM>-<NUM>) in Incomplete Freund's adjuvant (IFA) supplemented with Mycobacterium tuberculosis H37Ra on Day <NUM>.

Oral laquinimod was prepared in a saline solution. The ophthalmic formulation was given as eye drops. The composition of the ophthalmic formulation was S3-3A (containing <NUM>/ml laquinimod) and the corresponding vehicle control was the S3-3A formulation without laquinimod. Treatments were administered according to the schedule shown in TABLE <NUM>.

From Day <NUM> until the end of the experiment, animals were scored weekly for clinical signs of uveitis. Retinal images were captured using topical endoscopy fundus imaging (TEFI) in non-anaesthetised but restrained animals following pupil dilatation using tropicamide then phenylephrine hydrochloride.

Retinal images were scored using the scoring system described TABLE <NUM> with a maximum possible score of <NUM> per eye.

Analysis of the total posterior uveitis clinical signs obtained by summing up the clinical scores observed in the left (L) and right (R) eye of each animal in every experimental group, revealed a significant effect of time, thereby confirming that the disease was successfully induced, and a general effect of all the treatments in comparison to the two vehicle-treated groups.

Given the presence of two vehicles in the study design, Dunnett's multiple comparisons were performed vs. vehicle, topical, and again vs. vehicle, oral. The calculated p-values at <NUM>, <NUM> and <NUM> days of treatment (D14, D17 and D20) are presented in TABLE <NUM>.

No differences were observed between the two vehicle groups. Administration of the ophthalmic formulation of laquinimod onto the eye significantly inhibited the disease course in comparison to control animals treated with vehicle only (<FIG>).

A gel formulation was prepared (total batch size of <NUM> I) containing <NUM>/l of laquinimod sodium (<NUM>/l laquinimod base) and excipients as indicated in TABLE <NUM>.

The obtained formulation was an opalescent gel, which was tested for osmolality, pH, viscosity, and relative density. The methods and results are as shown in TABLE <NUM>.

When tested for drop size, drops of about <NUM>µl in volume were obtained.

The formulation of EXAMPLE <NUM> was filled into <NUM>-ml bottles (LDPE bottles from Nemera La Verpilliera, (reference No. <NUM>), equipped with nozzle and cap Pureflow® <NUM> (reference No. <NUM>), for dispensing as an eye drop formulation. In total, <NUM> bottles were prepared, each bottle containing <NUM> of formulation.

The formulation of EXAMPLE <NUM> was submitted to a stability test in accordance with the ICH guide Q1A (R2) at the conditions established for drug products packaged in semi-permeable containers, whereby the long-term storage conditions were <NUM> to <NUM> and the accelerated conditions were <NUM>/<NUM> % RH. The results, in terms of droplet volume, osmolality, pH, viscosity, and laquinimod assay, after a storage time t of <NUM>, <NUM>, <NUM>, and <NUM> months are presented in TABLES <NUM> and <NUM>.

The formulation was visually observed at the different time points and remained an opalescent gel throughout the entire test period. As may be seen from the above TABLES <NUM> and <NUM> the inventive formulation shows no significant change in any of the tested features under either of the studied conditions. Based on the obtained stability data, therefore, a shelf-life of at least <NUM> months, more preferably at least <NUM> months, even more preferably at least <NUM> months, and most preferably at least <NUM> months, is contemplated for the inventive formulation when stored at <NUM> to <NUM>.

A gel formulation was prepared, having pH <NUM> and ingredients as indicated in TABLE <NUM>.

The viscosity of the formulation represented in TABLE <NUM> was measured at <NUM> using the method as described herein above and was found to be <NUM> mPa.

Using the formulation of EXAMPLE <NUM>, a study was performed to determine the distribution in the eye of laquinimod following topical ocular administration to rabbits after single and repeated administrations. Briefly, the study was performed over a test period of <NUM> days using <NUM> male New Zealand white rabbits, weighing ca <NUM>-<NUM> at time of dosing. Animals were housed and maintained according to established procedures and had free access to tap water and Teklad Irradiated Certified Global Rabbit Diet® (Envigo, UK) throughout the duration of the study. The tested formulation was stored at <NUM> until use.

Of the <NUM> test animals, <NUM> were given the formulation of EXAMPLE <NUM> and <NUM> animal was given the same amount of a placebo formulation, having the same composition as the formulation of EXAMPLE <NUM> except for not containing any laquinimod. Each animal was treated as follows: On day <NUM>, one topical ocular dose was administered to both eyes; on days <NUM> and <NUM>, no dose was administered; on days <NUM>-<NUM>, three topical ocular doses were administered to each eye, <NUM> hours apart; and on day <NUM>, one topical ocular dose was administered to each eye. For the dosing, the animals were removed from their housing and appropriately restrained. Then, using a pipette, the topical ocular dose was administered directly onto the cornea of each eye of each animal. The dose was <NUM>µl for each eye at each dosing session. Following dosing, the animals were returned to their housing. Details of the study are summarized in TABLE <NUM>.

On day <NUM>, the animals were euthanized at <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> respectively after the last topical ocular administration, and immediately thereafter, the eyes were quickly enucleated, along with the surrounding eyelid tissue, embedded in tragacanth gum and snap frozen in isopentane chilled in dry ice. The resultant isolated eyes were stored in a freezer set to maintain a temperature of ≤ -<NUM>.

For the distribution study, the eyes (right hand eye from each animal) were sectioned with a cryostat at a temperature of -<NUM>. For each tissue, sections having a thickness of <NUM> were collected on indium-tin oxide-coated (ITO) glass slides for mass spectrometry imaging (MSI). The analyses were performed using matrix assisted laser desorption/ionisation with Fourier transform ion cyclotron resonance (MALDI-FTICR) on a SolariX mass spectrometer from Bruker Daltonix. All the analyses were run at a spatial resolution of <NUM> and using the following mass spectrometer parameters:.

The monitored m/z for laquinimod was <NUM> ([M+H]+).

The results are summarized in TABLE <NUM>.

Claim 1:
A formulation for ocular administration comprising, in an aqueous phase:
(i) a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof as active ingredient,
(ii) a pharmaceutically acceptable viscosity agent in an amount sufficient to provide a dynamic viscosity of <NUM> to <NUM> mPas, as measured at <NUM>,
(iii) a pharmaceutically acceptable tonicity adjusting agent, in an amount sufficient to provide an osmolality of <NUM> to <NUM> mOsm/kg,
(iv) a pharmaceutically acceptable humectant,
(v) a pharmaceutically acceptable antioxidant, and
(vi) a pharmaceutically acceptable pH regulating agent.