Ophthalmic laquinimod formulations

Abstract

A pharmaceutical formulation comprising laquinimod or a pharma- ceutical acceptable salt thereof as an active ingredient, a pharma- ceutical acceptable thickening agent, a pharma- ceutical acceptable tonicity agent, a pharma- ceutical acceptable humectant, a pharma- ceutical acceptable antioxidant, and a pharma- ceutical acceptable pH adjusting agent, the formulation being suitable for treating ophthalmic diseases by ocular administration, preferably by topical ophthalmic administration.

Description

[Technical field]

[0001] The present invention relates to an ophthalmic pharmaceutical formulation. More particularly, the present invention relates to an ophthalmic, preferably topical, pharmaceutical formulation containing laquinimod. [Background technology]

[0002] Laquinimod is a synthetic quinoline carboxamide with high oral bioavailability that has been proposed as an oral formulation for the treatment of, for example, multiple sclerosis (MS). Laquinimod and its pharmacologic acceptable salts are described in U.S. Patent No. 6,077,851.

[0003] The use of laquinimod in the treatment of ocular diseases such as glaucoma, ocular inflammatory diseases, diseases involving excessive vascularization of the eye has been disclosed previously. Thus, laquinimod for use in the treatment of glaucoma is disclosed in International Application No. PCT / US2014 / 065497, published as WO2015 / 073697. US Patent Application No. 15 / 816402, published as US2018 / 0071275A1, discloses the use of laquinimod to treat ocular inflammatory diseases. In International Application No. PCT / EP2020 / 086993, published as WO2021 / 123142A1, the use of laquinimod for treating diseases involving excessive vascularization of the eye is disclosed. For each type of ocular disease, systemic or local administration of laquinimod is proposed, in the latter case ocular or ophthalmic administration is described.

[0004] However, several challenges must be overcome with regard to topical ocular formulations and their effective use in the treatment of ocular disorders, especially those affecting the posterior segment of the eye. Indeed, the treatment of disorders in which drugs must reach the posterior segment of the eye is often hindered by inefficient delivery of active agents to the target site due to the corneal barrier, which has several compartments with opposing properties, mainly lipophilic or hydrophilic. Summary of the Invention

[0005] Provided herein is a pharmaceutical formulation comprising laquinimod, or a pharma- ceutically acceptable salt thereof, for use in treating an ophthalmic disease.

[0006] Also provided herein is a method of treating a subject suffering from an ocular disease, comprising administering locally, preferably topically, to the eye of the subject a formulation as described herein that contains a therapeutically effective amount of laquinimod, or a pharma- ceutically acceptable salt of laquinimod effective to treat the subject.

[0007] Accordingly, one aspect relates to a pharmaceutical formulation for partial, preferably local administration to the eye of a patient (partial or topical ophthalmic), comprising a therapeutically effective amount of laquinimod or a pharma- ceutical acceptable salt thereof as the therapeutically active agent.

[0008] Thus, in one embodiment, there is provided a pharmaceutical formulation for ocular administration, said formulation comprising in an aqueous phase: (i) laquinimod or a pharma- ceutically acceptable salt thereof as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent; (iii) a pharma- ceutically acceptable tonicity adjusting agent; (iv) a pharma- ceutically acceptable moisturizer; (v) a pharma- ceutically acceptable antioxidant, and (vi) Formulations are provided which include a pharma- ceutically acceptable pH adjusting agent.

[0009] In a further aspect, there is provided a pharmaceutical formulation for administration of laquinimod or a pharma- ceutically acceptable salt of laquinimod to the eye, wherein the formulation has a viscosity, measured at 20° C., of 2 mPas (mPa·s) to 200 mPas, an osmolality of 200 mOsm / kg to 600 mOsm / kg, and a pH of 6.8 to 8.5.

[0010] Thus, in some embodiments, the pharmaceutical formulation for ocular administration comprises: (i) a therapeutically effective amount of laquinimod or a pharma- ceutical acceptable salt thereof, as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent in an amount sufficient to provide a dynamic viscosity, measured at 20° C., of 2 to 200 mPas; (iii) a pharma- ceutically acceptable tonicity agent in an amount sufficient to provide an osmolality of 200 to 600 mOsm / kg; (iv) a pharma- ceutically acceptable moisturizer; (v) a pharma- ceutically acceptable antioxidant; and (vi) A pharma- ceutically acceptable pH adjusting agent in an amount sufficient to provide a pH of 6.8 to 8.5.

[0011] In some embodiments, the formulation further comprises: (vii) a pharma- ceutically acceptable preservative; (viii) a pharma- ceutically acceptable surfactant (surface active agent); (ix) a pharma- ceutically acceptable solubilizer; and (x) a pharma- ceutically acceptable oil. The composition comprises one or more components selected from the group consisting of

[0012] The formulation may be in the form of a gel containing laquinimod or a pharma- ceutically acceptable salt of laquinimod in the form of a solute and / or suspended particles, or a water- and oil-containing emulsion (i.e., an oil-in-water emulsion or a water-in-oil emulsion).

[0013] Thus, in some embodiments, the formulation is an oil-in-water emulsion comprising a pharma- ceutically acceptable oil and an aqueous phase that is in the form of a suspension or solution of laquinimod or a pharma- ceutically acceptable salt of laquinimod.

[0014] 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 pharma- ceutically acceptable salt of laquinimod in a pharma- ceutically acceptable oil phase. Preferably, the emulsions provided herein are oil-in-water emulsions.

[0015] In further embodiments, the formulation is a solution or suspension of laquinimod or a pharma- ceutically acceptable salt of laquinimod, wherein the formulation is a viscous gel.

[0016] The pharmaceutical formulations provided herein are useful for treating a variety of ocular diseases, such as glaucoma, ocular inflammatory diseases and diseases involving excessive angiogenesis of the eye.

[0017] In some embodiments, provided herein is a pharmaceutical formulation for treating glaucoma. In some further embodiments, provided herein is an ophthalmic formulation for treating ocular inflammatory diseases. In some further embodiments, provided herein is an ophthalmic formulation for treating diseases involving excessive vascularization of the eye.

[0018] In some embodiments, the eye disease is a disease affecting the middle or posterior segment of the eye.

[0019] An advantageous feature of the formulation is the high stability against chemical degradation of laquinimod or a pharma- ceutically acceptable salt of laquinimod present in the formulation.

[0020] A further advantageous feature of the formulation is the high degree of homogeneity throughout the formulation.

[0021] An additional advantageous feature is the ability of the formulation to contain laquinimod or a pharma- ceutically acceptable salt of laquinimod in a wide range of concentrations.

[0022] A further advantageous feature of the formulation is the high rate of 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.

[0023] A further advantageous aspect is the high efficacy of laquinimod when administered locally, e.g. topically, to the eye of a patient, e.g. at a level comparable to oral administration. Local administration of the drug may advantageously avoid undesirable systemic effects. Thus, one aspect is an ophthalmic pharmaceutical formulation comprising in an aqueous phase: (i) laquinimod or a pharma- ceutically acceptable salt thereof as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent; (iii) a pharma- ceutically acceptable tonicity agent; (iv) a pharma- ceutically acceptable moisturizer; (v) a pharma- ceutically acceptable antioxidant, and (vi) a pharma- ceutically acceptable pH adjusting agent; and optionally, (vii) a pharma- ceutically acceptable preservative; (viii) a pharma- ceutically acceptable surfactant; (ix) a pharma- ceutically acceptable solubilizer, and (x) a pharma- ceutically acceptable oil; The present invention relates to an ophthalmic pharmaceutical formulation comprising one or more ingredients selected from the group consisting of:

[0024] A further aspect is a dosage container containing the pharmaceutical ophthalmic formulation provided herein. Thus, a dosage container containing a pharmaceutical formulation for ophthalmic administration, comprising: (i) laquinimod or a pharma- ceutically acceptable salt thereof as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent; (iii) a pharma- ceutically acceptable tonicity agent; (iv) a pharma- ceutically acceptable moisturizer; (v) a pharma- ceutically acceptable antioxidant, and (vi) a pharma- ceutically acceptable pH adjusting agent; and optionally, (vii) a pharma- ceutically acceptable preservative; (viii) a pharma- ceutically acceptable surfactant; (ix) a pharma- ceutically acceptable solubilizer, and (x) a pharma- ceutically acceptable oil; Also provided herein is a dosage container containing one or more ingredients selected from:

[0025] The pharma- ceutically acceptable pH adjusting agent is preferably present in an amount to provide the formulation with a pH of at least 6.8.

[0026] A further aspect is a kit comprising a dosage container as described herein and instructions for use.

[0027] A further aspect is the use of a formulation of the invention in the manufacture of a medicament for treating an ocular disorder, for example an ocular disorder selected from glaucoma, ocular inflammatory diseases, and diseases involving excessive vascularization of the eye.

[0028] Advantageously, the formulations as disclosed herein provide a means for local, preferably topical, administration of laquinimod to the eye of a patient (a mammal such as an animal or a human, preferably a human) with little or low (tolerable) side effects such as eye stinging, temporary blurred vision, and / or eye tearing.

[0029] Thus, provided herein is a pharmaceutical formulation, preferably a topical formulation, of laquinimod or a pharma- ceutically acceptable salt of laquinimod, which allows for the treatment of ocular diseases by ocular administration to a mammal, e.g., a human, in need of such treatment.

[0030] Further aspects and advantageous embodiments will become apparent from the following detailed description and examples. [Brief description of the drawings]

[0031] [Figure 1] Photograph of a vial containing a formulation prepared herein. Arrows indicate sampling points (top, middle or bottom of the vial) for sedimentation analysis. [Diagram 2] Photographs of vials containing laquinimod (with API) and formulations E1, E2, and S1-S8 described herein, as well as vials of similar formulations but without laquinimod (without API), at t=0 after resuspension. [Diagram 3]A series of photographs of vials containing laquinimod-containing formulations E1, E2 and S1-S8 described herein after resuspension after storage at different temperatures (5° C., 25° C., 30° C. and 40° C.) for t=1 week. [Figure 4] A series of photographs of vials containing laquinimod-containing formulations E1, E2 and S1-S8 described herein before and after resuspension after storage at different temperatures (5°C, 25°C, 30°C and 40°C) for t=2 weeks. [Diagram 5] 13A-13C are FlowCam® micrographs of particles in gel formulation S2 (suspension) and particles in emulsion E1. [Figure 6] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) through in vitro bovine cornea (n=6) as a function of time (min) during a 4 hour exposure period to Formulation S3. [Figure 7] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) through in vitro bovine cornea (n=6) as a function of time (min) during a 4 hour exposure period to Formulation S4. [Figure 8] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) through in vitro bovine cornea (n=6) as a function of time (min) during a 4 hour exposure period to Formulation S7. [Figure 9] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) (n=6) through in vitro bovine cornea as a function of time (min) during a 4 hour exposure period to formulation E2-2A. [Figure 10] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) (n=6) through in vitro bovine cornea as a function of time (min) during a 4 hour exposure period to formulation S3-1. [Figure 11] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) (n=6) through in vitro bovine cornea as a function of time (min) during a 4 hour exposure period to formulation S3-3A. [Figure 12]1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) through bovine cornea (n=6) as a function of time (min) during a 4 hour exposure period to Formulation S3-6. [Figure 13] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) through bovine cornea (n=6) as a function of time (min) during a 4 hour exposure period to formulation S3-7. [Figure 14] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) through bovine cornea (n=6) as a function of time (min) during a 4 hour exposure period to formulation S3-8A. [Figure 15] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) (n=6) through in vitro bovine cornea as a function of time (min) during a 4 hour exposure period to laquinimod in PBS. [Figure 16] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) (n=6) through in vitro bovine cornea as a function of time (min) during a 4 hour exposure period to formulation S3-3A. [Figure 17] 1 is a graph showing the cumulative absorption of laquinimod (μg / cm2) (n=6) through in vitro bovine cornea as a function of time (min) during a 4 hour exposure period to formulation S7-1. [Figure 18] 1 is a graph showing the mean permeation profile (μg / cm2) of laquinimod through in vitro bovine cornea (n=6) over a 4 hour exposure period to PBS formulation, formulations S3-3A and S7-1, respectively. [Figure 19] FIG. 13 is a graph showing the total clinical signs of posterior uveitis obtained by summing the clinical scores observed in the left (L) and right (R) eyes of each animal in each experimental group following topical ocular administration of Formulation S3-3A, oral administration of laquinimod, or both topical ocular and oral administration of laquinimod, and topical ocular or oral administration of vehicle alone in an experimental in vivo uveitis mouse model for 20 days post-inoculation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] All technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs, unless otherwise defined or clearly indicated by context. However, definitions of some terms used herein are provided below.

[0033] definition Unless otherwise stated or clear 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.

[0034] As used herein, "API" is an abbreviation for "active pharmaceutical ingredient," and in the context of this disclosure, is laquinimod or a pharma- ceutically acceptable salt of laquinimod.

[0035] As used herein, "autoimmune disease-associated ocular inflammation" refers to inflammation affecting one or more portions of the eye or periocular tissues secondary to an autoimmune disease.

[0036] The term "autoimmune disease" includes cell-mediated (e.g., T cell) and antibody-mediated (e.g., B cell) disorders. Such disorders may be, inter alia, arthritic, demyelinating, and inflammatory diseases. For example, the autoimmune disease may 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, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, idiopathic myxedema, myasthenia gravis, psoriasis, pemphigus vulgaris, rheumatoid arthritis, or systemic lupus erythematosus.

[0037] The term "Carbomer Copolymer Type B" refers to a high molecular weight copolymer of acrylic acid and long chain alkyl methacrylates crosslinked with allyl ethers of polyhydric alcohols. Carbomer Copolymer Type B is commonly used as a thickener, stabilizer, and emulsifier in various pharmaceutical formulations.

[0038] As used herein, the term "dosage container" refers to a container, such as a bottle, vial, tube, flask, etc., suitable for containing a volume of the formulation provided herein, either a volume equivalent to one unit (single dose) or a volume equivalent to two or more doses (multi-dose). The dose container may include a means for instilling an appropriate amount of the formulation into a patient's eye, which may be separate from the container.

[0039] As used herein, "effective" as in an amount effective to achieve a certain purpose, i.e., a "therapeutically effective amount," means an amount of a component sufficient to effect a desired therapeutic response, commensurate with a reasonable benefit / risk ratio, without undue adverse side effects (toxicity, irritation, allergic reaction, etc.). Effective amounts 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.

[0040] The term "excipient" refers to a pharma- ceutically acceptable chemical to aid in the administration of a pharmaceutical agent, as known to those skilled in the art of pharmacy. Excipients are compounds that are useful in the preparation of pharmaceutical compositions and are generally safe, non-toxic, and not biologically or otherwise objectionable, and include excipients that are acceptable for veterinary use as well as for human pharmaceutical use.

[0041] The term "degree" as used in relation to angiogenesis refers to the severity of angiogenesis, which can be assessed using a number of different measurable parameters, such as the site of angiogenesis, the number of blood vessels at the site of angiogenesis, the length of the blood vessels at the site of angiogenesis, and the size of the blood vessels at the site of angiogenesis.

[0042] The term "humectant" refers to a hydrophilic compound capable of retaining moisture in the formulation.

[0043] The term "laquinimod" has the structure

[0044] [ka]

[0045] The compound refers to the compound 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide having the formula:

[0046] Unless otherwise stated or apparent from the context, the term laquinimod includes the free base form of the compound as well as salt forms thereof.

[0047] The term "macrogol 15 hydroxystearate" refers to a mixture of mono- and diesters of 12-hydroxystearic acid and macrogol obtained by ethoxylation of 12-hydroxystearic acid. Macrogol 15 hydroxystearate is also known as 12-hydroxyoctadecanoic acid polymer with α-hydro-ω-hydroxypoly(oxy-1,2-ethanediyl); 12-hydroxystearic acid polyethylene glycol copolymer; macrogol 15 hydroxystearate; polyethylene glycol-15-hydroxystearate; and polyethylene glycol 660 12-hydroxystearate. In some embodiments, macrogol 15 hydroxystearate is Kolliphor® HS 15 (BASF AG, Germany). Kolliphor® HS 15 consists of polyglycol mono- and diesters of 12-hydroxystearic acid and about 30% free polyethylene glycol.

[0048] The term "mammal" refers to a human or any mammal, such as a primate, farm animal, pet animal, laboratory animal, etc. Examples of such animals are monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice, rats, etc. Preferably, the mammal is a human.

[0049] The term "surfactant" refers to an organic compound that can reduce the surface tension (or interfacial tension) between two liquids, between a gas / liquid, or between a liquid / solid. Surfactants are amphiphilic compounds, i.e., compounds that contain a hydrophobic portion (the "hydrophobic tail") and a hydrophilic portion (the "hydrophilic head" or "polar head"). Most commonly, surfactants are classified by their hydrophilic head. "Nonionic surfactants" have no charged groups in the head, the hydrophilic head of a "cationic surfactant" has a positive net charge, and the hydrophilic head of an "anionic surfactant" has a negative net charge.

[0050] As used herein, the term "tonicity agent" (or alternatively "tonicity agent") refers to a compound that contributes to the osmotic pressure of a solution. The osmotic pressure of an ophthalmic formulation is preferably adjusted to minimize patient discomfort upon ocular administration.

[0051] As used herein, phrases such as "ocular administration" or "ophthalmic administration" of a formulation refer to instilling the formulation into the eye of a subject.

[0052] As used herein, the expressions "ophthalmic formulation", "ophthalmic formulation", and the like refer to a pharmaceutical composition formulated for administration to the eye of a subject.

[0053] As used herein, the term "ocular disease" (which term is considered synonymous herein with "ocular disorder," "ocular disease" or "ocular disorder") refers to a disease affecting the eye of a mammalian subject, i.e., an animal or a human, preferably a human.

[0054] As used herein, "ocular inflammatory disease" or "OID" refers to inflammation affecting one or more parts of the eye or periocular tissue. OID can include, but is not limited to, inflammation of the orbital tissue, lacrimal apparatus, eyelid, conjunctiva (conjunctivitis), cornea, retina, components of the visual pathway, such as the optic nerve, and components of the uveal pathway (uveitis), i.e., the iris, ciliary body, and choroid. Specific examples of OID 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.

[0055] "Optional" and "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur.

[0056] The term "pH adjusting agent" generally refers 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 adjusting agent is a pH buffer (or buffering agent).

[0057] "Pharmaceutically acceptable" means a substance that is not biologically or otherwise objectionable, i.e., a substance that may be administered to an individual, together with the active compound with which it is associated, without causing clinically unacceptable biological effects or interacting adversely with any of the other components of the formulation in which it is contained.

[0058] The term "polyoxyethylene-polyoxypropylene block copolymer" refers to poloxamer of CAS Registry Number 9003-11-6, including its salts and known equivalents. Examples of poloxamers are poloxamer 188 and poloxamer 407.

[0059] The term "polyoxyl castor oil" with CAS Registry Number 61791-12-6 (sometimes called ethoxylated castor oil or polyethylene glycol castor oil) is a mixture of ethoxylated glycerol triricinoleate with a small amount of polyethylene glycol ricinoleate and the corresponding free glycol. Polyoxyl castor oil is a non-ionic surfactant and can be used as an emulsifier or solubilizer. The mixture may also be called polyoxyl n castor oil, where n represents the number of oxyethylene units in the compound. An example of a commercial product is Kolliphor® EL, which is a polyoxyl 35 castor oil.

[0060] The term "polysorbate 80" refers to the compound having CAS Registry Number 9005-65-6, also known as polyoxyethylene (80) sorbitan monooleate, sorbitan monooleate ethoxylate, and salts and known equivalents thereof.

[0061] As used herein, "preservative" refers to an additive that inhibits the growth of microorganisms and kills microorganisms that may contaminate the formulation when exposed to the surrounding environment.

[0062] The term "solubilizing agent" (or "solubilizer") refers to a compound that, when added to a solvent phase or formulation, can increase the solubility of another compound in said solvent phase or formulation.

[0063] The term "solubilizing effective amount" of a substance ("solubilizer") in 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 the API (in this example, laquinimod or a pharma- ceutically acceptable salt thereof) such that the API is more therapeutically effective than in the absence of the solubilizing agent. In some embodiments, an "API solubilizing effective amount" is an amount sufficient to solubilize the API in an ophthalmic (ophthalmic) formulation, e.g., an ophthalmic topical formulation, such that the API is more therapeutically effective than in the absence of the solubilizing agent.

[0064] As used herein, "treating" includes, for example, inducing inhibition, regression or stasis of a disease, disorder or condition, or improving or alleviating the symptoms of a disease, disorder or condition. As used herein, "ameliorating" or "alleviating" a condition or state means alleviating or reducing the symptoms of the condition or state. As used herein, "inhibiting" disease progression or disease complications in a subject means preventing or alleviating disease progression and / or disease complications in a subject.

[0065] The term "unit dose" as used herein refers to the amount of a formulation of the invention administered to a subject in one administration, or the amount of laquinimod or a salt of laquinimod contained in said amount of a formulation of the invention. The unit dose disclosed herein may be administered once a day, twice a day, three times a day, four times a day, five times a day, every other day, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week.

[0066] "Angiogenesis" and "angiogenesis" refer to the process by which new blood vessels are formed. The terms "angiogenesis" and "angiogenesis" are used interchangeably herein.

[0067] As used herein, the term "ocular angiogenesis" is synonymous with ocular neovascularization.

[0068] "Excessive angiogenesis" refers to an event in which angiogenesis occurs to an extent that is detrimental to the normal function of the affected tissue. Such excessive angiogenesis occurs in or as a consequence of ocular diseases or disorders, such as corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, proliferative diabetic retinopathy, retinopathy of prematurity, ischemic retinopathy, retinal neovascularization, hypertensive retinopathy, wet age-related macular degeneration, and the like.

[0069] In the context of the present disclosure, the terms "ocular disease or disorder involving excessive ocular angiogenesis" and "ocular disease or disorder involving ocular angiogenesis" are taken to mean any ocular disease or disorder that would be considered by one of skill in the art to result from and / or affect angiogenesis in one or more tissues of the eye, e.g., detrimental to, angiogenesis, for the normal function of the affected tissue. Such diseases or disorders may lead to loss of vision.

[0070] As used herein, the term "viscosity" refers to dynamic viscosity.

[0071] The term "thickening agent" (which may also be referred to in the art as a viscosity improver, viscosity enhancer, viscosity modifier, viscosity imparting agent, thickener, thickening stabilizer, etc.) refers to an agent that, when mixed with a liquid, can increase the viscosity of the liquid.

[0072] Pharmaceutical preparations A pharmaceutical formulation for ocular administration comprising in an aqueous phase: (i) laquinimod or a pharma- ceutically acceptable salt thereof as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent; (iii) a pharma- ceutically acceptable tonicity agent; (iv) a pharma- ceutically acceptable moisturizer; (v) a pharma- ceutically acceptable antioxidant, and (vi) a pharma- ceutically acceptable pH adjusting agent; and optionally, (vii) a pharma- ceutically acceptable preservative; (viii) a pharma- ceutically acceptable surfactant; (ix) a pharma- ceutically acceptable solubilizer, and (x) a pharma- ceutically acceptable oil; Provided herein are pharmaceutical formulations comprising one or more ingredients selected from:

[0073] Active ingredient The ophthalmic (e.g., topical ophthalmic) formulations provided herein are pharmaceutical formulations comprising a therapeutically effective amount of laquinimod, or a pharma- ceutical effective amount of laquinimod or a pharma- ceutical acceptable salt thereof, in a concentration suitable to provide a therapeutically effective amount upon administration to the eye (ophthalmic administration), preferably topically to the eye, e.g., as eye drops.

[0074] In some embodiments, laquinimod is present in free base form (i.e., non-salt form). In other embodiments, the formulation comprises a pharma- ceutically 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 pharma- ceutically acceptable salt of laquinimod is laquinimod sodium.

[0075] In some embodiments, the concentration of laquinimod in the formulation is from about 5 g / l to about 100 g / l (or the corresponding concentration of a pharma- ceutically acceptable salt of laquinimod), e.g., from about 10 to about 100 g / l, or from about 20 to about 100 g / l, or from about 50 to about 100 g / l.

[0076] In some embodiments, the concentration of laquinimod in the formulation is in the range of 5-70 g / l, 10 g / l-70 g / l, or 20-70 g / l. In some embodiments, the concentration of laquinimod in the formulation is in the range of 5-50 g / l, 10-50 g / l, or 20-50 g / l. In some embodiments, the concentration of laquinimod in the formulation is in the range of 5-30 g / l, such as 10-30 g / l, or 20-30 g / l.

[0077] In some embodiments, the concentration of laquinimod in the formulation is in the range of 5-25 g / l, 10-25 g / l, or 20-25 g / l.

[0078] In some embodiments, the concentration of laquinimod in the formulation is within the range of 5-20 g / l, 5-19 g / l, 5-18 g / l, 5-17 g / l, 5-16 g / l, 5-15 g / l, 5-14 g / l, 5-13 g / l, 5-12 g / l, or 5-11 g / l.

[0079] In some embodiments, the concentration of laquinimod in the formulation is within the range of 6-20 g / l, 6-19 g / l, 6-18 g / l, 6-17 g / l, 6-16 g / l, 6-15 g / l, 6-14 g / l, 6-13 g / l, 6-12 g / l, or 6-11 g / l.

[0080] In some embodiments, the concentration of laquinimod in the formulation is within the range of 7-20 g / l, 7-19 g / l, 7-18 g / l, 7-17 g / l, 7-16 g / l, 7-15 g / l, 7-14 g / l, 7-13 g / l, 7-12 g / l, or 7-11 g / l.

[0081] In some embodiments, the concentration of laquinimod in the formulation is within the range of 8-20 g / l, 8-19 g / l, 8-18 g / l, 8-17 g / l, 8-16 g / l, 8-15 g / l, 8-14 g / l, 8-13 g / l, 8-12 g / l, or 8-11 g / l.

[0082] In some embodiments, the concentration of laquinimod in the formulation is within the range of 9-20 g / l, 9-19 g / l, 9-18 g / l, 9-17 g / l, 9-16 g / l, 9-15 g / l, 9-14 g / l, 9-13 g / l, 9-12 g / l, or 9-11 g / l.

[0083] In some embodiments, the concentration of laquinimod in the formulation is in the range of 10-20 g / l, 10-19 g / l, 10-18 g / l, 10-17 g / l, 10-16 g / l, 10-15 g / l, 10-14 g / l, 10-13 g / l, 10-12 g / l, or 10-11 g / l.

[0084] In some embodiments, the concentration of laquinimod in the formulation is 5 g / l. In some embodiments, the concentration of laquinimod is 10 g / l. In some embodiments, the concentration of laquinimod is 15 g / l. In some embodiments, the concentration of laquinimod is 20 g / l. In some embodiments, the concentration of laquinimod is 25 g / l. In some embodiments, the concentration of laquinimod is 30 g / l. In some embodiments, the concentration of laquinimod is 35 g / l. In some embodiments, the concentration of laquinimod is 40 g / l. In some embodiments, the concentration of laquinimod is 50 g / l. In some embodiments, the concentration of laquinimod is 60 g / l. In some embodiments, the concentration of laquinimod is 70 g / l. In some embodiments, the concentration of laquinimod is 80 g / l. In some embodiments, the concentration of laquinimod is 90 g / l. In some embodiments, the concentration of laquinimod is 100 g / l.

[0085] As used herein, "g / l" indicates the amount (g) of laquinimod (as the free base or in the form of a pharma- ceutically acceptable salt) per volume (l) of the formulation. Note that concentrations may also be expressed in mg / ml, with 1 g / l being equivalent to 1 mg / ml. Unless otherwise stated or clear from the context, the amounts indicated refer to the free base form, and one of skill in the art would be well able to calculate the corresponding concentration or amount of a salt of laquinimod, if one is using a salt of laquinimod.

[0086] In the pharmaceutical formulations provided herein, laquinimod has high stability against chemical degradation (or "degradation"), e.g., by oxidation, advantageously allowing for a long shelf life. Thus, in some advantageous embodiments, the amount of oxidative degradation products present in the composition is 0.1% w / w or less, more preferably 0.05% w / w or less, even more preferably 0.01% w / w or less, relative to the amount of laquinimod, or is undetectable after a period of, e.g., at least 3 months, preferably at least 6 months, more preferably at least 1 year, and even more preferably at least 2 years, when stored, e.g., at room temperature (about 18-25°C) in a sealed container suitable for the pharmaceutical formulation.

[0087] Pharmaceutically acceptable thickening agents The formulations provided herein have a (dynamic) viscosity of about 2 mPas to about 200 mPas when measured using the method described herein (falling ball method) at a temperature of 20° C. In some embodiments, the viscosity is in the range of about 2 mPas to about 180 mPas, about 2 mPas to about 160 mPas, about 2 mPas to about 150 mPas, about 2 mPas to about 140 mPas, about 2 mPas to about 130 mPas, about 2 mPas to about 120 mPas, about 2 mPas to about 110 mPas, about 2 mPas to about 100 mPas, about 2 mPas to about 90 mPas, or about 2 mPas to about 80 mPas, e.g., about 2 mPas to about 75 mPas.

[0088] In some of these embodiments, the viscosity is at least 3 mPas, at least 4 mPas, at least 5 mPas, at least 6 mPas, at least 7 mPas, at least 8 mPas, at least 9 mPas, at least 10 mPas, at least 11 mPas, at least 12 mPas, at least 13 mPas, at least 14 mPas, or at least 15 mPas.

[0089] In some of these embodiments, the viscosity is at most 180 mPas, at most 170 mPas, at most 160 mPas, at most 150 mPas, at most 130 mPas, at most 120 mPas, at most 110 mPas, at most 100 mPas, at most 90 mPas, at most 80 mPas, at most 75 mPas, at most 70 mPas, at most 65 mPas, at most 60 mPas, at most 55 mPas, at most 50 mPas, at most 45 mPas, at most 40 mPas, at most 35 mPas, at most 30 mPas, at most 25 mPas, or at most 20 mPas.

[0090] For example, in some embodiments, the viscosity is within the range of about 2 mPas to about 70 mPas, or about 2 mPas to about 65 mPas, or about 2 mPas to about 60 mPas, or about 2 mPas to about 55 mPas, or about 2 mPas to about 50 mPas, or about 2 mPas to about 45 mPas, or about 2 mPas to about 40 mPas, or about 2 mPas to about 35 mPas, or about 2 mPas to about 30 mPas, or about 2 mPas to about 25 mPas, or about 2 mPas to about 20 mPas. In some of these embodiments, the viscosity is at least 3 mPas, at least 4 mPas, at least 5 mPas, at least 6 mPas, at least 7 mPas, at least 8 mPas, at least 9 mPas, at least 10 mPas, at least 11 mPas, at least 12 mPas, at least 13 mPas, at least 14 mPas, or at least 15 mPas.

[0091] Thus, in some embodiments, the viscosity of the formulation is within the range of about 5 mPas to about 75 mPas, or about 5 mPas to about 70 mPas, or about 5 mPas to about 65 mPas, or about 5 mPas to about 60 mPas, or about 5 mPas to about 55 mPas, or about 5 mPas to about 50 mPas, or about 5 mPas to about 45 mPas, or about 5 mPas to about 40 mPas, or about 5 mPas to about 35 mPas, or about 5 mPas to about 30 mPas, or about 5 mPas to about 25 mPas, or about 5 mPas to about 20 mPas.

[0092] In some further embodiments, the viscosity of the formulation is within the range of about 10 mPas to about 75 mPas, or about 10 mPas to about 70 mPas, or about 10 mPas to about 65 mPas, or about 10 mPas to about 60 mPas, or about 10 mPas to about 55 mPas, or about 10 mPas to about 50 mPas, or about 10 mPas to about 45 mPas, or about 10 mPas to about 40 mPas, or about 10 mPas to about 35 mPas, or about 10 mPas to about 30 mPas, or about 10 mPas to about 25 mPas, or about 10 mPas to about 20 mPas. In some of these embodiments, the viscosity is at least 11 mPas, at least 12 mPas, at least 13 mPas, or at least 14 mPas.

[0093] Thus, in some further embodiments, the viscosity of the formulation is within the range of about 12 mPas to about 75 mPas, or about 12 mPas to about 70 mPas, or about 12 mPas to about 65 mPas, or about 12 mPas to about 60 mPas, or about 12 mPas to about 55 mPas, or about 12 mPas to about 50 mPas, or about 12 mPas to about 45 mPas, or about 12 mPas to about 40 mPas, or about 12 mPas to about 35 mPas, or about 12 mPas to about 30 mPas, or about 12 mPas to about 25 mPas, or about 12 mPas to about 20 mPas.

[0094] In some further embodiments, the viscosity of the formulation is within the range of about 15 mPas to about 75 mPas, or about 15 mPas to about 70 mPas, or about 15 mPas to about 65 mPas, or about 15 mPas to about 60 mPas, or about 15 mPas to about 55 mPas, or about 15 mPas to about 50 mPas, or about 15 mPas to about 45 mPas, or about 15 mPas to about 40 mPas, or about 15 mPas to about 35 mPas, or about 15 mPas to about 30 mPas, or about 15 mPas to about 25 mPas, or about 15 mPas to about 20 mPas.

[0095] The viscosities given herein are dynamic viscosities measured at a temperature of 20° C., for example using a falling ball viscometer as described herein.

[0096] The formulations include one or more pharma- ceutically acceptable thickening agents.

[0097] Suitable thickening agents for use herein include polyvinyl alcohol, poly(acrylic acid) homopolymers or copolymers (carbomers), and various cellulosic polymers such as hydroxypropyl methylcellulose and sodium carboxymethylcellulose.

[0098] In some embodiments, the pharma- ceutically acceptable thickening agent comprises one or more of the group consisting of polyvinyl alcohol, poly(acrylic acid) homopolymer or copolymer (carbomer), polyvinylpyrrolidone, and cellulose derivatives, such as hydroxypropylmethylcellulose and sodium carboxymethylcellulose.

[0099] In some embodiments, the thickening agent is selected from cellulosic polymers, polyvinyl alcohol, poly(acrylic acid) homo- and copolymers, and combinations thereof.

[0100] In some embodiments, the thickening agent comprises a cellulose-based polymer (or cellulose derivative), such as hydroxypropylmethylcellulose or sodium carboxymethylcellulose. For example, the thickening agent comprises sodium carboxymethylcellulose. In some embodiments, the thickening agent comprises polyvinyl alcohol. In some embodiments, the thickening agent comprises a poly(acrylic acid) homopolymer. In some embodiments, the thickening agent comprises a poly(acrylic acid) copolymer.

[0101] In the carbomer used herein, the polymer may be a homopolymer of acrylic acid, and may be crosslinked with an allyl ether of pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene. In some embodiments, the carbomer is a homopolymer of acrylic acid (carbomer homopolymer, e.g., carbomer homopolymer type B). In some other embodiments, the carbomer is a crosslinked copolymer.

[0102] The thickening agent (which term may refer to either one specific thickening agent or a mixture of such thickening agents) is present in a total amount sufficient to provide the desired viscosity in the formulation, i.e., within the range described hereinabove. As will be apparent to those skilled in the art, the exact amount will vary depending on the specific thickening agent(s) selected, and will also depend on the other ingredients in the formulation and the concentrations of these other ingredients. In light of this specification and the examples provided herein, those skilled in the art will be able to determine the required amount of thickening agent.

[0103] It should be noted that the viscosity of the formulation tends to decrease with increasing laquinimod concentration, and the amount of any given thickening agent generally needs to be determined and adjusted depending on the particular laquinimod concentration of the formulation.

[0104] Pharmaceutically acceptable tonicity agents Tear fluid is isotonic with blood and has an isotonicity equivalent to a 0.9% NaCl aqueous solution. Thus, an ophthalmic formulation is ideally isotonic with tear fluid, but generally, a tonicity of about 0.6% to 2% NaCl aqueous solution is tolerated by the eye. When small amounts of ophthalmic formulations are administered, the tonicity may be outside this range, since dilution with tear fluid may quickly relieve discomfort. However, preferably, the formulation should be approximately isotonic. The formulations provided herein include one or more compounds selected from a pharma- ceutically acceptable tonicity agent, preferably a non-ionic tonicity agent, such as mannitol, sorbitol, glycerol, polyethylene glycol (PEG), polypropylene glycol (PPG) and sorbitol, but the tonicity agent is not limited to this selection, as other alternative tonicity agents are well known in the art. The preferred non-ionic tonicity agent is mannitol.

[0105] In some embodiments, the tonicity agent comprises mannitol. In some embodiments, the tonicity agent is mannitol.

[0106] In some embodiments, the tonicity agent (e.g., mannitol) is present in the formulation at a concentration of about 0.5 to about 5 g / L, about 0.5 to about 4.5 g / L, about 0.5 to about 4 g / L, about 0.5 to about 3.5 g / L, or about 0.5 to about 3 g / L of the formulation.

[0107] In some embodiments, the tonicity agent (e.g., mannitol) is present in the formulation at a concentration of about 1 to about 5 g / l, about 1 to about 4.5 g / l, about 1 to about 4 g / l, about 1 to about 3.5 g / l, or about 1 to about 3 g / l.

[0108] In some embodiments, the tonicity agent (e.g., mannitol) is present in the formulation at a concentration of about 1.5 to about 5 g / L, about 1.5 to about 4.5 g / L, about 1.5 to about 4 g / L, about 1.5 to about 3.5 g / L, or about 1.5 to about 3 g / L.

[0109] In some embodiments, the tonicity agent (e.g., mannitol) is present in the formulation at a concentration of about 2 to about 5 g / l, about 2 to about 4.5 g / l, about 2 to about 4 g / l, about 2 to about 3.5 g / l, or about 2 to about 3 g / l. In some embodiments, the tonicity agent (e.g., mannitol) is present in the formulation at a concentration of about 2.5 to about 5 g / l, about 2.5 to about 4.5 g / l, about 2.5 to about 4 g / l, about 2.5 to about 3.5 g / l, or about 2.5 to about 3 g / l.

[0110] Pharmaceutical preparations for ocular administration ideally have an osmolality within the range of 200 to 600 mOsm / kg so as not to cause discomfort when instilled, but values ​​somewhat outside this range may be acceptable when the amount of preparation to be instilled is small.

[0111] In some embodiments, the formulations of the invention have an osmolality in the range of about 200 to about 550 mOsm / kg, about 200 to about 500 mOsm / kg, about 200 to about 450 mOsm / kg, or about 200 to about 400 mOsm / kg, or about 200 to about 350 mOsm / kg.

[0112] In some embodiments, the formulations of the invention have an osmolality within the range of about 300 to about 600 mOsm / kg, about 300 to about 550 mOsm / kg, about 300 to about 500 mOsm / kg, about 300 to about 450 mOsm / kg, about 300 to about 400 mOsm / kg, or about 300 to about 350 mOsm / kg.

[0113] In some embodiments, the formulations of the present invention have an osmolality within the range of about 400 to about 600 mOsm / kg, about 400 to about 550 mOsm / kg, about 400 to about 500 mOsm / kg, or about 400 to about 450 mOsm / kg.

[0114] In some embodiments, the formulations of the invention have an osmolality within the range of about 450 to about 600 mOsm / kg, about 450 to about 550 mOsm / kg, or about 450 to about 500 mOsm / kg.

[0115] In some embodiments, the formulations of the invention have an osmolality in the range of about 500 to about 600 mOsm / kg, or about 500 to about 550 mOsm / kg.

[0116] In some embodiments, the formulations of the invention have an osmolality within the range of about 250 to about 500 mOsm / kg, about 250 to about 450 mOsm / kg, about 250 to about 400 mOsm / kg, about 250 to about 375 mOsm / kg, about 250 to about 350 mOsm / kg, or about 250 to about 325 mOsm / kg.

[0117] In some embodiments, the formulations of the invention have an osmolality within the range of about 260 to about 375 mOsm / kg, about 270 to about 375 mOsm / kg, about 280 to about 375 mOsm / kg, or about 290 to about 375 mOsm / kg.

[0118] In some embodiments, the formulations of the invention have an osmolality within the range of about 260 to about 350 mOsm / kg, about 270 to about 350 mOsm / kg, about 280 to about 350 mOsm / kg, or about 290 to about 350 mOsm / kg.

[0119] In some embodiments, the formulations of the invention have an osmolality in the range of about 260 to about 320 mOsm / kg, about 270 to about 320 mOsm / kg, or about 280 to about 320 mOsm / kg, or about 285 to about 315 mOsm / kg, or about 290 to about 310 mOsm / kg, or about 295 to about 305 mOsm / kg, e.g., about 300 mOsm / kg.

[0120] A pharma- ceutically acceptable moisturizer The formulations of the present invention include a humectant (sometimes referred to in the art as a "humectant"), such as a polyol, such as a C3-C6 polyol, such as 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 includes glycerol. In some embodiments, the humectant is glycerol.

[0121] In some embodiments, the humectant (e.g., glycerol) is present in the formulation at a concentration of about 5 to about 50 g / L, about 5 to about 45 g / L, about 5 to about 40 g / L, about 5 to about 35 g / L, or about 5 to about 30 g / L of the formulation. In some embodiments, the humectant (e.g., glycerol) is present in the formulation at a concentration of about 10 to about 50 g / L, about 10 to about 45 g / L, about 10 to about 40 g / L, about 10 to about 35 g / L, about 10 to about 30 g / L, about 10 to about 25 g / L, or about 10 to about 20 g / L. In some embodiments, the humectant (e.g., glycerol) is present in the formulation at a concentration of about 15 to about 50 g / l, about 15 to about 45 g / l, about 15 to about 40 g / l, about 15 to about 35 g / l, about 15 to about 30 g / l, about 15 to about 25 g / l, or about 15 to about 20 g / l. In some embodiments, the humectant is present in the formulation at a concentration of about 16 to about 20 g / l, about 16 to about 19 g / l, or about 16 to about 18 g / l, such as about 17 g / l. In some embodiments, the humectant (e.g., glycerol) is present in the formulation at a concentration of about 20 to about 50 g / l, about 20 to about 45 g / l, about 20 to about 40 g / l, about 20 to about 35 g / l, or about 20 to about 30 g / l.

[0122] Pharmaceutically acceptable antioxidants In particular, to protect laquinimod from chemical degradation, the formulation contains a pharma- ceutically acceptable antioxidant, such as the disodium salt of ethylenediaminetetraacetic acid (EDTA).

[0123] In some embodiments, the pharma- ceutically acceptable antioxidant comprises the disodium salt of ethylenediaminetetraacetic acid (EDTA). In some embodiments, the pharma- ceutically acceptable antioxidant is the disodium salt of ethylenediaminetetraacetic acid (EDTA).

[0124] In some embodiments, the concentration of the antioxidant in the formulation is in the range of about 0.1 g / l to about 5 g / l, about 0.2 g / l to about 5 g / l, or about 0.5 g / l to about 5 g / l. In some embodiments, the concentration of the antioxidant is in the range of about 0.1 g / l to about 2 g / l, about 0.2 g / l to about 2 g / l, or about 0.5 g / l to about 2 g / l. In some embodiments, the concentration of the antioxidant is in the range of about 0.1 g / l to about 1.5 g / l, about 0.2 g / l to about 1.5 g / l, or about 0.5 g / l to about 1.5 g / l.

[0125] The amount of antioxidant present in the formulation generally depends on the amount of laquinimod contained in the formulation. In some embodiments, the formulation can contain an antioxidant in a weight ratio to laquinimod (weight of antioxidant:weight of laquinimod) ranging from about 1:50 to about 1:5, about 1:25 to about 1:5, about 1:20 to about 1:5, or about 1:15 to about 1:5, such as about 1:50 to about 1:8, about 1:25 to about 1:8, about 1:20 to about 1:8, about 1:15 to about 1:8, or about 1:12 to about 1:8, such as about 1:10.

[0126] Pharmaceutically acceptable pH adjusters The pH adjusting agent is preferably present in the formulation in an amount sufficient to provide the formulation with a pH of at least 6.8. Preferably, the formulations provided herein have a pH of about 6.8 to about 8.5, such as a pH of 7 to 8.5, or a pH of 7.4 to 8.5 (when measured at a temperature of 25° C.). In some embodiments, the pH is up to 8.4. For example, in some embodiments, the formulation has a pH of 7.0 to 8.4, such as 7.4 to 8.4, or 8.0 to 8.4. In some embodiments, the pH is up to 8.0. For example, in some embodiments, the formulation has a pH of 7.0 to 8.0, such as 7.4 to 8.0. In some further embodiments, the formulation has a pH in the range of 6.8 to 8.0, such as 6.8 to 7.9, or 6.8 to 7.8, or 6.8 to 7.7, or 6.8 to 7.6, or 6.8 to 7.5, or 6.8 to 7.4. In some further embodiments, the formulation has a pH in the range of 6.9 to 8.0, such as 6.9 to 7.9, or 6.9 to 7.8, or 6.9 to 7.7, or 6.9 to 7.6, or 6.9 to 7.5. In some further embodiments, the formulation has a pH in the range of 7.0 to 7.9, or 7.0 to 7.8, or 7.0 to 7.7, or 7.0 to 7.6, or 7.0 to 7.5. In some further embodiments, the formulation has a pH in the range of 7.1 to 7.9, or 7.1 to 7.8, or 7.1 to 7.7, or 7.1 to 7.6, or 7.1 to 7.5. In some further embodiments, the formulation has a pH in the range of 7.2 to 7.9, or 7.2 to 7.8, or 7.2 to 7.7, or 7.2 to 7.6, or 7.2 to 7.5. In some further embodiments, the formulation has a pH in the range of 7.3 to 7.9, or 7.3 to 7.8, or 7.3 to 7.7, or 7.3 to 7.6, or 7.3 to 7.5. In some embodiments, the formulation has a pH of about 7.4.

[0127] The formulation contains a pH adjuster to provide a pH within the above range. For example, the formulation may contain about 1 to about 5 g / l of pH adjuster, such as about 1 to about 2 g / l of pH adjuster.

[0128] In some embodiments, the pH adjuster comprises one or more pH buffers, such as a pH buffer selected from TRIS (tris(hydroxymethyl)aminomethane, IUPAC name: 2-amino-2-(hydroxymethyl)propane-1,3-diol) and disodium hydrogen phosphate dihydrate. In some embodiments, the pH adjuster comprises TRIS. In some embodiments, the pH adjuster comprises disodium hydrogen phosphate dihydrate. In some embodiments, the pH adjuster is TRIS. In some embodiments, the pH adjuster is disodium hydrogen phosphate dihydrate.

[0129] If necessary, the pH of the formulation may be adjusted by the addition of a base or acid, e.g. a strong base such as sodium hydroxide or a strong acid such as hydrochloric acid, and optionally maintained at the desired pH by the use of a suitable buffer, e.g. as described herein above.

[0130] Pharmaceutically acceptable preservatives In some embodiments, the formulation comprises an API preservative effective amount of a pharma- ceutically acceptable preservative. In some embodiments, the formulation comprises a preservative selected from benzalkonium chloride and benzethonium chloride (IUPAC name: N-benzyl-N,N-dimethyl-2-{2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy}ethanaminium chloride). In some embodiments, the preservative comprises benzalkonium chloride. In some embodiments, the preservative is benzalkonium chloride. Benzalkonium chloride (CAS number 8001-54-5) has the general formula

[0131] [ka]

[0132] (wherein n is an integer ranging from 8 to 16) It is a mixture of alkylbenzyldimethylammonium chlorides.

[0133] The concentration of the preservative can typically range from about 0.01 g / l to about 0.2 g / l, from about 0.02 g / l to about 0.2 g / l, from about 0.05 g / l to about 0.2 g / l, or from about 0.1 g / l to about 0.2 g / l. In some embodiments, the concentration of the preservative is up to 0.15 g / l. Thus, in some embodiments, the concentration of the preservative is within the range of about 0.01 g / l to about 0.15 g / l, from about 0.02 g / l to about 0.15 g / l, from about 0.05 g / l to about 0.15 g / l, or from about 0.1 g / l to about 0.15 g / l.

[0134] In some embodiments, the formulation provided herein does not contain preservative.For example, in some embodiments, when the formulation is provided in a single-use container (i.e., a container that is used only once) or a single-dose container (i.e., a container that contains only one dose), preservative may not be included.In some of these embodiments, the formulation does not contain preservative.

[0135] There are also multi-dose containers that eliminate the need for preservatives, such as the Novelia® PFMD bottles sold by Nemera (France) and similar devices, such as those described in the article "OPHTHALMIC SQUEEZE DISPENSER - Eliminating the Need for Additives in Multidose Preservative-Free Eyecare Formulations" (Drug Development & Delivery, October 2017, Vol. 17, No. 7, pp. 40-44). Thus, in some further embodiments, the formulation is a preservative-free formulation provided in a multi-dose container suitable for administering the preservative-free formulation to the eye.

[0136] Pharmaceutically acceptable surfactants In some embodiments, the formulation further comprises a surfactant (surface active agent), preferably a non-ionic surfactant. For example, the formulation may comprise a non-ionic surfactant selected from a polysorbate, such as polysorbate 80, and a poloxamer, such as poloxamer 188 or poloxamer 407. In some embodiments, the formulation comprises polysorbate 80 as a surfactant.

[0137] In the formulations described herein, e.g., gel formulations, suitable concentrations of the surfactant may range, for example, from 0.1 to 5 g / l, 0.2 to 5 g / l, 0.5 to 5 g / l, 0.1 to 4 g / l, 0.2 to 4 g / l, 0.5 to 4 g / l, 0.1 to 3 g / l, 0.2 to 3 g / l, 0.5 to 3 g / l; 0.1 to 2 g / l, 0.2 to 2 g / l, or 0.5 to 2 g / l. In some embodiments, suitable concentrations of the surfactant in the formulations described herein, e.g., gel formulations, are within the range of 0.1 to 1.5 g / l, 0.2 to 1.5 g / l, 0.5 to 1.5 g / l, or 0.8 to 1.5 g / l; for example, within the range of 0.1 to 1.2 g / l, 0.2 to 1.2 g / l, 0.5 to 1.2 g / l, or 0.8 to 1.2 g / l. In some embodiments, a suitable concentration of the surfactant in the gel formulations described herein is in the range of 0.9 to 1.1 g / l, for example about 1.0 g / l. In some of these embodiments, the surfactant is polysorbate 80.

[0138] In the emulsion formulations described herein, the concentration of surfactant is generally higher than in gel formulations, and suitable concentrations of surfactant may be in the ranges of, for example, 5-50 g / l, 10-50 g / l, 15-50 g / l, 5-45 g / l, 10-45 g / l, 15-45 g / l, 5-40 g / l, 10-40 g / l, or 15-40 g / l.

[0139] In some embodiments, the formulations provided herein do not contain a surfactant. In some embodiments, the formulation is a gel formulation that does not contain a surfactant.

[0140] Pharmaceutically acceptable solubilizing agent In some embodiments, the formulations provided herein comprise a solubilizing effective amount of a pharma- ceutically acceptable solubilizer (or solubilizing agent), such as macrogol 15 hydroxystearate, polyoxyl castor oil, polyvinylpyrrolidone, or a cyclodextrin (e.g., β-cyclodextrin).

[0141] In some embodiments, the formulation contains a cyclodextrin, such as a β-cyclodextrin, in a concentration ranging from about 10 to about 100 g / l, such as from 20 to 100 g / l, or from 50 to 100 g / l, such as from 70 to 100 g / l, or from 80 to 100 g / l.

[0142] In some embodiments, the formulation contains macrogol 15 hydroxystearate, for example in a concentration ranging from about 0.5 to 5 g / l, such as 1 to 4.5 g / l, or 1.5 to 4 g / l, such as 2 to 3 g / l.

[0143] In some embodiments, the formulation contains polyoxyl castor oil in a concentration ranging, for example, from about 10 to about 100 g / l, such as from 20 to 80 g / l, or from 30 to 70 g / l, such as from 40 to 60 g / l.

[0144] In some embodiments, the formulation contains polyoxyl castor oil in a concentration ranging, for example, from about 1 to about 30 g / l, such as from 2 to 25 g / l, or from 4 to 20 g / l, such as from 7 to 15 g / l.

[0145] In some embodiments, the formulations provided herein do not contain a solubilizing agent.

[0146] Finally, it should be noted that some ingredients have several functional attributes and therefore may be present in the formulations of the present invention in different capacities. For example, those skilled in the art will know that carbomer copolymer (type B) is used in the field of pharmaceutical formulations as a thickener, a gel former, a stabilizer, and an emulsifier. Similarly, polyoxyl castor oil is utilized not only as a non-ionic solubilizer, but also as an oil-in-water emulsifier. Other ingredients with multiple uses described herein are, for example, macrogol 15 hydroxystearate (non-ionic solubilizer, emulsifier), polyvinylpyrrolidone (solubilizer, viscosity enhancer), etc.

[0147] It should also be noted that any functional agent referred to herein (e.g., thickening agents, tonicity agents, moisturizing agents, etc.) may generally comprise one or more compounds having the requisite functionality, i.e., unless otherwise stated or clear from the context, the functional agent may consist of only one such compound or may comprise a mixture of two or more such compounds.

[0148] In some embodiments, the formulations provided herein do not contain any of optional ingredients (vii)-(ix), or in the case of gel formulations, do not contain any of optional ingredients (vii)-(x).

[0149] In some further embodiments, the formulations provided herein comprise: (i) a therapeutically effective amount of laquinimod or a pharma- ceutical acceptable salt thereof, as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent, e.g., a thickening agent selected from carbomer copolymers (e.g., type B) and / or cellulose derivatives, such as sodium carboxymethylcellulose, in an amount sufficient to provide a viscosity as defined herein, preferably from about 2 to 50 mPas, about 2 to 40 mPas, about 2 to 30 mPas, about 10 to 50 mPas, about 10 to 40 mPas, about 10 to 30 mPas, about 10 to about 25 mPas, about 15 to 50 mPas, about 15 to 40 mPas, about 15 to 30 mPas, or about 15 to about 25 mPas; (iii) a pharma- ceutically acceptable tonicity agent, e.g., a non-ionic tonicity agent such as mannitol, in an amount sufficient to provide an osmolality as described herein, preferably between about 200 and 400 mOsm / kg, or between about 250 and 350 mOsm / kg, or between about 280 and 320 mOsm / kg; (iv) a pharma- ceutically acceptable humectant, e.g., a polyol such as glycerol; (v) a pharma- ceutically acceptable antioxidant, such as Na-EDTA; and (vi) a pharma- ceutically acceptable pH adjusting agent, e.g., a basic buffer such as TRIS or disodium hydrogen phosphate dihydrate, in an amount sufficient to provide a pH of at least 6.8, e.g., a pH of about 7 to 8.4, e.g., about 7.4 to about 8.4, about 7.4 to 8.0, or about 8.0 to 8.4; and, optionally, (vii) a pharma- ceutically acceptable preservative, e.g., benzalkonium chloride; (viii) a pharma- ceutically acceptable surfactant, e.g., a polysorbate such as polysorbate 80; (ix) a pharma- ceutically acceptable solubilizer, such as macrogol 15 hydroxystearate; and (x) a pharma- ceutically acceptable oil, e.g. a vegetable oil such as castor oil; The composition comprises one or more components selected from the group consisting of

[0150] In some embodiments, the formulation for ocular administration comprises: (i) a therapeutically effective amount of laquinimod or a pharma- ceutical acceptable salt thereof, as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent in an amount sufficient to provide a dynamic viscosity, measured at 20° C., of 10 to 45 mPas, e.g., 15 to 45 mPas; (iii) a pharma- ceutically acceptable tonicity agent in an amount sufficient to provide an osmolality of 200-400 mOsm / kg, e.g., 250-375 mOsm / kg; (iv) a pharma- ceutically acceptable moisturizer; (v) a pharma- ceutically acceptable antioxidant; and (vi) A pharma- ceutically acceptable pH adjusting agent in an amount sufficient to provide a pH of 6.8 to 8.0.

[0151] In some embodiments, the formulation for ocular administration comprises: (i) a therapeutically effective amount of laquinimod or a pharma- ceutical acceptable salt thereof, as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent in an amount sufficient to provide a dynamic viscosity of 10 to 30 mPas, measured at 20° C.; (iii) a pharma- ceutically acceptable tonicity agent in an amount sufficient to provide an osmolality of 200-400 mOsm / kg; (iv) glycerol; (v) a pharma- ceutically acceptable antioxidant; and (vi) A pharma- ceutically acceptable pH adjusting agent in an amount sufficient to provide a pH of 6.8 to 8.5, e.g., 7.4 to 8.4.

[0152] In some embodiments, the formulations provided herein have a viscosity of about 2-50 mPas, about 2-45 mPas, about 2-40 mPas, about 2-30 mPas, about 10-50 mPas, about 10-45 mPas, about 10-40 mPas, about 10-30 mPas, about 15-50 mPas, about 15-45 mPas, about 15-40 mPas, or about 15-30 mPas; an osmolarity of about 200-400 mOsm / kg, about 250-375 mOsm / kg, about 250-350 mOsm / kg, or about 250-320 mOsm / kg; and a pH of about 6.8-8.5, about 6.8-8.4, about 6.8-8.0, about 7.0 to about 8.0, for example about 7.4-8.0.

[0153] In some embodiments, the formulations provided herein have a viscosity of about 15 to 45 mPas; an osmolality of about 250 to 375 mOsm / kg; and a pH of about 6.8 to about 8.0.

[0154] In some embodiments, the formulations provided herein have a viscosity of about 20-40 mPas; an osmolality of about 280-320 mOsm / kg; and a pH of about 7.0 to about 8.0, for example about 7.4.

[0155] In some embodiments, the formulation comprises: (i) a therapeutically effective amount of laquinimod or a pharma- ceutical acceptable salt thereof, as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent, e.g., a thickening agent described herein, in an amount sufficient to provide a viscosity as defined herein, preferably about 2-50 mPas, about 2-45 mPas, about 2-40 mPas, about 2-35 mPas, about 10-50 mPas, about 10-45 mPas, about 10-40 mPas, about 10-35 mPas, about 15-50 mPas, about 15-45 mPas, about 15-40 mPas, or about 15-35 mPas; (iii) a pharma- ceutically acceptable tonicity agent, e.g., an isotonicity agent described herein, in an amount sufficient to provide an osmolality as indicated herein, preferably about 200-400 mOsm / kg, about 250-350 mOsm / kg, about 250-375 mOsm / kg, or about 280-320 mOsm / kg; (iv) a hydrating agent, such as a hydrating agent described herein, e.g., glycerol; (v) a pharma- ceutically acceptable antioxidant, e.g., an antioxidant described herein, e.g., Na-EDTA; and (vi) a pharma- ceutically acceptable pH adjusting agent, e.g., a pH adjusting agent described herein, in an amount sufficient to provide a pH of at least 6.8, e.g., about 6.8 to 8.5, or about 6.8 to 8.0, or about 7.0 to 8.0, e.g., about 7.4; and, optionally, (vii) a pharma- ceutically acceptable preservative; (viii) a pharma- ceutically acceptable surfactant; (ix) a pharma- ceutically acceptable solubilizer; and (x) a pharma- ceutically acceptable oil; The composition comprises one or more components selected from the group consisting of

[0156] 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, water for injection, etc.

[0157] Water and oil-containing emulsions In some embodiments, the formulation is a water and oil containing emulsion, for example an oil in water emulsion.

[0158] In water and oil-containing emulsion formulations, the oil is a pharma- ceutically acceptable oil, for example an oil selected from vegetable oils such as castor oil, corn oil, olive oil, or camelina oil. In some embodiments, the oil is castor oil. As will be readily understood by those skilled in the art, the ratio of oil to aqueous phase will vary depending on whether the oil forms the external or internal phase. Thus, in a water-in-oil emulsion, the volume of the oil will usually be greater than the volume of the aqueous phase, and vice versa in an oil-in-water emulsion. In the emulsion, it is contemplated that the internal phase (e.g., oil phase) may be present in an amount of, for example, 10-100 g / l, or 20-80 g / l, for example, 30-70 g / l, for example, about 40-60 g / l.

[0159] In some embodiments, the formulations provided herein are water and oil containing emulsions, preferably oil-in-water emulsions, comprising: - laquinimod or a pharma- ceutically acceptable salt thereof; - a thickening agent, such as a carbomer copolymer and / or sodium carboxymethylcellulose, in a concentration sufficient to provide a viscosity within the ranges set forth herein; - Tonicity agents such as mannitol; - A humectant such as glycerol; -Antioxidants such as Na-EDTA; - a pH buffer resulting in a pH in the range of 6.8 to 8.5, or 7.0 to 8.5, or 7.4 to 8.4, or 8.0 to 8.4, for example a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS; - optionally a preservative, such as benzalkonium chloride; - optionally surfactants such as polysorbates (e.g. polysorbate 80) and / or poloxamers (e.g. poloxamer 407); - optionally a solubilizer (or emulsifier), such as macrogol 15 hydroxystearate, polyoxyl castor oil; and - A water and oil containing emulsion, including vegetable oils such as castor oil.

[0160] In some embodiments, the water and oil containing emulsion (preferably an oil-in-water emulsion) comprises: - laquinimod or a pharma- ceutically acceptable salt thereof; - a thickening agent, such as, for example, a carbomer copolymer and / or sodium carboxymethylcellulose, in a concentration sufficient to provide a viscosity within the ranges indicated herein; - Tonicity agents such as mannitol; - A humectant such as glycerol; -Antioxidants such as Na-EDTA; - a pH buffer resulting in a pH in the range of 6.8 to 8.5, or 7.0 to 8.5, or 7.4 to 8.4, or 8.0 to 8.4, for example a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS; - Preservatives such as benzalkonium chloride; - surfactants such as polysorbates (e.g. polysorbate 80) and / or poloxamers (e.g. poloxamer 407); - solubilizers (or emulsifiers) such as macrogol 15 hydroxystearate, polyoxyl castor oil; and - Contains vegetable oils such as castor oil.

[0161] In some embodiments, the water and oil containing emulsion (preferably an oil-in-water emulsion) comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, for example about 5 to about 100 g / l, about 10 to about 100 g / l, about 20 to 80 g / l, or about 50 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof; from about 2 to about 10 g / l, for example from about 3 to about 8 g / l, or from about 4 to about 6 g / l, of sodium carboxymethylcellulose and / or from about 0.2 to 1 g / l, for example from about 0.3 to about 0.8, for example about 0.5 g / l, of a carbomer copolymer (for example carbomer polymer type B); - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 7.0 to 8.5, such as a pH of 7.4 to 8.4, or a pH of 8.0 to 8.4, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (e.g. TRIS in an amount of about 1 to 1.5 g / l); optionally from about 0.05 to about 0.2 g / l, for example from about 0.1 to about 0.15 g / l, of benzalkonium chloride; - optionally from about 10 to about 50 g / l, for example from about 20 to about 40 g / l, of a surfactant, preferably a non-ionic surfactant, for example a polysorbate and / or a poloxamer, for example polysorbate 80 and / or poloxamer 407; optionally from about 1 to about 5 g / l, such as from about 1.5 to about 3.5 g / l, such as from about 2.5 g / l, of macrogol 15 hydroxystearate, or from about 30 to about 70 g / l, such as from about 40 to about 60 g / l, such as from about 50 g / l of polyoxyl castor oil (e.g. polyoxyl 35 castor oil); and from about 20 to about 100 g / l, for example from about 30 to about 70 g / l, for example about 50 g / l of a vegetable oil, such as castor oil.

[0162] In some embodiments, the water and oil containing emulsion (preferably an oil-in-water emulsion) comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, for example about 5 to about 100 g / l, about 10 to about 100 g / l, about 20 to 80 g / l, or about 50 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof; from about 2 to about 10 g / l, for example from about 3 to about 8 g / l, or from about 4 to about 6 g / l, of sodium carboxymethylcellulose and / or from about 0.2 to 1 g / l, for example from about 0.3 to about 0.8, for example about 0.5 g / l, of a carbomer copolymer (for example carbomer polymer type B); - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 7.0 to 8.5, such as a pH of 7.4 to 8.4, or a pH of 8.0 to 8.4, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (e.g. TRIS in an amount of about 1 to 1.5 g / l); - from about 0.05 to about 0.2 g / l, for example from about 0.1 to about 0.15 g / l of benzalkonium chloride; from about 10 to about 50 g / l, for example from about 20 to about 40 g / l, of a surfactant, preferably a non-ionic surfactant, such as a polysorbate and / or a poloxamer, for example polysorbate 80 and / or poloxamer 407; from about 1 to about 5 g / l, for example from about 1.5 to about 3.5 g / l, for example about 2.5 g / l of macrogol 15 hydroxystearate, or from about 30 to about 70 g / l, for example from about 40 to about 60 g / l, for example about 50 g / l of polyoxyl castor oil (for example polyoxyl 35 castor oil); from about 20 to about 100 g / l, for example from about 30 to about 70 g / l, for example about 50 g / l of a vegetable oil, such as castor oil.

[0163] Some additional emulsion formulations provided herein are as shown in Tables 1-12.

[0164] [Table 1]

[0165] [Table 2]

[0166] [Table 3]

[0167] [Table 4]

[0168] [Table 5]

[0169] [Table 6]

[0170] [Table 7]

[0171] [Table 8]

[0172] [Table 9]

[0173] [Table 10]

[0174] [Table 11]

[0175] [Table 12]

[0176] Gel formulation In some embodiments, the formulation is a gel formulation. In some embodiments, the gel formulation is - laquinimod or a pharma- ceutically acceptable salt thereof; - a thickening agent, such as carbomer copolymer, hydroxypropyl methylcellulose, polyvinyl alcohol, and / or sodium carboxymethylcellulose, in a concentration sufficient to provide a viscosity within the ranges set forth herein; - Tonicity agents such as mannitol; - A humectant such as glycerol; -Antioxidants such as Na-EDTA; - a pH buffer resulting in a pH in the range of 6.8-8.5, 7.0-8.5, 7.4-8.4, 7.4-8.0, or 8.0-8.4, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS; - optionally a preservative, such as benzalkonium chloride; - optionally surfactants such as polysorbates (e.g. polysorbate 80) and / or poloxamers (e.g. poloxamer 188, or poloxamer 407); and - Optionally, solubilizers such as macrogol 15 hydroxystearate, polyvinylpyrrolidone, etc.

[0177] In some embodiments, the gel formulation comprises: - laquinimod or a pharma- ceutically acceptable salt thereof; - a thickening agent, such as carbomer copolymer, hydroxypropyl methylcellulose, polyvinyl alcohol, and / or sodium carboxymethylcellulose, in a concentration sufficient to provide a viscosity within the ranges set forth herein; - Tonicity agents such as mannitol; - A humectant such as glycerol; -Antioxidants such as Na-EDTA; - Preservatives such as benzalkonium chloride; - a pH buffer resulting in a pH in the range of 6.8-8.5, 7.0-8.5, 7.4-8.4, 7.4-8.0, or 8.0-8.4, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS; - surfactants such as polysorbates (e.g. polysorbate 80) and / or poloxamers (e.g. poloxamer 188, or poloxamer 407); and - Optionally, containing a solubilizer such as macrogol 15 hydroxystearate, polyvinylpyrrolidone, or polyoxyl castor oil.

[0178] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, for example about 10 to about 100 g / l, about 20 to 80 g / l, or about 50 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof; from about 1 to about 10 g / l, such as from about 2 to about 8 g / l, or from about 3 to about 5 g / l, of sodium carboxymethylcellulose and / or from about 0.5 to about 6 g / l, such as from about 1 to about 5 g / l, for example from about 1.5 to about 3 g / l, of a carbomer copolymer (for example carbomer polymer type B), or from about 2 to about 10 g / l, such as from about 3 to about 7 g / l, for example about 5 g / l, of hydroxypropyl methylcellulose, or from about 20 to about 60 g / l, such as from about 30 to about 50 g / l, for example about 40 g / l, of polyvinyl alcohol; - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (for example TRIS in an amount of about 1 to 1.5 g / l); optionally from about 0.05 to about 0.2 g / l, for example from about 0.1 to about 0.15 g / l, of benzalkonium chloride; - optionally from about 0.1 to about 5 g / l, for example from about 0.2 to about 3 g / l, or from about 0.5 to about 2 g / l, of a surfactant, preferably a non-ionic surfactant, such as a polysorbate and / or a poloxamer, for example polysorbate 80 and / or poloxamer 407 or poloxamer 188; and optionally from about 1 to about 5 g / l, such as from about 1.5 to about 3.5 g / l, for example about 2.5 g / l of macrogol 15 hydroxystearate, or from about 30 to about 70 g / l, such as from about 40 to about 60 g / l, for example about 50 g / l of polyoxyl castor oil (e.g. polyoxyl 35 castor oil), or from about 5 to about 20 g / l, such as from about 8 to about 15 g / l, for example about 10 g / l of polyvinylpyrrolidone.

[0179] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, for example about 10 to about 100 g / l, about 20 to 80 g / l, or about 50 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof; from about 1 to about 10 g / l, such as from about 2 to about 8 g / l, or from about 3 to about 5 g / l, of sodium carboxymethylcellulose and / or from about 0.5 to about 6 g / l, such as from about 1 to about 5 g / l, for example from about 1.5 to about 3 g / l, of a carbomer copolymer (for example carbomer polymer type B), or from about 2 to about 10 g / l, such as from about 3 to about 7 g / l, for example about 5 g / l, of hydroxypropyl methylcellulose, or from about 20 to about 60 g / l, such as from about 30 to about 50 g / l, for example about 40 g / l, of polyvinyl alcohol; - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (for example TRIS in an amount of about 1 to 1.5 g / l); - from about 0.05 to about 0.2 g / l, for example from about 0.1 to about 0.15 g / l of benzalkonium chloride; - optionally from about 0.1 to about 5 g / l, for example from about 0.2 to about 3 g / l, or from about 0.5 to about 2 g / l, of a surfactant, preferably a non-ionic surfactant, such as a polysorbate and / or a poloxamer, for example polysorbate 80 and / or poloxamer 407 or poloxamer 188; and optionally from about 1 to about 5 g / l, such as from about 1.5 to about 3.5 g / l, for example about 2.5 g / l of macrogol 15 hydroxystearate, or from about 30 to about 70 g / l, such as from about 40 to about 60 g / l, for example about 50 g / l of polyoxyl castor oil (e.g. polyoxyl 35 castor oil), or from about 5 to about 20 g / l, such as from about 8 to about 15 g / l, for example about 10 g / l of polyvinylpyrrolidone.

[0180] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutical acceptable salt thereof; - sodium carboxymethylcellulose, and / or carbomer copolymers (e.g., carbomer polymer type B); - tonicity agent; - Moisturizer; - Antioxidants; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0; - Preservatives; optionally a surfactant, such as a non-ionic surfactant; and - optionally including macrogol 15 hydroxystearate, polyoxyl castor oil (e.g. polyoxyl 35 castor oil), or polyvinylpyrrolidone.

[0181] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, for example about 10 to about 100 g / l, about 20 to 80 g / l, or about 50 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof; from about 1 to about 10 g / l, for example from about 2 to about 8 g / l, or from about 3 to about 5 g / l, of sodium carboxymethylcellulose and / or from about 0.5 to about 6 g / l, for example from about 1 to about 5 g / l, for example from about 1.5 to about 3 g / l of a carbomer copolymer (e.g. carbomer polymer type B); - tonicity agent; - Moisturizer; - Antioxidants; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0; - Preservatives; optionally a surfactant, such as a non-ionic surfactant; and optionally from about 1 to about 5 g / l, such as from about 1.5 to about 3.5 g / l, for example about 2.5 g / l of macrogol 15 hydroxystearate, or from about 30 to about 70 g / l, such as from about 40 to about 60 g / l, for example about 50 g / l of polyoxyl castor oil (e.g. polyoxyl 35 castor oil), or from about 5 to about 20 g / l, such as from about 8 to about 15 g / l, for example about 10 g / l of polyvinylpyrrolidone.

[0182] In some embodiments, the gel formulation comprises: - a therapeutically effective amount, for example about 10-100 g / l of laquinimod or a pharma- ceutically acceptable salt thereof; from about 1 to about 10 g / l and / or from about 0.5 to about 6 g / l of a carbomer copolymer (e.g., carbomer polymer type B); - isotonic agent; - Moisturizer; - Antioxidants; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0; - Preservatives; optionally a surfactant, such as a non-ionic surfactant; and optionally, from about 1 to about 5 g / l of macrogol 15 hydroxystearate, or from about 30 to about 70 g / l of polyoxyl castor oil (e.g. polyoxyl 35 castor oil), or from about 5 to about 20 g / l of polyvinylpyrrolidone.

[0183] In some embodiments, the gel formulation comprises: - a therapeutically effective amount, for example about 10-100 g / l of laquinimod or a pharma- ceutically acceptable salt thereof; from about 1 to about 10 g / l and / or from about 0.5 to about 6 g / l of a carbomer copolymer (e.g., carbomer polymer type B); - Mannitol, about 1.5-4 g / l; - glycerol about 10-40 g / l; - Na-EDTA at about 0.2-2 g / l; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0; - about 0.05 to about 0.2 g / l of benzalkonium chloride; - optionally a surfactant, such as a non-ionic surfactant, for example from about 0.1 to about 5 g / l of a surfactant, preferably a non-ionic surfactant; and optionally, from about 1 to about 5 g / l of macrogol 15 hydroxystearate, or from about 30 to about 70 g / l of polyoxyl castor oil (e.g. polyoxyl 35 castor oil), or from about 5 to about 20 g / l of polyvinylpyrrolidone.

[0184] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, for example about 10 to about 100 g / l, about 20 to 80 g / l, or about 50 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof; from about 1 to about 10 g / l, for example from about 2 to about 8 g / l, or from about 3 to about 5 g / l, of sodium carboxymethylcellulose and / or from about 0.5 to about 6 g / l, for example from about 1 to about 5 g / l, for example from about 1.5 to about 3 g / l of a carbomer copolymer (e.g. carbomer polymer type B); - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (for example TRIS in an amount of about 1 to 1.5 g / l); - from about 0.05 to about 0.2 g / l, for example from about 0.1 to about 0.15 g / l of benzalkonium chloride; optionally a surfactant, for example a non-ionic surfactant, for example from about 0.1 to about 5 g / l, for example from about 0.2 to about 3 g / l, or from about 0.5 to about 2 g / l of a surfactant, preferably a non-ionic surfactant, for example a polysorbate and / or a poloxamer, for example polysorbate 80 or poloxamer 407; and from about 1 to about 5 g / l, such as from about 1.5 to about 3.5 g / l, for example about 2.5 g / l of macrogol 15 hydroxystearate, or from about 30 to about 70 g / l, such as from about 40 to about 60 g / l, for example about 50 g / l of polyoxyl castor oil (for example polyoxyl 35 castor oil), or from about 5 to about 20 g / l, such as from about 8 to about 15 g / l, for example about 10 g / l of polyvinylpyrrolidone.

[0185] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, e.g., about 10 to about 100 g / l, about 20 to 80 g / l, or about 20 to about 50 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof; from about 1 to about 10 g / l, for example from about 2 to about 8 g / l, or from about 3 to about 5 g / l, of sodium carboxymethylcellulose and / or from about 0.5 to about 6 g / l, for example from about 1 to about 5 g / l, for example from about 1.5 to about 3 g / l of a carbomer copolymer (e.g. carbomer polymer type B); - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (e.g. TRIS in an amount of about 1 to 1.5 g / l, or disodium hydrogen phosphate dihydrate in an amount of about 1.5 to 2 g / l); and optionally, - a pharma- ceutically acceptable preservative, for example benzalkonium chloride at about 0.05 to about 0.2 g / l, for example about 0.1 to about 0.15 g / l; - a pharma- ceutically acceptable surfactant, for example a non-ionic surfactant, for example from about 0.1 to about 5 g / l, for example from about 0.2 to about 3 g / l, or from about 0.5 to about 2 g / l, for example about 1 g / l of a surfactant, preferably a non-ionic surfactant, for example a polysorbate, for example polysorbate 80; and a pharma- ceutically acceptable solubilizer, for example from about 1 to about 5 g / l, for example from about 1.5 to about 3.5 g / l, for example about 2.5 g / l of macrogol 15 hydroxystearate; The composition comprises one or more components selected from the group consisting of

[0186] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, e.g., about 10 to about 100 g / l, about 20 to 80 g / l, or about 20 to about 50 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof; from about 1 to about 10 g / l, for example from about 2 to about 8 g / l, or from about 3 to about 5 g / l, of sodium carboxymethylcellulose and / or from about 0.5 to about 6 g / l, for example from about 1 to about 5 g / l, for example from about 1.5 to about 3 g / l of a carbomer copolymer (e.g. carbomer polymer type B); - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (for example TRIS in an amount of about 1 to 1.5 g / l); and optionally, - a pharma- ceutically acceptable preservative, for example from about 0.05 to about 0.2 g / l, for example from about 0.1 to about 0.15 g / l of benzalkonium chloride; and a pharma- ceutically acceptable solubilizer, for example from about 1 to about 5 g / l, for example from about 1.5 to about 3.5 g / l, for example about 2.5 g / l of macrogol 15 hydroxystearate; The composition comprises one or more components selected from the group consisting of

[0187] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, e.g., about 10 to about 100 g / l, about 20 to 80 g / l, or about 20 to about 50 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof; from about 1 to about 10 g / l, for example from about 2 to about 8 g / l, or from about 3 to about 5 g / l, of sodium carboxymethylcellulose and / or from about 0.5 to about 6 g / l, for example from about 1 to about 5 g / l, for example from about 1.5 to about 3 g / l of a carbomer copolymer (e.g. carbomer polymer type B); - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 7.0 to 8.5, for example a pH of 7.4 to 8.4, a pH of 7.4 to 8.0, or a pH of 8.0 to 8.4, for example a pH of about 8.0, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (for example TRIS in an amount of about 1 to 1.5 g / l); and optionally, - a pharma- ceutically acceptable preservative, for example from about 0.05 to about 0.2 g / l, for example from about 0.1 to about 0.15 g / l of benzalkonium chloride; and - a pharma- ceutically acceptable surfactant, for example a non-ionic surfactant, for example from about 0.1 to about 5 g / l, for example from about 0.2 to about 3 g / l, or from about 0.5 to about 2 g / l, for example about 1 g / l of a surfactant, preferably a non-ionic surfactant, for example a polysorbate, for example polysorbate 80 The composition comprises one or more components selected from the group consisting of

[0188] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, e.g., about 10 to about 100 g / l, about 10 to about 80 g / l, about 10 to about 50 g / l, or about 10 to about 20 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof, e.g., the sodium salt of laquinimod; from about 1 to about 10 g / l, for example from about 2 to about 8 g / l, or from about 3 to about 5 g / l, of sodium carboxymethylcellulose and / or from about 0.5 to about 6 g / l, for example from about 1 to about 5 g / l, for example from about 1.5 to about 3 g / l of a carbomer copolymer (e.g. carbomer polymer type B); - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 10 to about 30 g / l, or about 15 to about 20 g / l, of glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 6.8 to 8.0, for example a pH of 7.0 to 8.0, or a pH of 7.4 to 8.0, for example a pH of about 7.4, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (e.g. TRIS in an amount of about 1 to 1.5 g / l, or disodium hydrogen phosphate dihydrate in an amount of about 1.5 to 2 g / l); and optionally, - a pharma- ceutically acceptable preservative, for example from about 0.05 to about 0.2 g / l, for example from about 0.1 to about 0.15 g / l of benzalkonium chloride; and - a pharma- ceutically acceptable surfactant, for example a non-ionic surfactant, for example from about 0.1 to about 5 g / l, for example from about 0.2 to about 3 g / l, or from about 0.5 to about 2 g / l, for example about 1 g / l of a surfactant, preferably a non-ionic surfactant, for example a polysorbate, for example polysorbate 80 The composition comprises one or more components selected from the group consisting of

[0189] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, e.g., about 10 to about 100 g / l, about 10 to about 80 g / l, about 10 to about 50 g / l, or about 10 to about 20 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof, e.g., the sodium salt of laquinimod; from about 1 to about 10 g / l, for example from about 2 to about 8 g / l, or from about 3 to about 5 g / l, of sodium carboxymethylcellulose and from about 0.5 to about 6 g / l, for example from about 1 to about 5 g / l, for example from about 1.5 to about 3 g / l of a carbomer copolymer (e.g. carbomer polymer type B); - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l mannitol; - about 10 to 40 g / l, for example about 10 to about 30 g / l, or about 15 to about 20 g / l, of glycerol; - about 0.2-2 g / l, for example about 0.5-1.5 g / l, or about 0.8-1.2 g / l Na-EDTA; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.5, or 6.8 to 8.0, for example a pH of 7.0 to 8.0, or a pH of 7.4 to 8.0, for example a pH of about 7.4, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS (e.g. TRIS in an amount of about 1 to 1.5 g / l, or disodium hydrogen phosphate dihydrate in an amount of about 1.5 to 2 g / l); and optionally, - a pharma- ceutically acceptable preservative, for example from about 0.05 to about 0.2 g / l, for example from about 0.1 to about 0.15 g / l of benzalkonium chloride; and - a pharma- ceutically acceptable surfactant, for example a non-ionic surfactant, for example from about 0.1 to about 5 g / l, for example from about 0.2 to about 3 g / l, or from about 0.5 to about 2 g / l, for example about 1 g / l of a surfactant, preferably a non-ionic surfactant, for example a polysorbate, for example polysorbate 80 The composition comprises one or more components selected from the group consisting of

[0190] In some embodiments, the gel formulation comprises: - a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof, e.g., about 10 to about 100 g / l, about 10 to about 80 g / l, about 10 to about 50 g / l, or about 10 to about 20 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt thereof, e.g., the sodium salt of laquinimod; - from about 3 to about 5 g / l sodium carboxymethylcellulose and from about 1.5 to about 3 g / l carbomer copolymer (e.g. carbomer polymer type B); - about 2.5 to about 3 g / l mannitol; - about 15 to about 20 g / l glycerol; - Na-EDTA approximately 0.8-1.2 g / l; - a pH buffer in an amount effective to provide a pH of 6.8 to 8.0, for example a pH of about 7.4 (e.g., disodium hydrogen phosphate dihydrate in an amount of about 1.5 to 2 g / l); and preferably - from about 0.1 to about 0.15 g / l of benzalkonium chloride; and - about 0.5 to about 1.5 g / l of polysorbate 80 The compound includes one or more (e.g., both) components selected from:

[0191] In some embodiments, the gel formulation comprises: (i) a therapeutically effective amount of laquinimod or a pharma- ceutical acceptable salt thereof, as an active ingredient; (ii) a pharma- ceutically acceptable thickening agent, e.g., a thickening agent selected from carbomer copolymers (e.g., type B) and / or cellulose derivatives such as sodium carboxymethylcellulose, in an amount sufficient to provide a viscosity as defined herein, preferably from about 2 to 50 mPas, about 2 to 40 mPas, about 2 to 30 mPas, about 10 to 50 mPas, about 10 to 40 mPas, about 10 to 30 mPas, about 10 to about 25 mPas, about 15 to 50 mPas, about 15 to 45 mPas, about 15 to 40 mPas, about 15 to 35 mPas, about 15 to 30 mPas, or about 15 to about 25 mPas; (iii) a pharma- ceutically acceptable tonicity agent, e.g., a non-ionic tonicity agent such as mannitol, in an amount sufficient to provide an osmolality as described herein, preferably about 200-400 mOsm / kg, about 250-375 mOsm / kg, or about 250-350 mOsm / kg, or about 280-320 mOsm / kg; (iv) a pharma- ceutically acceptable humectant, e.g., a polyol such as glycerol; (v) a pharma- ceutically acceptable antioxidant, such as Na-EDTA; and (vi) a pharma- ceutically acceptable pH adjusting agent, e.g., a basic buffer such as TRIS or disodium hydrogen phosphate dihydrate, in an amount sufficient to provide a pH of at least 6.8, e.g., about 6.8 to about 8.4, about 7.0 to about 8.4, e.g., about 7.4 to about 8.4, 6.8 to about 8.0, about 7.0 to about 8.0, about 7.4 to 8.0, or about 8.0 to 8.4; and, optionally, (vii) a pharma- ceutically acceptable preservative, e.g., benzalkonium chloride; (viii) a pharma- ceutically acceptable surfactant, e.g., a polysorbate, such as polysorbate 80; and (ix) a pharma- ceutically acceptable solubilizer, such as macrogol 15 hydroxystearate; The composition comprises one or more components selected from the group consisting of

[0192] In some further embodiments, the gel formulation comprises: (i) 10 to 100 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt of laquinimod; (ii) 1 to 10 g / l sodium carboxymethylcellulose and / or 0.5 to about 6 g / l carbomer copolymer; (iii) mannitol at 1.5-4 g / l; (iv) glycerol between 10 and 40 g / l; (v) 0.2 to 2 g / l Na-EDTA; and (vi) A pH adjusting agent in an amount effective to provide a pH of 6.8 to 8.4, for example, 7.4 to 8.4.

[0193] In some embodiments, the gel formulation for ocular administration, e.g., topical administration to the eye, comprises: (i) 10 to 12 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt of laquinimod, e.g. the sodium salt of laquinimod; (ii) 2-4 g / l sodium carboxymethylcellulose and 1-2 g / l carbomer copolymer; (iii) 2–3 g / l mannitol; (iv) glycerol between 15 and 20 g / l; (v) 0.5 to 1.5 g / l Na-EDTA; and (vi) A pH adjusting agent in an amount effective to provide a pH in the range of 6.8 to 8.0, e.g., about 7.4.

[0194] In some embodiments, the gel formulation comprises, in addition to components (i)-(vi), (vii) a pharma- ceutically acceptable preservative; and (viii) further comprising a pharma- ceutically acceptable surfactant (surface active agent).

[0195] In some embodiments, the gel formulation comprises: (i) 10 to 12 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt of laquinimod, e.g. the sodium salt of laquinimod; (ii) 2-4 g / l sodium carboxymethylcellulose and 1-2 g / l carbomer copolymer; (iii) 2–3 g / l mannitol; (iv) glycerol between 15 and 20 g / l; (v) 0.5-1.5 g / l Na-EDTA; (vi) a pH adjusting agent in an amount effective to provide a pH in the range of 6.8 to 8.0, e.g., about 7.4; (vii) 0.05 to 0.1 g / l of benzalkonium chloride; and (viii) Contains 0.5 to 1.5 g / l of polysorbate 80.

[0196] In some embodiments, the gel formulations provided herein do not contain a surfactant. In some embodiments, the gel formulations provided herein do not contain a solubilizing agent. In some embodiments, the gel formulations provided herein do not contain a preservative. In some embodiments, the gel formulations provided herein do not contain any of optional ingredients (vii)-(ix).

[0197] Some additional gel formulations provided herein are as shown in Tables 13-37.

[0198] [Table 13]

[0199] [Table 14]

[0200] [Table 15]

[0201]

Table 16

[0202]

Table 17

[0203]

Table 18

[0204]

Table 19

[0205]

Table 20

[0206]

Table 21

[0207]

Table 22

[0208]

Table 23

[0209]

Table 24

[0210]

Table 25

[0211]

Table 26

[0212]

Table 27

[0213]

Table 28

[0214]

Table 29

[0215]

Table 30

[0216]

Table 31

[0217]

Table 32

[0218]

Table 33

[0219]

Table 34

[0220]

Table 35

[0221]

Table 36

[0222] [Table 37]

[0223] Preparation method A method for preparing the formulation of the present invention comprises the steps of: (1) mixing excipients other than the thickening agent with water to obtain an aqueous solution; (2) mixing the thickening agent(s) with the aqueous solution and stirring for 8 to 12 hours while cooling; (3) adding a suitable pH adjusting agent, such as a basic buffer, to the viscous solution; (4) optionally, adjusting the volume of the viscous solution by adding more water; (5) mixing laquinimod with the viscous solution, optionally with mechanical dispersion; (6) In the case of oil-in-water emulsions, if necessary, a method is also provided herein further comprising the steps of adjusting the volume of the aqueous phase and mixing a pharma- ceutically acceptable oil with the aqueous phase.

[0224] Use of the formulation The formulations provided herein are administered locally, preferably topically, to the patient's eye from a dose container that allows for the instillation of small amounts of the formulation, for example, allowing administration of 1-10 drops to the eye, with a drop volume of 10-100 μl, or 10-50 μl, or 10-40 μl, for example 20-40 μl. In some embodiments, the formulation is instilled from a single-dose container, or a single-use container. In some embodiments, the formulation is instilled from a multi-dose container that includes PureFlow® technology, such as the Novelia® multi-dose eye dropper sold by Nemera (France).

[0225] Thus, in some embodiments, the formulations of the invention, which are advantageously free of preservatives, are provided in multi-dose containers, e.g., Novelia® multi-dose eye droppers, having a valve configuration that can effectively protect the formulation from microbial contamination.

[0226] The therapeutically effective amount of laquinimod can be in the range of 0.05-4.0 mg per dose (or the equivalent amount of a pharma- ceutically acceptable salt of laquinimod). In some embodiments, the therapeutically effective amount of laquinimod is 0.05-2.0 mg per dose. In some embodiments, the therapeutically effective amount of laquinimod is about 0.05 mg per dose. In some embodiments, the therapeutically effective amount of laquinimod is about 0.1 mg per dose. In some embodiments, the therapeutically effective amount is about 0.5 mg per dose. In some embodiments, the therapeutically effective amount of laquinimod is at least 0.05 mg / day.

[0227] Preferably, the formulations provided herein are administered on a regular basis, such as 1-6 times per day, e.g., 1-5 times per day, 1-3 times per day, or 1-2 times per day. In some embodiments, the regular administration is once per day. In some embodiments, the regular administration is twice per day. In some embodiments, the regular administration is three times per day. In some embodiments, the regular administration is once every two days. In some embodiments, the formulation is administered once per week.

[0228] In some embodiments, the formulation is administered once daily for 2-14 days or for a longer period, such as for 1-6 months, 2-6 months, or 3-6 months. In some embodiments, the formulation is administered once daily for 3 days. In some embodiments, the formulation is administered once daily for 5-14 days. In some embodiments, the formulation is administered once daily for 10-14 days. In some embodiments, the formulation is administered once daily for about 7 days. In some embodiments, the formulation is administered once weekly for 1-12 months, or 1-6 months, or 1-3 months, such as once weekly for 3-6 months. However, the exact dosage regimen and length of treatment will typically be determined by the treating physician.

[0229] A further aspect is a dosage container containing the laquinimod formulation provided herein. The dosage container may include an integrated means that allows for administration of a suitable dose of the formulation to the patient's eye, or such means may be provided separately. In some embodiments, the dosage container is a multi-dose container, allowing for instillation of a suitable dose of the formulation to the patient's eye. 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 similar type of bottle. In some of these embodiments, the formulations provided herein do not contain a preservative.

[0230] A further aspect is a kit (sometimes referred to as a kit of parts) comprising a dosage container as disclosed herein and instructions for use. In some embodiments, such kits also include one or more additional containers containing additional implements or materials useful in connection with administration of the formulation, such as cleaning, wiping, alternative administration means, etc.

[0231] The ophthalmic formulations disclosed herein are useful for treating ophthalmic diseases in which laquinimod provides a therapeutically beneficial effect, such as glaucoma, ocular inflammatory diseases, and diseases involving excessive vascularization of the eye. In some embodiments, the OID is a disease affecting the middle or posterior segment of the eye.

[0232] The therapeutic activity of laquinimod in treating such diseases is described in the patent documents referred to herein above, the contents of which are incorporated herein by reference.

[0233] In some embodiments, the ocular disease is an inflammatory eye disease (OID). In some embodiments, the OID is selected from uveitis, bacterial conjunctivitis, viral conjunctivitis, or inflammation of the orbital tissue, lacrimal apparatus, eyelid, cornea, retina, or optic nerve pathway.

[0234] 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.

[0235] In some embodiments, the OID is uveitis. Uveitis is inflammation of the uvea or uveal tract, which includes the iris, ciliary body, and choroidal portions of the eye. Inflammation of the retina, called retinitis, and inflammation of the optic nerve, called optic neuritis, can occur with or without uveitis. Anatomically, uveitis can be classified as anterior, intermediate, posterior, or diffuse, depending on which part of the uveal tract is affected. Anterior uveitis is primarily localized to the front of the eye and includes iritis and iridocyclitis. Intermediate uveitis, also called peripheral uveitis, is centered in the area of ​​the ciliary body and squamous epithelium just behind the iris and lens. For this reason, it is sometimes called "cyclitis" and "pars planitis." Posterior uveitis can refer to any of several forms of retinitis, choroiditis, or optic neuritis. Diffuse uveitis refers to inflammation affecting all parts of the eye, including the anterior, intermediate, and posterior structures (The Merck Manual, 1999). Inflammation from uveitis can lead to a variety of other ocular conditions, including glaucoma, cataracts, and cystoid macular edema, which can ultimately lead to permanent vision loss.

[0236] In some embodiments, the uveitis is intermediate uveitis, posterior uveitis, or diffuse uveitis. In some embodiments, the uveitis is posterior uveitis or diffuse uveitis. In some embodiments, the uveitis comprises posterior uveitis. In some embodiments, the uveitis is posterior uveitis. In some embodiments, the uveitis is diffuse uveitis.

[0237] In some embodiments, the OID is 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, Graves' disease, Guillain-Barre 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.

[0238] In some embodiments, the eye disease involves excessive (or harmful) angiogenesis of the eye, for example in response to an external stimulus to the eye or as a natural consequence of aging. The eye is composed of many different tissues, such as the cornea, iris, ciliary body, choroid, retina, and macula, which may be subject to harmful angiogenesis. In some embodiments, the eye disease involves excessive angiogenesis of the cornea, iris, ciliary body, choroid, retina, and / or macula. In some embodiments, the eye disease involves excessive angiogenesis of tissues in the front of the eye, such as the cornea, iris, and ciliary body.

[0239] In some embodiments, the ocular disease is selected from the group consisting of corneal neovascularization, iris neovascularization, ciliary body neovascularization, corneal pannus, choroidal neovascularization, retinal neovascularization, hypertensive retinopathy, wet age-related macular degeneration, proliferative diabetic retinopathy, retinopathy of prematurity, and ischemic retinopathy.

[0240] Moreover, in some embodiments, the eye disease involves excessive vascularization of tissues behind the eye, such as the choroid, retina, and macula.

[0241] In some embodiments, the eye disease associated with excessive angiogenesis is retinal neovascularization. In some further embodiments, the eye disease associated with excessive angiogenesis is macular angiogenesis, also known as wet age-related macular degeneration. EXAMPLES

[0242] The following abbreviations may be used hereinafter: β-CD β-Cyclodextrin EP European Pharmacopoeia HPLC High Performance Liquid Chromatography HPMC Hydroxypropyl methylcellulose kDa kilodalton (kg / mol) MFI Microflow Imaging NaCMC Sodium Carboxymethylcellulose pa pro analysis PVA Polyvinyl Alcohol PVDF Polyvinylidene Fluoride rH / RH Relative Humidity RP-HPLC Reversed-phase high-performance liquid chromatography RT room temperature SD standard deviation SVP Subvisible Particles USP United States Pharmacopeia WFI water for injection

[0243] material All excipients used in the formulation were of United States Pharmacopoeia (USP) and / or European Pharmacopoeia (EP) quality. Excipients were selected for ophthalmic administration. All chemicals used in analytical methods were of appropriate quality for the individual analytical method (e.g., pro-analysis).

[0244] Preparation of gel and emulsion formulations The formulation was prepared as follows: weighing the excipients, dissolving them in water for injection (WFI) to approximately 80% of the final volume overnight at 2-8°C on a magnetic stirrer, adjusting the pH of the formulation at 23-25°C, bringing it up to the final volume, and dissolving laquinimod. The pH adjustment of the highly viscous formulation was performed on day 2, and dispensing of the formulation and initiation of the accelerated degradation study were performed on day 3.

[0245] The excipients were weighed out in the order according to solubility, i.e., the more soluble excipients were dosed first in the formulation, and the less soluble excipients, i.e., the gelling agents, were added last. In detail, the process is as follows: Water (Aqua B. Braun, Braun) is placed in a non-sterile 0.5 L PP beaker (Sarstedt) and excipients are added stepwise as above to prepare approximately 80% of the final volume, stirring the formulation with a stirrer magnet bar (CIMARECi Poly, Thermo Scientific) between additions.

[0246] Although complete dissolution of all excipients is necessary for pH adjustment, it was difficult to completely dissolve all formulations even after overnight stirring because some formulations contained excipients with low solubility such as carbomer type B. Therefore, the formulations after overnight stirring were visually inspected, and if incomplete dissolution of the excipients was observed, a high-performance rod disperser (T 18 digital ULTRA-TURRAX (registered trademark), IKA) equipped with a dispersion tool (S 18 N - 19 G, IKA) was applied to the formulation.

[0247] A sufficient amount of formulation was saved for the placebo sample and laquinimod was dissolved in the gel formulation at 50 mg / ml using a container-mounted disperser (ULTRA-TURRAX® Tube Drive P control, IKA) fitted with a single-use mixing container (DIS-300-SM.10, IKA). Laquinimod and formulation were combined in the mixing container, the disperser was set at 950 rpm, and the formulation was stirred for at least 5 minutes or until laquinimod was completely dissolved by visual inspection.

[0248] For emulsion formulations, the aqueous phase of the formulation was blended with the oil phase; that is, laquinimod was dissolved in the aqueous phase before the castor oil was added. Thus, the volume of the aqueous phase was corrected for the volume of oil before dissolving laquinimod, as described above. Emulsification was performed with a disperser set at a stirring speed that created a vortex between the stirrer and the liquid surface (1200 rpm for the 100 ml formulation and 750 rpm for the 50 ml placebo). Stirring was performed for 2 minutes, during which the oil was slowly added to the aqueous solution over approximately 20 seconds using a reverse pipette method (500-5000 μl pipette, Eppendorf), taking into account the high viscosity of the oil.

[0249] Adjusting pH Final pH adjustments of all formulations and buffers, as well as pH measurements of the resulting formulations, were performed at temperatures between 23°C and 25°C (in accordance with both EP and USP) using a calibrated pH electrode (VWR) connected to a SevenEasy pH-Meter (Mettler Toledo).

[0250] Vial filling Manual filling procedures were performed using standard laboratory pipettes and sterile tips. Prior to filling, formulations were mixed and emulsified to ensure homogeneity of the formulations, and 3 ml of each formulation was transferred to sterile particle-free 2R vials (Adelphi) under a laminar flow cabinet. Vials were closed with sterile FluroTec-coated (ethylene tetrafluoroethylene; ETFE) chlorobutyl stoppers (13 mm; Adelphi) and crimped with suitable aluminum caps. Reversed-phase high-performance liquid chromatography (RP-HPLC) Analysis by RP-HPLC was extrapolated to EpiQMmax with the parameters shown in Table 38.

[0251] [Table 38]

[0252] Osmolality measurement Osmolarity measurements were performed by freezing point depression with an osmometer (Osmomat 3000, Gonotec). The osmolarity of the total aqueous solution was determined by comparative measurements of the freezing points of pure water and the aqueous solution. Each measurement was performed in a 50 μl aliquot after calibration with sodium chloride standard (600 mOsm / kg) and purified water. Gels and emulsions were measured in two replicates, or in three replicates if the deviation between duplicate measurements was more than 10%. Arithmetic means and SD were then calculated.

[0253] Particle Size Measurement Particle size was determined by flow imaging analysis using a FlowCam 8100 system, 10x objective (ANASYSTA) with manual sample loading. Particle size measurements were performed on formulations containing laquinimod (as API) at a concentration of 50 mg / ml. The acceptance criteria for subvisible particle (SVP) measurements are defined as follows: ≤20 particles >25 μm, ≤2 particles >50 μm, and no particles >90 μm per 10 μg of laquinimod (PhEur monograph "Eye preparations" dosage form monograph no. 1163, version 01 / 2008). Results were reported as particles / 10 μg of laquinimod for each of the particle filter groups described.

[0254] Sample preparation for particle size measurement included diluting the samples 1:10 with the same pH buffer to which laquinimod was added to supersaturation. Sodium phosphate buffers with pH values ​​of 6.8 and 7.4 and Tris buffers with pH values ​​of 8.0 and 8.4 were prepared and added with laquinimod to the point of supersaturation, followed by centrifugation at 2000xg for 3 min, and the supernatant was used for sample dilution. Before diluting the samples, an appropriate amount of buffer was filtered through a syringe filter (0.02 μm alumina membrane). The FlowCam 8100 system was washed with water (Aqua B Braun) between repeated measurements and with 4% surfactant (Hellmanex®, Hellma Analytics) to prevent cross-contamination and ensure reproducibility between measurements.

[0255] Visual inspection The samples were visually controlled for changes during storage. Evaluation was performed using an inspection light box equipped with a non-blinking fluorescent lamp and a black and white background. Samples were evaluated for 5 seconds without magnification.

[0256] Sample storage During characterization, all samples (duplicates) were stored at 5°C, 25°C, 30°C, and 40°C, protected from light, for up to 2 weeks. Retests were performed at 5°C, 30°C, and 40°C. Samples stored at 5±3°C were kept in a refrigerator with external temperature monitoring. Samples undergoing accelerated aging were stored in humidity-controlled cabinets (Memmert) at 25±2°C / relative humidity (RH) 60±5%, 30±2°C / RH 65±5%, and 40±2°C / RH 75±5% (ICH Q1 guideline), respectively. Temperature was monitored throughout the entire storage period.

[0257] Density measurement The sample density was measured using a Gay-Lussac pycnometer (Carl Roth) with a sample volume of 1.103 ml at room temperature (RT). The weight of the pycnometer was measured using an analytical balance (SECURA 124-1S, Sartorius).

[0258] Viscosity measurement The dynamic viscosity of the samples was measured using a falling-ball viscometer Microviscometer Lovis 2000 ME (manufactured by Anton Paar) with capillaries of different diameters at 20°C, or at both 20°C and 37°C. The dynamic viscosity η of each sample was calculated using the known ball density (ρb = 7.66 g / cm 3 ) and the measured sample density (ρs), and the characteristic constant of the capillary (C1), was calculated according to the following formula:

[0259] η=C1*t1*(ρb-ρs) The fall time (t1) is the average value of the last six individual measurements with the capillary angle set at 70°. A total of 12 measurements were performed, and the individual fall times reached equilibrium within the first six measurement cycles due to the polymeric properties of the sample.

[0260] The materials used in Examples 1 to 7, as well as the supplier and part number of each material, are listed in Table 39.

[0261] [Table 39-1]

[0262] [Table 39-2]

[0263] Example 1 Ten different formulations, two emulsions (E1 and E2) and eight gels (S1-S8), were prepared using the methods described herein above. The components of the formulations are shown in Table 40.

[0264] [Table 40]

[0265] chemical stability RP-HPLC analysis was performed after storage at 30° C. for 1 and 2 weeks, respectively, and at 40° C. A very low degradation level of 0.03% (average) was observed after 2 weeks at 30° C., while at 40° C. the degradation level was slightly higher (average 0.34%). The highest degradation level (based on RP-HPLC peak area) was observed for emulsion formulations E1 and E2, which showed a decrease in the main peak relative area of ​​≥0.9% compared to the initial concentration (t=0) (Table 41).

[0266] [Table 41]

[0267] Stability of formulations against particle formation, sedimentation and creaming Some precipitation was observed in some formulations and the precipitation profile was determined by RP-HPLC. For this purpose, samples were taken at different heights (Figure 1) before and after resuspension. The absolute peak areas of the samples (after the same dilution) were compared (Table 42).

[0268] [Table 42]

[0269] As can be seen from Table 42, the absolute peak area of ​​the main peak in all samples was similar before and after resuspension. This indicates that the visible particles represent only a small portion of the total amount of laquinimod in the formulation. Therefore, it was concluded that laquinimod in the supernatant must either be dissolved or the suspended particles of laquinimod are small enough not to precipitate. It was hypothesized that the precipitation was an interaction between carbomer and laquinimod and was influenced by pH. Formulation S1 was titrated from pH 7.4 to pH 8.0 and the precipitate disappeared. This supported the hypothesis of a pH-dependent interaction between carbomer and laquinimod.

[0270] At each time point, samples were visually inspected (Figures 2-4). At t=0, all gel formulations without laquinimod were optically clear, whereas the emulsion formulations were slightly turbid. After the addition of laquinimod, all gel formulations except S3 became turbid. Since the pH of formulation S3 was 8.0, laquinimod was completely dissolved. In formulation S8, slight precipitation was observed even at t=0.

[0271] During storage, the emulsion formulations showed creaming at 5° C. and 25° C., whereas the emulsions broke at 30° C. and 40° C. (30° C.: formulation E1; 40° C.: both formulations E1 and E2). After resuspension, all emulsions were visually homogenous again.

[0272] Precipitation was observed in all gel formulations except S3. S1 showed the most precipitate, followed by S2 and S8. Little precipitation was observed in formulations S4, S5, S6, and S7. The precipitate could not be completely resuspended in formulations S5 and S6, while the other gel formulations were homogenous after resuspension. Little precipitation was observed in formulations S4 and S7, suggesting that the β-cyclodextrin in formulation S4 and the polysorbate in formulation S7 appear to have a stabilizing effect on laquinimod.

[0273] According to Ph Eur 10.0 "Eye preparations", particle size was measured in classes >25 μm, >50 μm, and >90 μm. For each class, the number of particles per 10 μg of laquinimod was calculated. Particles were found in formulations E1, E2, S1, S2, and S8. Cylindrical particles were detected in suspensions (gels) and mainly oil droplets in emulsions (Figure 5). It was observed that an increase in pH resulted in a decrease in the particle number.

[0274] Osmolarity The osmolality of formulations E1, E2, and S1-S8 was measured, as well as that of a similar formulation except that it did not contain laquinimod (the "blank" formulation) for comparison. The theoretical and measured osmolality of these formulations and the "blank" formulation that did not contain laquinimod are shown in Table 43.

[0275] [Table 43]

[0276] viscosity To evaluate the optimal concentration of the thickening agent, various concentrations of the thickening agent were tested in a "placebo" formulation (i.e., without laquinimod) with a target viscosity of 15 mPas. After the addition of laquinimod, the viscosity was significantly reduced, indicating an interaction between laquinimod and the thickening agent. The viscosities of all formulations were in the same range, except for formulation S5, which contained HPMC. The viscosity of the different formulations was adjusted using different thickening agents. The amount of thickening agent was determined in the placebo formulation. The viscosities of formulations E1-S8 measured at 20°C are shown in Table 44, along with the type and concentration of thickening agent used.

[0277] [Table 44]

[0278] Example 2 Formulations E2 (renamed E2-0) and S3 (renamed S3-0) were selected as starting points for further formulations, namely emulsion formulations E2-1 to E2-4 and gel formulations S3-1 to S3-10. In both types of formulations, the pH was at least 8 and laquinimod was completely dissolved.

[0279] Because there was a significant difference in viscosity between the placebo and laquinimod-containing formulations, the viscosity of laquinimod-containing formulations E2-1 to E2-4 and S3-1 to S3-10 was adjusted by the addition of sodium carboxymethylcellulose.

[0280] The ingredients of the emulsion formulation are shown in Table 45 and the ingredients of the gel formulation are shown in Table 46.

[0281] [Table 45]

[0282] [Table 46-1]

[0283] [Table 46-2]

[0284] Chemical stability of laquinimod Samples of all formulations were stored at 5° C., 30° C. and 40° C. for up to 2 weeks and then analyzed by RP-HPLC. No significant decrease in the main peak relative area was detected during storage at 5° C. and 30° C., but a slight decrease was observed after 2 weeks of storage at 40° C. The RP-HPLC analysis results are shown in Tables 47 and 48.

[0285] [Table 47]

[0286] [Table 48]

[0287] Stability of formulations against particle formation, sedimentation and creaming After aging, the appearance of all formulation samples was examined in the same manner as described for Example 1, with similar results.

[0288] Osmolarity The osmolality of formulations E2-0 through E2-4 and S3-0 through S3-10 was measured, as was the osmolality of a similar formulation except that it did not contain laquinimod (the "blank" formulation).

[0289] The theoretical and measured osmolalities of these formulations are shown in Table 49.

[0290] [Table 49]

[0291] viscosity The viscosity of some formulations containing laquinimod and carbomer was adjusted with sodium carboxymethylcellulose. Formulations containing Kolliphor® HS15, Kolliphor® ELP, or Kollidon® 17PF had lower viscosities.

[0292] In addition to measurements at 20° C., the viscosity was also measured at 37° C. to approximate intraocular conditions. The results are shown in Table 50.

[0293] [Table 50]

[0294] Example 3 Starting with formulation S7, an additional gel formulation was prepared by adding additional thickening agents, formulation S7-1. The ingredients of formulations S7 (for comparison) and S7-1 are shown in Table 51.

[0295] [Table 51]

[0296] Formulation S7-1 had a viscosity of 17.6 mPas at 20° C. as measured using the same viscosity measurement system as described herein above.

[0297] Example 4 The ocular permeability of laquinimod in the formulation of the present invention was investigated using bovine cornea.

[0298] material Three formulations of the invention (S3, S4 and S7) containing laquinimod at a concentration of 50 mg / ml were used in the assay. As a control, a formulation of laquinimod (50 mg / ml) in saline (0.9% w / v) was used. The formulations were stored in a refrigerator maintained at +4°C.

[0299] Bovine eyes were supplied by ABP Ltd (Ruthvenfield Road, Inveralmond Industrial Estate, Perth, PH1 3XB, UK). Eyes were collected from freshly slaughtered cattle and placed in a container containing cold Hank's balanced salt solution (HBSS). During transport to the testing facility, the eyes were kept cold using cool packs.

[0300] The receptor solution for the drug permeation assay was a HEPES solution (0.1 M, pH 7.4±0.1, containing 0.01% w / v EDTA).

[0301] Experimental design overview Six replicates were treated with each formulation for a 4-hour exposure. Permeation samples were collected from test article-treated corneas only, immediately prior to dosing and at 30-minute intervals after dosing. A final sample was collected 4 hours after dosing (a total of nine samples per cornea). Corneal opacity was measured pre-dose and after the final permeation sample was collected. Laquinimod concentrations in the permeation samples were measured throughout the exposure period.

[0302] Test system setup Corneas were peeled from fresh eyes. Upon arrival, the eyes were washed with HBSS and then inspected for obvious defects or signs of damage (e.g., scratches, opacities, neovascularization). Corneas from intact eyes were removed leaving a scleral margin of approximately 3 mm. Harvested corneas were placed epithelial side down in HBSS and stored at room temperature until required. Corneas were then mounted with the epithelial side anterior in specially designed corneal holders from Duratec Analysentechnik GmbH (Rheinauer Strasse 4, D-68766 Hockenheim, Germany). These holders consist of anterior and posterior compartments that allow access to the corneal epithelium and endothelium, respectively.

[0303] After mounting, both chambers of each corneal holder were filled with prewarmed phenol red-free minimum essential medium (MEM). The posterior chamber was filled first to encourage the cornea to return to its original curvature, and care was taken to avoid introducing air bubbles into the medium. The holders were then equilibrated in an incubator maintained at 32°C for at least 1 h before administration.

[0304] After the equilibration period, the medium in both chambers was replaced with fresh pre-warmed MEM without phenol red. Baseline opacity was then measured, and damaged corneas or corneas with opacity greater than 7 opacity units were excluded from further use. Corneas passing these tests were assigned to the test treatment groups. The MEM in the posterior chamber was replaced with pre-warmed receptor fluid using a syringe, allowing measurement of the volume of fluid added to the posterior chamber. The volume of the posterior chamber was recorded.

[0305] Pre-treatment The MEM in the anterior chamber was removed immediately prior to dosing. A pre-dose sample of receptor fluid was collected from each test article-treated cornea. No receptor fluid samples were collected from corneas treated with the vehicle control. The access port to the posterior chamber was sealed with tape to prevent leakage during the incubation period.

[0306] Administration Laquinimod formulations and saline control were administered undiluted. Prior to dosing, the corneal holder was tilted forward to avoid contact of the dosing solution with the corneal epithelium. Doses (approximately 750 μl) were administered through the anterior chamber access port using a syringe. Each dose was administered to six replicate corneas and exposed for 4 hours. Prior to withdrawing the dose from the vial, the vial was gently swirled to resuspend the formulation.

[0307] exposure After dosing, exposure was initiated by tilting the corneal holder horizontally, taking care to cover the epithelial surface of each cornea with the test article. Corneas were exposed to the test article or vehicle control for 4 hours in an incubator maintained at 32°C.

[0308] Receptor fluid sampling Receptor fluid samples (approximately 1 ml) were collected from the posterior chamber of each test article-treated cornea before and at 30-minute intervals after dosing. The final receptor fluid sample was collected 4 hours after dosing. Immediately after sampling, the removed receptor fluid was replaced with fresh prewarmed receptor fluid, and the posterior chamber was resealed, taking care to avoid loss of sample or introduction of air bubbles. Collected receptor fluid samples were stored in a freezer maintained at -20°C until analysis.

[0309] Washing After the final receptor fluid collection, the dosing solution was removed from the anterior chamber and the cornea was washed with MEM supplemented with phenol red (approximately 5 ml per wash). The cornea was washed at least three times in both the anterior and posterior chambers or until no residual test article was visible. Once washing was complete, one additional wash with MEM without phenol red was performed to remove the phenol red to prevent interference with subsequent optical measurements. Both chambers were then refilled with MEM without phenol red before proceeding.

[0310] Turbidity measurement After washing, the 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 value.

[0311] Analysis of transmission samples The samples were stored in a freezer maintained at -20°C until analysis. An aliquot of 10 μl of calibration standard (in the range of 50.0 - 25000 ng / ml), quality control sample, or test sample was transferred to a 96-round well plate, and 10 μl of internal standard was added to each well. This was diluted with 200 μl of methanol and 200 μl of 0.1% trifluoroacetic acid. Then, the 96-round well plate was capped, vortexed, and centrifuged at 2400 g for 5 minutes at 4°C. Subsequently, the sample was injected into a Sciex API4000 (trademark) mass spectrometer combined with a Waters Acquity UPLC (registered trademark) system to generate known concentrations of lacinimod.

[0312] Test samples were extracted and analyzed in batches with calibration standards and quality confirmation (QC) samples using an established method. Calibration samples were extracted twice.

[0313] The detector response was plotted against the lacinimod concentration, and a calibration curve excluding the origin was created from regression analysis. The measured concentration of each prepared standard used to create the calibration curve should be within 100 ± 20% of the nominal concentration. At least 75% (minimum 6 species) of the calibration standards should meet the above criteria. The concentration measured in at least 67% of the bracketing QC samples should be within 100 ± 20% of the nominal concentration, and at least 50% at each concentration level should meet this criterion.

[0314] Test samples with measured concentrations above the assay's analytical range were re-measured after dilution. Test samples with measured concentrations below the analytical range were reported as <LLOQ (limit of quantitation).

[0315] Data collection was performed using Analyst® software from Applied Biosystems, Inc. Statistical analysis, including regression analysis, descriptive statistics including arithmetic mean and standard deviation, accuracy and precision, was performed using Watson Laboratory Information Management System (Watson LIMS™) and Microsoft® Excel®.

[0316] Sample storage Receptor fluid samples were stored in a −20°C freezer until analysis.

[0317] Computer Systems The computer systems used in this study, and the data collected and / or analyzed by these systems, are presented in Table 52.

[0318] [Table 52]

[0319] result Statistical analysis was limited to calculation of means, standard deviations, and coefficients of variation, as appropriate.

[0320] turbidity The turbidity was calculated using the following formula:

[0321]

number

[0322] (In the formula, I = opacitometer reading (lux) of the corneal holder containing only MEM; I = the measurement (lux) of the holder containing the cornea (either baseline or post-dose) The turbidity change and corrected turbidity change were calculated as follows: Opacity change = post-administration occlusion - baseline occlusion Corrected turbidity change = turbidity change (test substance) - turbidity change (saline) Table 53 shows the results of the pre- and post-dose turbidity measurements.

[0323] [Table 53]

[0324] Treatment with formulations S3 or S4 caused little or no change in turbidity, while treatment with formulation S7 caused a slight increase in turbidity.

[0325] Laquinimod permeability The total amount of laquinimod permeated was calculated from the results obtained by LC-MS / MS analysis.

[0326] Cumulative absorption of laquinimod (μg / cm) through bovine corneas (n=6) after exposure to formulations S3, S4, and S7, respectively. 2 The permeation results are shown in Tables 54 to 56 and Figures 6 to 8.

[0327] [Table 54]

[0328] [Table 55]

[0329] [Table 56]

[0330] Cumulative laquinimod absorption increased throughout the exposure period for each of the invention formulations. Results were similar for all three formulation treatments and followed the same general pattern. Formulation S4 had the least laquinimod penetration and was the most consistent across different corneas. Formulations S3 and S7 showed higher laquinimod penetration, but results were more variable across corneas.

[0331] Example 5 Formulations E2-2A, S3-3A and S3-8A were prepared with pH values ​​and compositions as listed in Table 57.

[0332] [Table 57]

[0333] The viscosities of formulations E2-2A, S3-3A and S3-8A, measured at 20° C. using the method described herein above, were found to be 15.7 mPa.s, 21.5 mPa.s and 23.7 mPa.s, respectively.

[0334] Example 6 The corneal opacity change and permeability of formulations E2-2A, S3-1, S3-3A, S3-6, S3-7 and S3-8A were measured using the same test system and protocol as in Example 4. Table 58 shows the results of pre- and post-dose opacity measurements for the different formulations and the saline control.

[0335] [Table 58-1]

[0336] [Table 58-2]

[0337] As can be seen from the data in Table 58, all treatments caused little or no change in opacity. Results were similar to those from the control group. Little or no evidence of damage was detected in corneas treated with any of the formulations. Formulation S3-6 caused the greatest increase in opacity (2.74±2.36), but this treatment group also had the greatest variability in post-treatment changes in opacity, ranging from 0.71 to 6.93.

[0338] Cumulative absorption of laquinimod (μg / cm) through bovine corneas (n=6) following exposure to formulations E2-2A, S3-1, S3-3A, S3-6, S3-7, and S3-8A, respectively. 2 The permeation results are shown in Tables 59 to 64 and Figures 9 to 14.

[0339] [Table 59]

[0340] [Table 60]

[0341] [Table 61]

[0342] [Table 62]

[0343] [Table 63]

[0344] [Table 64]

[0345] Example 7 Using the same test system and protocol as in Example 4, corneal opacity changes and bovine corneal permeability were measured in vitro for formulations S3-3A and S7-1, and laquinimod 50 mg / ml in physiological saline (PBS), pH 8, after a single 4-hour exposure.

[0346] Six replicate corneas were treated with each formulation or saline (negative control) for 4 hours of exposure. Permeation samples were taken from test article-treated corneas only, immediately prior to dosing and at 30 minute intervals after dosing. A final sample was taken 4 hours after dosing (a total of 9 samples per cornea). Corneal opacity was measured pre-dose and after the final permeation sample was taken. The concentration of active ingredient was measured by LC-MS / MS in permeation samples taken throughout the exposure period. The results of the pre- and post-dose opacity measurements are shown in Table 65.

[0347] [Table 65]

[0348] The results, shown in Table 65, show that all treatments caused little or no change in turbidity.

[0349] Cumulative absorption of laquinimod (μg / cm) through bovine corneas (n=6) following exposure to formulations S3-3A, S71, and laquinimod in saline, respectively. 2 The transmission results for the above are shown in Tables 66 to 69 and Figures 15 to 18.

[0350] [Table 66]

[0351] [Table 67]

[0352] [Table 68]

[0353] [Table 69]

[0354] The results, shown in Tables 66-69, indicate that cumulative absorption of laquinimod increased throughout the exposure period for each formulation. Four hours after administration, the formulations could be ranked in the following order from most to least permeable: Formulation S7-1 > Formulation S3-3A > laquinimod in PBS.

[0355] Example 8 The efficacy of the formulations of the present invention was tested in vivo using a mouse model of uveitis.

[0356] Experimental conditions Female B10.RIII mice (approximately 6 weeks old at the start of the study) were inoculated on day 0 with an emulsion containing interphotoreceptor retinoid binding protein peptide 161-180 (IRBP161-180) in incomplete Freund's adjuvant (IFA) supplemented with Mycobacterium tuberculosis H37Ra.

[0357] Oral laquinimod was prepared in saline. The ophthalmic formulation was in the form of eye drops. The composition of the ophthalmic formulation was S3-3A (containing laquinimod 50 mg / ml) and the corresponding vehicle control was the S3-3A formulation without laquinimod. Treatments were administered according to the schedule shown in Table 70.

[0358] [Table 70]

[0359] Animals were scored weekly for clinical signs of uveitis from day 0 to the end of the experiment. Retinal images were taken using topical endoscopy fundus imaging (TEFI) in unanesthetized, restrained animals after pupil dilation with tropicamide followed by phenylephrine hydrochloride.

[0360] Retinal images were scored using the scoring system described in Table 71, with a maximum of 20 points per eye.

[0361] [Table 71]

[0362] result Analysis of the total clinical signs of posterior uveitis, obtained by summing the clinical scores observed in the left (L) and right (R) eyes of each animal in each experimental group, revealed a significant effect of time, thereby confirming the successful induction of the disease, and the overall effect of all treatments compared with the two vehicle-treated groups.

[0363] Due to the presence of two vehicles in the study design, Dunnett's multiple comparison test was performed vs. vehicle, topical, and again vs. vehicle, oral. The calculated p-values ​​at treatment days 14, 17, and 20 (D14, D17, and D20) are shown in Table 72.

[0364] [Table 72]

[0365] No differences were observed between the two vehicle groups. Ocular administration of the ophthalmic formulation of laquinimod significantly inhibited the disease course compared to control animals treated with vehicle alone (FIG. 19).

[0366] Example 9 A gel formulation containing 10.62 g / L laquinimod sodium (10 g / L laquinimod base) and the excipients shown in Table 73 was prepared (total batch size 50.0 L).

[0367] [Table 73]

[0368] The resulting formulation was a milky white gel and was tested for osmolality, pH, viscosity and relative density. The methods and results are shown in Table 74.

[0369] [Table 74]

[0370] Droplet size testing revealed that droplets with a volume of approximately 34 μl were obtained.

[0371] Example 10 The formulation of Example 9 was filled into 5 ml bottles (LDPE bottles from Nemera La Verpilliera, reference number 20059681) equipped with nozzles and caps Pureflow® 200 (reference number 20060322) for administration as eye drops. A total of 130 bottles were prepared, each containing 5 ml of the formulation.

[0372] Example 11 The formulation of Example 9 was subjected to stability testing at conditions set for drug products packaged in semipermeable containers (long-term storage conditions: 2°C to 8°C, accelerated storage conditions: 25°C / RH40%) in accordance with ICH Guide Q1A(R2). The results of drop volume, osmolality, pH, viscosity, and laquinimod assay after storage times t of 0, 2, 3, and 6 months are shown in Tables 75 and 76.

[0373] [Table 75]

[0374] [Table 76]

[0375] The formulation was visually observed at each time point and remained a milky gel throughout the entire test period. As can be seen from Tables 75 and 76 above, the formulation of the present invention did not show any significant change in any of the tested properties at any of the test conditions. Therefore, based on the stability data obtained, it is believed that the shelf life of the formulation of the present invention when stored at 2°C to 8°C is at least 6 months, more preferably at least 8 months, even more preferably at least 9 months, and most preferably at least 12 months.

[0376] Example 12 A gel formulation was prepared having the ingredients shown in Table 77, at pH 7.4.

[0377] [Table 77]

[0378] The viscosity of the formulation shown in Table 77 was measured using the method described herein above at 20° C. and found to be 17.3 mPa.s.

[0379] Example 13 A study was conducted to determine the intraocular distribution of laquinimod after single and repeated ocular topical administration to rabbits using the formulation of Example 12. Briefly, the study was conducted over a 10 day study period using seven male New Zealand White rabbits weighing approximately 2.3-3.0 kg at the time of dosing. The 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 study period. The test formulations were stored at 4°C until use.

[0380] Of the seven test animals, six received the formulation of Example 12 and one received an equal amount of a placebo formulation with the same composition as the formulation of Example 12, except that it did not contain laquinimod. Each animal was treated as follows: on day 1, one ocular topical dose was administered to each eye; on days 2 and 3, no dose was administered; on days 4-9, three ocular topical doses were administered to each eye at two-hour intervals; and on day 10, one ocular topical dose was administered to each eye. For dosing, the animals were removed from their housing and appropriately restrained. Then, each animal was given a topical ocular dose directly onto the cornea of ​​each eye using a pipette. The dose volume was 30 μl per eye for each dosing session. After dosing, the animals were returned to their housing cages. The details of the study are summarized in Table 78.

[0381] [Table 78]

[0382] On day 10, 30 min, 1 h, 2 h, 4 h, and 8 h after the last ocular topical administration, the animals were euthanized and the eyeballs were rapidly enucleated together with the surrounding eyelid tissue, embedded in tragacanth gum, and flash frozen in isopentane cooled on dry ice. The isolated eyeballs were then stored in a freezer maintained at -65°C or below.

[0383] For distribution studies, the eyes (right eye of each animal) were sectioned using a cryostat at a temperature of -20 °C. For each tissue, 10 μm thick sections were taken on indium-tin oxide (ITO) coated glass slides for mass spectrometry imaging (MSI). The analysis was performed by matrix-assisted laser desorption / ionization with Fourier transform ion cyclotron resonance (MALDI-FTICR) using a Bruker Daltonix SolariX mass spectrometer. All analyses were performed with a spatial resolution of 60 μm and the following mass spectrometer parameters: - Mode: CASI (Continuous Accumulation of Selected Ions) - Ionization: Positive - Mass range: 0 to 1000 Daltons - Laser frequency: 2000Hz - Calibration Mode: 2 The observed m / z for laquinimod was 357.10 ([M+H] + ) was.

[0384] The results are summarized in Table 79.

[0385] [Table 79]

[0386] The results in Table 79 show that high concentrations of laquinimod were detected in the cornea and external tissues 30 minutes after topical ocular administration of the formulation of Example 12. Although concentrations of laquinimod in the cornea and external tissues were lower after 4 and 8 hours, at these later time points, laquinimod could be detected in the posterior segment of the eye, i.e., the retina / choroid and sclera.

Claims

1. A formulation for ocular administration comprising in an aqueous phase: (i) as an active ingredient, a therapeutically effective amount of laquinimod or a pharma- ceutically acceptable salt thereof; (ii) a pharma- ceutically acceptable thickening agent in an amount sufficient to provide a dynamic viscosity of 2 to 200 mPas, measured at 20° C.; (iii) a pharma- ceutically acceptable tonicity agent in an amount sufficient to provide an osmolality of 200-600 mOsm / kg; (iv) a pharma- ceutically acceptable moisturizer; (v) a pharma- ceutically acceptable antioxidant, and (vi) The formulation comprises a pharma- ceutically acceptable pH adjusting agent.

2. 2. The formulation of claim 1, wherein the pharma- ceutically acceptable thickening agent is present in an amount sufficient to provide a dynamic viscosity of 5 to 100 mPas measured at 20°C.

3. 3. A formulation according to claim 2, wherein the pharma- ceutically acceptable thickening agent is present in an amount sufficient to provide a dynamic viscosity of from 10 to 50 mPas, for example from 15 to 45 mPas, measured at 20°C.

4. 4. The formulation of any one of claims 1 to 3, wherein the pharma- ceutically acceptable thickening agent comprises one or more of the group consisting of polyvinyl alcohol, poly(acrylic acid) homopolymer or copolymer (carbomer), polyvinylpyrrolidone, and cellulose derivatives, such as hydroxypropylmethylcellulose and sodium carboxymethylcellulose.

5. 5. The formulation of any one of claims 1 to 4, wherein the pharma- ceutically acceptable tonicity agent is present in an amount sufficient to provide an osmolality of 200 to 500 mOsm / kg.

6. 6. The formulation of claim 5, wherein the pharma- ceutically acceptable tonicity agent is present in an amount sufficient to provide an osmolality of 200-400 mOsm / kg, such as 250-375 mOsm / kg.

7. 7. The formulation of claim 1, wherein the pharma- ceutically acceptable tonicity agent is a non-ionic tonicity agent.

8. 8. The formulation of claim 7, wherein the non-ionic tonicity agent is mannitol.

9. 9. The formulation of claim 1, wherein the pharma- ceutically acceptable moisturizer is a polyol.

10. The formulation of claim 9, wherein the polyol is a C3 to C6 polyol, preferably glycerol.

11. 11. The formulation of any one of claims 1 to 10, wherein the pharma- ceutically acceptable pH adjusting agent is present in an amount sufficient to provide a pH in the range of 6.8 to 8.

5.

12. 12. The formulation of claim 11, wherein the pharma- ceutically acceptable pH adjusting agent is present in an amount sufficient to provide a pH in the range of 6.8 to 8.

0.

13. 13. The formulation of any one of claims 1 to 12, further comprising (vii) a pharma- ceutically acceptable preservative.

14. 14. The formulation of claim 13, wherein the pharma- ceutically acceptable preservative is benzalkonium chloride.

15. 15. The formulation of any one of claims 1 to 14, further comprising (viii) a pharma- ceutically acceptable surfactant.

16. 16. The formulation of claim 15, wherein the pharma- ceutically acceptable surfactant is a non-ionic surfactant.

17. 17. The formulation of claim 1, further comprising (ix) a pharma- ceutically acceptable solubilizing agent.

18. said pharma- ceutically acceptable thickening agent is present in an amount sufficient to provide a dynamic viscosity of 10 to 45 mPas, measured at 20° C.; the pharma- ceutically acceptable tonicity agent is present in an amount sufficient to provide an osmolality of 200-400 mOsm / kg; and 18. The formulation of any one of claims 1 to 17, wherein the pharma- ceutically acceptable pH adjusting agent is present in an amount sufficient to provide a pH of from 6.8 to 8.

0.

19. 19. The formulation according to any one of claims 1 to 18, which is in the form of a gel.

20. (i) 5-100 g / l of laquinimod, or a corresponding amount of a pharma- ceutically acceptable salt of laquinimod; (ii) 1 to 10 g / l of sodium carboxymethylcellulose, and / or 0.5 to 6 g / l of carbomer copolymer; (iii) 1.5 to 4 g / l mannitol; (iv) 10 to 40 g / l glycerol; (v) 0.2 to 2 g / l Na-EDTA, and (vi) a pH buffering agent in an amount effective to provide a pH in the range of 6.8 to 8.

0.

21. 21. The formulation of claim 20 further comprising 0.1 to 5 g / l of polysorbate.

22. 19. The formulation according to any one of claims 1 to 18, which is in the form of a water- and oil-containing emulsion, preferably an oil-in-water emulsion.

23. 23. The formulation of any one of claims 1 to 22, wherein the ocular administration is topical administration to the eye.

24. 24. A formulation according to any one of claims 1 to 23 for use in the treatment of an eye disorder.

25. 25. The formulation of claim 24, wherein the ocular disorder is selected from glaucoma, ocular inflammatory diseases, and diseases involving excessive ocular angiogenesis.

26. 26. A dosage container containing the formulation according to any one of claims 1 to 25.

27. 24. Use of a formulation according to any one of claims 1 to 23 in the manufacture of a medicament for treating an eye disorder.

28. 28. The use of claim 27, wherein the eye disorder is selected from glaucoma, ocular inflammatory diseases, and diseases involving excessive ocular angiogenesis.

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