Laquinimod preparations for ophthalmology

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 preparation. More specifically, the present invention relates to a pharmaceutical preparation containing laquinimod for ophthalmic use, preferably for topical ophthalmic use.

Background Art

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

[0003] The use of laquinimod in the treatment of ophthalmic diseases such as glaucoma, ocular inflammatory diseases, and diseases accompanied by excessive ocular angiogenesis has been previously disclosed. Accordingly, laquinimod for use in the treatment of glaucoma is disclosed in International Application No. PCT / US2014 / 065497, published as WO2015 / 073697. U.S. Patent Application No. 15 / 816402, published as US2018 / 0071275A1, discloses the treatment of ocular inflammatory diseases through the use of laquinimod. In International Application No. PCT / EP2020 / 086993, published as WO2021 / 123142A1, the use of laquinimod for treating diseases accompanied by excessive ocular angiogenesis is disclosed. Systemic or topical administration of laquinimod is proposed depending on the type of ocular disease, and in the latter case, ocular or ophthalmic administration is described.

[0004] However, several problems must be overcome with respect to topical ophthalmic preparations and their effective use in the treatment of ocular disorders, particularly disorders affecting the posterior segment of the eye. In fact, due to the corneal barrier having several compartments with opposing properties, mainly lipophilicity and hydrophilicity, inefficient delivery of the active agent to the target site often hinders the treatment of disorders where the drug must reach the posterior segment of the eye.

Summary of the Invention

[0005] Pharmaceutical formulations comprising laquinimod or a pharmaceutically acceptable salt thereof for use in the treatment of eye diseases are provided herein.

[0006] Furthermore, the present invention provides a method for treating a subject suffering from an eye disease, comprising partially, preferably topically, administering to the eye of the subject a formulation described herein, which contains a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt of laquinimod effective in treating the subject.

[0007] Accordingly, one embodiment relates to a pharmaceutical formulation for partial, preferably topical, administration to a patient's eye (partial or topical ophthalmotherapy), comprising a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof as a therapeutically effective agent.

[0008] Therefore, in one embodiment, a pharmaceutical preparation for ocular administration, wherein the preparation is in an aqueous phase, (i) Laquinimod or a pharmaceutically acceptable salt thereof as an active ingredient, (ii) Pharmaceutically acceptable viscosity modifiers, (iii) A pharmaceutically acceptable tonicity adjusting agent, (iv) Pharmaceutically acceptable humectants, (v) pharmaceutically acceptable antioxidants, and (vi) A formulation is provided which contains a pharmaceutically acceptable pH adjuster.

[0009] In a further embodiment, a pharmaceutical formulation for administering laquinimod or a pharmaceutically acceptable salt of laquinimod to the eye is provided, wherein the formulation has a viscosity 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, as measured at 20°C.

[0010] Therefore, in some embodiments, pharmaceutical formulations for ocular administration are (i) a therapeutically effective dose of laquinimod or a pharmaceutically acceptable salt thereof as the active ingredient; (ii) A pharmaceutically acceptable thickening agent in an amount sufficient to yield a dynamic viscosity of 2–200 mPas when measured at 20°C; (iii) A pharmaceutically acceptable isotonic agent in an amount sufficient to produce an osmotic pressure of 200–600 mOsm / kg; (iv) Pharmaceutically acceptable humectants; (v) pharmaceutically acceptable antioxidants; and (vi) Contains a pharmaceutically acceptable pH adjuster in an amount sufficient to produce a pH of 6.8 to 8.5.

[0011] In some embodiments, the formulation further comprises (vii) a pharmaceutically acceptable preservative, (viii) a pharmaceutically acceptable surfactant, (ix) a pharmaceutically acceptable solubilizer, and (x) a pharmaceutically acceptable oil. It contains one or more components selected from the following.

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

[0013] Therefore, in some embodiments, the formulation is an oil-in-water emulsion comprising a pharmaceutically acceptable oil and an aqueous phase which is in the form of a suspension or solution of laquinimod or a pharmaceutically 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 pharmaceutically acceptable salt of laquinimod in a pharmaceutically acceptable oil phase. Preferably, the emulsions provided herein are oil-in-water emulsions.

[0015] In still some embodiments, the formulation is a solution or suspension of larqinimod or a pharmaceutically acceptable salt of larqinimod, and the formulation is a viscous gel.

[0016] The pharmaceutical formulations provided herein are useful for treating various ocular diseases, such as glaucoma, ocular inflammatory diseases, and diseases associated with excessive ocular angiogenesis.

[0017] In some embodiments, provided herein are pharmaceutical formulations for treating glaucoma. In some further embodiments, provided herein are ophthalmic formulations for treating ocular inflammatory diseases. In some further embodiments, provided herein are ophthalmic formulations for treating diseases associated with excessive ocular angiogenesis.

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

[0019] An advantageous feature of the formulation is its high stability against chemical degradation of larqinimod or the pharmaceutically acceptable salt of larqinimod present in the formulation.

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

[0021] A further advantageous feature is the ability of the formulation to contain larqinimod or a pharmaceutically acceptable salt of larqinimod in a wide range of concentrations.

[0022] A further advantageous feature of the formulation is the high delivery rate of the therapeutically active agent through the cornea of the eye, which advantageously allows partial (e.g., topical) administration of larqinimod to the eye of a subject.

[0023] A further advantageous aspect is the high efficacy of larqinimod when administered partially, e.g., topically, to the eye of a patient, for example, an efficacy level comparable to that of oral administration. Partial administration of the drug can advantageously avoid undesirable systemic effects. Accordingly, one aspect is an ophthalmic pharmaceutical formulation, which comprises in an aqueous phase: (i) lacrimimod as an active ingredient, or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutically acceptable thickening agent, (iii) a pharmaceutically acceptable isotonic agent, (iv) a pharmaceutically acceptable humectant, (v) a pharmaceutically acceptable antioxidant, and (vi) a pharmaceutically acceptable pH adjuster, and optionally, (vii) a pharmaceutically acceptable preservative, (viii) a pharmaceutically acceptable surfactant, (ix) a pharmaceutically acceptable solubilizing agent, and (x) a pharmaceutically acceptable oil which is an ophthalmic pharmaceutical preparation comprising one or more components selected from the foregoing.

[0024] A further aspect is a dosage container containing the pharmaceutical ophthalmic preparation provided herein. Accordingly, there is provided herein a dosage container containing a pharmaceutical preparation for ocular administration, (i) lacrimimod as an active ingredient, or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutically acceptable thickening agent, (iii) a pharmaceutically acceptable isotonic agent, (iv) a pharmaceutically acceptable humectant, (v) a pharmaceutically acceptable antioxidant, and (vi) a pharmaceutically acceptable pH adjuster, and optionally, (vii) a pharmaceutically acceptable preservative, (viii) a pharmaceutically acceptable surfactant, (ix) a pharmaceutically acceptable solubilizing agent, and (x) a pharmaceutically acceptable oil a dosage container comprising one or more components selected from the foregoing is also provided herein.

[0025] A pharmaceutically acceptable pH adjuster is preferably present in an amount that brings the formulation to a pH of at least 6.8.

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

[0027] A further embodiment is the use of the formulations of the present invention in the manufacture of pharmaceuticals for treating eye disorders, such as glaucoma, inflammatory eye diseases, and diseases involving excessive vascularization of the eye.

[0028] Advantageously, formulations such as those disclosed herein provide means for the partial, preferably topical, administration of laquinimod to the eye of a patient (an animal or mammal such as a human, preferably a human) with little to no (acceptable) side effects such as eye stinging, temporary blurred vision, and / or eye lacrimation.

[0029] Accordingly, the following are provided herein: pharmaceutical formulations of laquinimod or pharmaceutically acceptable salts thereof, preferably topical formulations, which enable the treatment of eye diseases by ocular administration to mammals in need of treatment, such as humans.

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

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

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

[0033] definition Unless otherwise specified or evident from the context, the articles “a” and “an” are used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” generally means one or more elements.

[0034] As used herein, “API” is an abbreviation for “active pharmaceutical ingredient,” and in the context of this disclosure, it refers to laquinimod or a pharmaceutically acceptable salt of laquinimod.

[0035] As used herein, "autoimmune disease-related ocular inflammation" refers to inflammation affecting one or more parts of the eyeball or surrounding tissues that are 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 include, in particular, arthritis, demyelinating diseases, and inflammatory diseases. For example, autoimmune diseases may include multiple sclerosis, autoimmune hemolytic anemia, autoimmune oophoritis, autoimmune thyroiditis, autoimmune uveoretinitis, Crohn's disease, chronic immunothrombocytopenic purpura, colitis, contact sensitivity disease, diabetes mellitus, Graves' disease, Guillain-Barré 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 in which acrylic acid and long-chain alkyl methacrylate are crosslinked with polyhydric alcohol allyl ethers. 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, or flask suitable for holding the volume of the formulation provided herein, i.e., a volume equivalent to one unit (single dose) or a volume equivalent to two or more doses (multi-dose). The dosage container may include means for instilling an appropriate amount of the formulation into the patient’s eye, and such means may be provided separately from the container.

[0039] In this specification, "effective" as an effective amount to achieve a certain objective, i.e., a "therapeutic effective amount," means an amount of an ingredient sufficient to produce a desirable therapeutic response that is commensurate with a reasonable benefit-to-risk ratio, without excessive adverse side effects (such as toxicity, irritation, or allergic reactions) when used in the methods of this disclosure. The effective amount may vary according to factors known in the art, such as the disease state of the human or animal being treated, age, sex, and weight.

[0040] The term "excipient" refers to a pharmaceutically acceptable chemical substance used to assist in the administration of a pharmaceutical agent, as is known to those skilled in the art in the field of pharmacy. Excipients are compounds that are useful in the preparation of pharmaceutical compositions, are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients that are acceptable for both human and animal use.

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

[0042] The term "humectant" refers to a hydrophilic compound that can retain moisture in a formulation.

[0043] The term "lakinimod" refers to the structural formula

[0044] [ka]

[0045] This refers to the compound 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, which has [this characteristic].

[0046] Unless otherwise specified or made clear from the context, the term raquinimod includes the free base form of the compound and its salt form.

[0047] The term "macrogol 15 hydroxystearate" primarily refers to a mixture of monoesters 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 having α-hydro-ω-hydroxypoly(oxy-1,2-ethanediyl); 12-hydroxystearate 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 monoesters and diesters of 12-hydroxystearic acid and about 30% free polyethylene glycol.

[0048] The term "mammal" refers to humans or any other mammal, such as primates, farm animals, pets, or laboratory animals. Examples of such animals include monkeys, cattle, sheep, horses, pigs, dogs, cats, rabbits, mice, and rats. Preferably, the mammal is human.

[0049] The term "surfactant" refers to an organic compound that can reduce surface tension (or interfacial tension) between two liquids, gas / liquid, or liquid / solid. Surfactants are amphiphilic compounds, that is, compounds that contain a hydrophobic part ("hydrophobic tail") and a hydrophilic part ("hydrophilic head" or "polar head"). Most commonly, surfactants are classified by their hydrophilic head. "Nonionic surfactants" do not have a charged group in their head, "cationic surfactants" have a positive net charge in their hydrophilic head, and "anionic surfactants" have a negative net charge in their hydrophilic head.

[0050] As used herein, the term “isotonic agent” (or alternatively “tensioning 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 during ophthalmic administration.

[0051] As used herein, expressions such as “ocular administration” or “ophthalmic administration” of the formulation refer to instilling the formulation into the eyes of the subject.

[0052] In this specification, expressions such as "ophthalmic preparation" and "ophthalmic preparation" refer to pharmaceutical compositions formulated for administration to the eyes of a subject.

[0053] As used herein, the term “eye disease” (which is considered to be synonymous with “eye disorder,” “eye disease,” or “eye impairment” in this specification) refers to a disease affecting the eye of a mammalian subject, i.e., an animal or human, preferably a human.

[0054] As used herein, “ocular inflammatory disease” or “OID” means inflammation affecting one or more parts of the eyeball or periocular tissues. OID may include, but is not limited to, inflammation of the orbital tissues, lacrimal apparatus, eyelids, conjunctiva (conjunctivitis), cornea, retina, components of the visual pathway, such as the optic nerve, and components of the uveoid pathway (uveitis), namely the iris, ciliary body, and choroid. Specific examples of OID include uveitis, acute conjunctivitis, viral conjunctivitis, non-gonococcal 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 event or situation described thereafter may or may not occur, and such description includes both cases in which such event or situation occurs and cases in which it does not occur.

[0056] The term "pH adjuster" generally refers to a compound or mixture of compounds that can change and / or maintain the pH of an aqueous phase. A common example of a pH adjuster is a pH buffer (or buffering agent).

[0057] "Pharmacologically acceptable" means a substance that is not biologically or otherwise undesirable, i.e., a substance that can be administered to an individual together with the relevant active compound without causing a clinically unacceptable biological effect or having adverse interactions with any other components of a preparation containing the substance.

[0058] The term "polyoxyethylene-polyoxypropylene block copolymer" refers to the poloxamer of CAS Registry No. 9003-11-6, and includes its salts and known equivalents. Examples of poloxamers are poloxamer 188 and poloxamer 407.

[0059] The term "polyoxyl castor oil" (sometimes called ethoxylated castor oil or polyethylene glycol castor oil), with CAS registry number 61791-12-6, is a mixture of ethoxylated glycerol triricinoleate, a small amount of polyethylene glycol ricinoleate, and the corresponding free glycol. Polyoxyl castor oil is a nonionic 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 commercially available product is Kolliphor® EL, which is polyoxyl 35 castor oil.

[0060] The term "polysorbate 80" refers to the compound with CAS registry number 9005-65-6, also known as polyoxyethylene (80) sorbitan monooleate, sorbitan monooleate ethoxylate, as well as their salts and known equivalents.

[0061] As used herein, "preservative" refers to an additive that inhibits the growth of microorganisms and kills microorganisms that contaminate a formulation 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 “effective solubilizing amount” of a substance in a formulation (“solubilizer”) refers to the amount of substance sufficient to solubilize another component of the composition. For example, “effective API solubilizing amount” is the amount sufficient to solubilize the API (in this example, laquinimod or a pharmaceutically acceptable salt thereof) so that the API is more therapeutically effective than in the absence of a solubilizer. In some embodiments, “effective API solubilizing amount” is the amount sufficient to solubilize the API in an ophthalmic formulation, such as a topical ophthalmic formulation, so that the API is more therapeutically effective than in the absence of a solubilizer.

[0064] In this specification, “to treat” includes, for example, inducing the suppression, regression, or cessation of a disease, disorder, or condition, or improving or alleviating the symptoms of a disease, disorder, or condition. As used herein, “to improve” or “alleviate” a condition or state means to alleviate or reduce the symptoms of that condition or state. As used herein, “to inhibit” disease progression or disease complications in a subject means to prevent or reduce disease progression and / or disease complications in a subject.

[0065] As used herein, the term “unit dose” refers to the amount of the formulation of the present invention administered to a subject in a single dose, or the amount of laquinimod or a salt of laquinimod contained in the said amount of the formulation of the present invention. The unit doses disclosed herein may be administered once daily, twice daily, three times daily, four times daily, five times daily, every other day, once weekly, twice weekly, three times weekly, four times weekly, five times weekly, or six times weekly.

[0066] "Vascular formation" and "angiogenesis" refer to the process by which new blood vessels are formed. In this specification, the terms "vascular formation" and "angiogenesis" are used interchangeably.

[0067] As used herein, the expression "ocular vascularization" is synonymous with neovascularization of the ocular ball.

[0068] "Excessive vascularization" refers to the phenomenon in which vascularization occurs to a degree that is detrimental to the normal function of the affected tissue. Such excessive vascularization occurs in or as a result of eye diseases or disorders such as corneal neovascularization, iris neovascularization, ciliary neovascularization, corneal pannus, choroidal neovascularization, proliferative diabetic retinopathy, retinopathy of prematurity, ischemic retinopathy, retinal neovascularization, hypertensive retinopathy, and wet age-related macular degeneration.

[0069] In the context of this disclosure, the terms “ocular disease or disorder with excessive vascularization of the eye” and “ocular disease or disorder with excessive vascularization of the eye” are to be interpreted as meaning any ocular disease or disorder in which vascularization of one or more tissues of the eye is considered by a person skilled in the art to be detrimental to the normal function of the affected tissue, resulting in and / or affecting the vascularization. Such diseases or disorders may lead to loss of vision.

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

[0071] The term "viscosity enhancer" (which in the technical field of the present invention may also be called a viscosity improver, viscosity enhancer, viscosity modifier, viscosity imparter, thickener, or viscosity stabilizer) refers to a chemical agent that can increase the viscosity of a liquid when mixed with it.

[0072] Pharmaceutical preparations A pharmaceutical preparation for ocular administration, wherein in the aqueous phase, (i) Laquinimod or a pharmaceutically acceptable salt thereof as an active ingredient, (ii) Pharmaceutically acceptable viscosity modifiers, (iii) Pharmaceutically acceptable isotonic agents, (iv) Pharmaceutically acceptable humectants, (v) pharmaceutically acceptable antioxidants, and (vi) Pharmacologically acceptable pH adjusters, In addition, optionally, (vii) Pharmaceutically acceptable preservatives, (viii) pharmaceutically acceptable surfactants, (ix) pharmaceutically acceptable solubilizers, and (x) Pharmaceutically acceptable oils Pharmaceutical formulations comprising one or more components selected from are provided herein.

[0073] Active ingredients The ophthalmic (e.g., topical) formulations provided herein are pharmaceutical formulations comprising laquinimod or a pharmaceutically acceptable salt thereof in a concentration suitable to provide a therapeutically effective amount of laquinimod or a pharmaceutically effective amount when administered to the eye (ocular administration), preferably topically to the eye, for example as eye drops.

[0074] In some embodiments, laquinimod exists in a free base form (i.e., a non-salt form). In other embodiments, the formulation comprises a pharmaceutically acceptable salt of laquinimod, e.g., a metal salt, e.g., a salt containing a metal selected from lithium, sodium, potassium, magnesium, calcium, manganese, copper, zinc, aluminum, and iron. In some embodiments, the pharmaceutically acceptable salt of laquinimod is laquinimod sodium.

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

[0076] In some embodiments, the concentration of laquinimod in the formulation is in the range of 5 to 70 g / l, 10 to 70 g / l, or 20 to 70 g / l. In some embodiments, the concentration of laquinimod in the formulation is in the range of 5 to 50 g / l, 10 to 50 g / l, or 20 to 50 g / l. In some embodiments, the concentration of laquinimod in the formulation is in the range of 5 to 30 g / l, for example, 10 to 30 g / l, or 20 to 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 within 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 lakinimod in the formulation is 5 g / l. In some embodiments, the concentration of lakinimod is 10 g / l. In some embodiments, the concentration of lakinimod is 15 g / l. In some embodiments, the concentration of lakinimod is 20 g / l. In some embodiments, the concentration of lakinimod is 25 g / l. In some embodiments, the concentration of lakinimod is 30 g / l. In some embodiments, the concentration of lakinimod is 35 g / l. In some embodiments, the concentration of lakinimod is 40 g / l. In some embodiments, the concentration of lakinimod is 50 g / l. In some embodiments, the concentration of lakinimod is 60 g / l. In some embodiments, the concentration of lakinimod is 70 g / l. In some embodiments, the concentration of lakinimod is 80 g / l. In some embodiments, the concentration of lakinimod is 90 g / l. In some embodiments, the concentration of lakinimod is 100 g / l.

[0085] Where used herein, "g / l" indicates the amount (g) of laquinimod (as a free base or in the form of a pharmaceutically acceptable salt) per volume (l) of the formulation. Note that the concentration may also be expressed in mg / ml, and 1 g / l is equivalent to 1 mg / ml. Unless otherwise specified or evident from the context, the amounts indicated refer to the form of the free base, and those skilled in the art will be able to calculate the corresponding concentration or amount of the laquinimod salt if a salt of laquinimod is used.

[0086] In the pharmaceutical formulations provided herein, laquinimod has high stability against chemical degradation (or "decomposition"), for example, by oxidation, which is advantageous in that it allows for a long shelf life. Therefore, 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, and even more preferably 0.01% w / w or less, relative to the amount of laquinimod, or, for example, undetectable after a period of 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 at room temperature (about 18-25°C) in a sealed container suitable for pharmaceutical formulations.

[0087] Pharmaceutically acceptable viscosity modifiers The formulations provided herein have a (dynamic) viscosity of about 2 mPas to about 200 mPas when measured at a temperature of 20°C using the method described herein (falling ball method). 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, for example, 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 up to 180 mPas, up to 170 mPas, up to 160 mPas, up to 150 mPas, up to 130 mPas, up to 120 mPas, up to 110 mPas, up to 100 mPas, up to 90 mPas, up to 80 mPas, up to 75 mPas, up to 70 mPas, up to 65 mPas, up to 60 mPas, up to 55 mPas, up to 50 mPas, up to 45 mPas, up to 40 mPas, up to 35 mPas, up to 30 mPas, up to 25 mPas, or up to 20 mPas.

[0090] For example, in some embodiments, the viscosity is in the range of approximately 2 mPas to approximately 70 mPas, or approximately 2 mPas to approximately 65 mPas, or approximately 2 mPas to approximately 60 mPas, or approximately 2 mPas to approximately 55 mPas, or approximately 2 mPas to approximately 50 mPas, or approximately 2 mPas to approximately 45 mPas, or approximately 2 mPas to approximately 40 mPas, or approximately 2 mPas to approximately 35 mPas, or approximately 2 mPas to approximately 30 mPas, or approximately 2 mPas to approximately 25 mPas, or approximately 2 mPas to approximately 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] Therefore, in some embodiments, the viscosity of the formulation is in the range of approximately 5 mPas to approximately 75 mPas, or approximately 5 mPas to approximately 70 mPas, or approximately 5 mPas to approximately 65 mPas, or approximately 5 mPas to approximately 60 mPas, or approximately 5 mPas to approximately 55 mPas, or approximately 5 mPas to approximately 50 mPas, or approximately 5 mPas to approximately 45 mPas, or approximately 5 mPas to approximately 40 mPas, or approximately 5 mPas to approximately 35 mPas, or approximately 5 mPas to approximately 30 mPas, or approximately 5 mPas to approximately 25 mPas, or approximately 5 mPas to approximately 20 mPas.

[0092] In some further embodiments, the viscosity of the formulation is in 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] Therefore, in some further embodiments, the viscosity of the formulation is in the range of approximately 12 mPas to approximately 75 mPas, or approximately 12 mPas to approximately 70 mPas, or approximately 12 mPas to approximately 65 mPas, or approximately 12 mPas to approximately 60 mPas, or approximately 12 mPas to approximately 55 mPas, or approximately 12 mPas to approximately 50 mPas, or approximately 12 mPas to approximately 45 mPas, or approximately 12 mPas to approximately 40 mPas, or approximately 12 mPas to approximately 35 mPas, or approximately 12 mPas to approximately 30 mPas, or approximately 12 mPas to approximately 25 mPas, or approximately 12 mPas to approximately 20 mPas.

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

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

[0096] The formulation contains one or more pharmaceutically acceptable thickening agents.

[0097] Suitable viscosifiers 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, pharmaceutically acceptable thickening agents include one or more from the group consisting of polyvinyl alcohol, poly(acrylic acid) homopolymer or copolymer (carbomer), polyvinylpyrrolidone, and cellulose derivatives, such as hydroxypropyl methylcellulose and sodium carboxymethylcellulose.

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

[0100] In some embodiments, the thickening agent comprises a cellulosic polymer (or cellulose derivative) such as hydroxypropyl methylcellulose 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 poly(acrylic acid) homopolymer. In some embodiments, the thickening agent comprises poly(acrylic acid) copolymer.

[0101] In the carbomers 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 (a carbomer homopolymer, e.g., a carbomer homopolymer of type B). In some other embodiments, the carbomer is a crosslinked copolymer.

[0102] The thickening agent (this term may refer to either one specific thickening agent or a mixture of such thickening agents) is present in a total amount sufficient to produce the desired viscosity in the formulation, i.e., the viscosity within the range described herein. As will be apparent to those skilled in the art, the exact amount varies depending on the selected specific thickening agent(s), and further depends on the other components in the formulation and their concentrations. Those skilled in the art will be able to determine the required amount of thickening agent in light of this specification and the examples provided herein.

[0103] It should be noted that the viscosity of the formulation tends to decrease as the laquinimod concentration increases, and therefore, any given amount of viscous agent generally needs to be determined and adjusted in accordance with the laquinimod concentration of the formulation.

[0104] Pharmacologically acceptable isotonic agents Tear fluid is isotonic with blood and has isotonicity equivalent to a 0.9% NaCl aqueous solution. Therefore, it is ideal for ophthalmic formulations to be isotonic with tear fluid, but generally, a tension of about 0.6% to 2% NaCl aqueous solution is acceptable in the eye. When a small amount of ophthalmic formulation is administered, the tension may be outside this range, as dilution with tear fluid can quickly alleviate discomfort. However, preferably, the formulation should be approximately isotonic. The formulations provided herein contain one or more compounds selected from pharmaceutically acceptable isotonic agents, preferably nonionic isotonic agents, such as mannitol, sorbitol, glycerol, polyethylene glycol (PEG), polypropylene glycol (PPG), and sorbitol, but the isotonic agent is not limited to this selection, as other alternative isotonic agents are well known in the art. A preferred nonionic isotonic agent is mannitol.

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

[0106] In some embodiments, an isotonic agent (e.g., mannitol) is present in the formulation at concentrations of approximately 0.5 to 5 g / l, 0.5 to 4.5 g / l, 0.5 to 4 g / l, 0.5 to 3.5 g / l, or 0.5 to 3 g / l.

[0107] In some embodiments, an isotonic agent (e.g., mannitol) is present in the formulation at concentrations of approximately 1 to 5 g / l, approximately 1 to 4.5 g / l, approximately 1 to 4 g / l, approximately 1 to 3.5 g / l, or approximately 1 to 3 g / l.

[0108] In some embodiments, an isotonic agent (e.g., mannitol) is present in the formulation at concentrations of approximately 1.5 to 5 g / l, approximately 1.5 to 4.5 g / l, approximately 1.5 to 4 g / l, approximately 1.5 to 3.5 g / l, or approximately 1.5 to 3 g / l.

[0109] In some embodiments, the isotonic agent (e.g., mannitol) is present in the formulation at concentrations 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 isotonic agent (e.g., mannitol) is present in the formulation at concentrations 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] Ideally, pharmaceutical formulations for ophthalmic administration should have an osmotic pressure in the range of 200 to 600 mOsm / kg to avoid causing discomfort when instilled. However, if the amount of formulation instilled is small, values ​​slightly outside this range may be acceptable.

[0111] In some embodiments, the formulations of the present invention have an osmotic pressure 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 present invention have an osmotic pressure in 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 osmotic pressure in 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 present invention have an osmotic pressure in 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 present invention have an osmotic pressure 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 present invention have an osmotic pressure in 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 present invention have an osmotic pressure in 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 present invention have an osmotic pressure in 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 present invention have an osmotic pressure 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, for example, about 300 mOsm / kg.

[0120] Pharmaceutically acceptable moisturizers The formulations of the present invention include a humectant (sometimes called a "wetting agent" in the art), 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 is glycerol. In some embodiments, the humectant is glycerol.

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

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

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

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

[0125] The amount of antioxidant present in a formulation generally depends on the amount of laquinimod contained in the formulation. In some embodiments, the formulation may contain antioxidants in a weight ratio (weight of antioxidant:weight of laquinimod) in the range of 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, for example, 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, for example, in the range of about 1:10.

[0126] Pharmaceutically acceptable pH adjusters The pH adjuster is preferably present in the formulation in an amount sufficient to bring the formulation to a pH of at least 6.8. Preferably, the formulations provided herein have a pH of about 6.8 to about 8.5, for example, 7 to 8.5, or 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, for example, 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, for example, 7.4 to 8.0. In some further embodiments, the formulation has a pH in the range of 6.8 to 8.0, for example, 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, for example, 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 7.3–7.9, 7.3–7.8, 7.3–7.7, 7.3–7.6, or 7.3–7.5. In some embodiments, the formulation has a pH of about 7.4.

[0127] The formulation contains a pH adjuster to achieve a pH within the above range. For example, the formulation may contain approximately 1 to 5 g / l of a pH adjuster, for example, approximately 1 to 2 g / l of a pH adjuster.

[0128] In some embodiments, the pH adjuster comprises one or more pH buffers, for example, 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 adding a base or acid, such as a strong base like sodium hydroxide or a strong acid like hydrochloric acid, and optionally, it may be maintained at a desired pH by using a suitable buffer, such as those described herein.

[0130] Pharmaceutically acceptable preservatives In some embodiments, the formulation contains a pharmaceutically acceptable amount of an API-stored effective amount of a preservative. In some embodiments, the formulation contains 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}ethanaminonium chloride). In some embodiments, the preservative contains benzalkonium chloride. In some embodiments, the preservative is benzalkonium chloride. Benzalkonium chloride (CAS number 8001-54-5) has the general formula

[0131] [ka]

[0132] (In the formula, n is an integer in the range of 8 to 16.) It is a mixture of alkylbenzyldimethylammonium chloride.

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

[0134] In some embodiments, the formulations provided herein do not contain preservatives. For example, in some embodiments, if the formulation is provided in a single-use container (i.e., a container for use only once) or a single-dose container (i.e., a container containing only a single dose), it may not contain preservatives. In some of these embodiments, the formulation does not contain preservatives.

[0135] Furthermore, there are similar devices such as multidose containers that eliminate the need for preservatives, like the Novelia® PFMD bottle sold by Nemera (France), and multidose containers like those described in the paper "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 multidose container suitable for administering a preservative-free formulation to the eye.

[0136] Pharmaceutically acceptable surfactants In some embodiments, the formulation further comprises a surfactant, preferably a nonionic surfactant. For example, the formulation may contain a polysorbate such as polysorbate 80 and a nonionic surfactant selected from poloxamers such as poloxamer 188 or poloxamer 407. In some embodiments, the formulation comprises polysorbate 80 as the surfactant.

[0137] In the formulations described herein, such as gel formulations, the preferred concentration of the surfactant may be in the range of, for example, 0.1-5 g / l, 0.2-5 g / l, 0.5-5 g / l, 0.1-4 g / l, 0.2-4 g / l, 0.5-4 g / l, 0.1-3 g / l, 0.2-3 g / l, 0.5-3 g / l; 0.1-2 g / l, 0.2-2 g / l, or 0.5-2 g / l. In some embodiments, the preferred concentration of the surfactant in the formulations described herein, such as gel formulations, is in the range of 0.1-1.5 g / l, 0.2-1.5 g / l, 0.5-1.5 g / l, or 0.8-1.5 g / l; for example, in the range of 0.1-1.2 g / l, 0.2-1.2 g / l, 0.5-1.2 g / l, or 0.8-1.2 g / l. In some embodiments, a preferred concentration of the surfactant in the gel formulation 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 the surfactant is generally higher than in gel formulations, and the preferred concentrations of the surfactant may be in the range 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 surfactants. In some embodiments, the formulation is a surfactant-free gel formulation.

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

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

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

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

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

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

[0146] Finally, it should be noted that some components possess several functional attributes and therefore may exist in different capacities within the formulations of the present invention. For example, those skilled in the art will know that carbomer copolymers (type B) are used in the field of pharmaceutical formulations as thickeners, gel-forming agents, stabilizers, and emulsifiers. Similarly, polyoxyl castor oil is used not only as a nonionic solubilizer but also as an oil-in-water emulsifier. Other components with multiple uses described herein include, for example, macrogol 15-hydroxystearate (nonionic solubilizer, emulsifier) ​​and polyvinylpyrrolidone (solubilizer, viscosity enhancer).

[0147] Furthermore, it should be noted that any functional agent referred to herein (e.g., viscosity modifiers, isotonic agents, humectants, etc.) may generally contain one or more compounds having the required functionality; that is, unless otherwise specified or evident from the context, a functional agent may consist of only one such compound or a mixture of two or more such compounds.

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

[0149] In some further embodiments, the formulations provided herein are (i) a therapeutically effective dose of laquinimod or a pharmaceutically acceptable salt thereof as the active ingredient; (ii) A pharmaceutically acceptable thickening agent, selected from cellulose derivatives such as carbomer copolymers (e.g., type B) and / or sodium carboxymethylcellulose, in an amount sufficient to give a viscosity as defined herein, preferably 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 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 pharmaceutically acceptable isotonic agent, such as a nonionic isotonic agent such as mannitol, in an amount sufficient to produce an osmotic pressure as specified herein, preferably about 200-400 mOsm / kg, or about 250-350 mOsm / kg, or about 280-320 mOsm / kg; (iv) pharmaceutically acceptable humectants, such as polyols including glycerol; (v) pharmaceutically acceptable antioxidants, e.g., Na-EDTA; and (vi) a pharmaceutically acceptable pH adjuster, such as a basic buffer such as TRIS or disodium hydrogen phosphate dihydrate, in an amount sufficient to bring the pH to at least 6.8, e.g., 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) Pharmacopoecially acceptable preservatives, e.g., benzalkonium chloride; (viii) Pharmaceutically acceptable surfactants, such as polysorbates including polysorbate 80; (ix) A pharmaceutically acceptable solubilizer, e.g., macrogol 15-hydroxystearate; and (x) Pharmaceutically acceptable oils, such as vegetable oils like castor oil. It contains one or more components selected from the following.

[0150] In some embodiments, the formulation for ocular administration is (i) a therapeutically effective dose of laquinimod or a pharmaceutically acceptable salt thereof as the active ingredient; (ii) A pharmaceutically acceptable viscosifier in an amount sufficient to produce a dynamic viscosity of 10–45 mPas, for example, 15–45 mPas, as measured at 20°C; (iii) A pharmaceutically acceptable isotonic agent in an amount sufficient to produce an osmotic pressure of 200–400 mOsm / kg, for example, 250–375 mOsm / kg; (iv) Pharmaceutically acceptable humectants; (v) pharmaceutically acceptable antioxidants; and (vi) Contains a pharmaceutically acceptable pH adjuster in an amount sufficient to produce a pH of 6.8 to 8.0.

[0151] In some embodiments, the formulation for ocular administration is (i) a therapeutically effective dose of laquinimod or a pharmaceutically acceptable salt thereof as the active ingredient; (ii) A pharmaceutically acceptable thickening agent in an amount sufficient to yield a dynamic viscosity of 10–30 mPas when measured at 20°C; (iii) A pharmaceutically acceptable isotonic agent in an amount sufficient to produce an osmotic pressure of 200–400 mOsm / kg; (iv) Glycerol; (v) pharmaceutically acceptable antioxidants; and (vi) Contains a pharmaceutically acceptable pH adjuster in an amount sufficient to produce a pH of 6.8 to 8.5, for example, 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 osmotic pressure 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–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 osmotic pressure 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 to 40 mPas; an osmotic pressure of about 280 to 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 is (i) a therapeutically effective dose of laquinimod or a pharmaceutically acceptable salt thereof as the active ingredient; (ii) A pharmaceutically acceptable thickening agent, such as the thickening agents described herein, in an amount sufficient to give a viscosity as defined herein, preferably about 2 to 50 mPas, about 2 to 45 mPas, about 2 to 40 mPas, about 2 to 35 mPas, about 10 to 50 mPas, about 10 to 45 mPas, about 10 to 40 mPas, about 10 to 35 mPas, about 15 to 50 mPas, about 15 to 45 mPas, about 15 to 40 mPas, or about 15 to 35 mPas; (iii) A pharmaceutically acceptable isotonic agent in an amount sufficient to produce an osmotic pressure as specified herein, preferably about 200-400 mOsm / kg, about 250-350 mOsm / kg, about 250-375 mOsm / kg, or about 280-320 mOsm / kg, such as an isotonic agent described herein; (iv) pharmaceutically acceptable humectants, such as those described herein, such as glycerol; (v) pharmaceutically acceptable antioxidants, such as those described herein, such as Na-EDTA; and (vi) a pharmaceutically acceptable pH adjuster in an amount sufficient to bring about 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, e.g., pH adjusters described herein; and optionally, (vii) Pharmaceutically acceptable preservatives; (viii) pharmaceutically acceptable surfactants; (ix) pharmaceutically acceptable solubilizers; and (x) Pharmaceutically acceptable oils It contains one or more components selected from the following.

[0156] The formulations provided herein are either gel formulations or water- and oil-containing emulsion formulations. In some embodiments, the water- and oil-containing emulsion formulations are oil-in-water emulsions. The water present in the formulation should be suitable for pharmaceutical use, such as distilled water, purified water, or water for injection.

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

[0158] In water- and oil-containing emulsion formulations, the oil is a pharmaceutically acceptable 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 apparent to those skilled in the art, the ratio of oil to the aqueous phase varies depending on whether the oil forms the outer or inner phase. Thus, in water-in-oil emulsions, the volume of oil is usually greater than the volume of the aqueous phase, and vice versa in oil-in-water emulsions. In the emulsion, the inner phase (e.g., the oil phase) can be present in amounts such as 10-100 g / l, 20-80 g / l, 30-70 g / l, or approximately 40-60 g / l.

[0159] In some embodiments, the formulations provided herein are water- and oil-containing emulsions, preferably oil-in-water emulsions, - Laquinimod or any pharmaceutically acceptable salt thereof; - A viscosity agent such as a carbomer copolymer and / or sodium carboxymethylcellulose in a concentration sufficient to produce a viscosity within the range indicated herein; - Isotonic agents such as mannitol; - Moisturizers such as glycerol; - Antioxidants such as Na-EDTA; - A pH buffer that provides 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, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS; - Optionally, preservatives such as benzalkonium chloride; - Optionally, surfactants such as polysorbate (e.g., polysorbate 80) and / or poloxamer (e.g., poloxamer 407); - Optionally, solubilizers (or emulsifiers) such as macrogol 15-hydroxystearate, polyoxyl castor oil; and - A water and oil-containing emulsion containing vegetable oils such as castor oil.

[0160] In some embodiments, a water- and oil-containing emulsion (preferably an oil-in-water emulsion) is, - Laquinimod or any pharmaceutically acceptable salt thereof; - A viscosity agent, such as a carbomer copolymer and / or sodium carboxymethylcellulose, in a concentration sufficient to produce a viscosity within the range indicated herein; - Isotonic agents such as mannitol; - Moisturizers such as glycerol; - Antioxidants such as Na-EDTA; - A pH buffer that provides 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, such as a pH buffer selected from disodium hydrogen phosphate dihydrate and TRIS; - Preservatives such as benzalkonium chloride; - Surfactants such as polysorbate (e.g., polysorbate 80) and / or poloxamer (e.g., poloxamer 407); - Solubilizers (or emulsifiers) such as macrogol 15-hydroxystearate and polyoxyl castor oil; and - Contains vegetable oils such as castor oil.

[0161] In some embodiments, a water- and oil-containing emulsion (preferably an oil-in-water emulsion) is, - A therapeutically effective dose of laquinimod or a pharmaceutically acceptable salt thereof, e.g., about 5 to about 100 g / l, about 10 to about 100 g / l, about 20 to about 80 g / l, or about 50 g / l of laquinimod, or a corresponding amount of a pharmaceutically acceptable salt thereof; - Sodium carboxymethylcellulose in approximately 2 to 10 g / l, for example, approximately 3 to 8 g / l, or approximately 4 to 6 g / l, and / or carbomer copolymer (e.g., carbomer polymer type B) in approximately 0.2 to 1 g / l, for example, approximately 0.3 to 0.8 g / l, or for example, approximately 0.5 g / l; - Mannitol at approximately 1.5-4 g / l, for example, approximately 2.5-3 g / l, for example, approximately 2.7 g / l; - Glycerol of approximately 10-40 g / l, for example, approximately 20-30 g / l, for example, approximately 25 g / l; - Na-EDTA at approximately 0.2-2 g / l, for example, approximately 0.5-1.5 g / l, or approximately 0.8-1.2 g / l; - A pH buffer effective in bringing the pH to 7.0-8.5, for example, 7.4-8.4, or 8.0-8.4, for example, about 8.4, selected from pH buffers such as disodium hydrogen phosphate dihydrate and TRIS (for example, about 1-1.5 g / l of TRIS); - Optionally, approximately 0.05 to 0.2 g / l of benzalkonium chloride, for example, approximately 0.1 to 0.15 g / l; - Optionally, a surfactant in an amount of about 10 to about 50 g / l, for example, about 20 to about 40 g / l, preferably a nonionic surfactant, such as polysorbate and / or poloxamer, for example, polysorbate 80 and / or poloxamer 407; - Optionally, macrogol 15 hydroxystearate in a concentration of approximately 1 to 5 g / l, for example, approximately 1.5 to 3.5 g / l, for example, approximately 2.5 g / l, or polyoxyl castor oil (e.g., polyoxyl 35 castor oil) in a concentration of approximately 30 to 70 g / l, for example, approximately 40 to 60 g / l, for example, approximately 50 g / l; and - Contains vegetable oils such as castor oil, at a concentration of approximately 20 to 100 g / l, for example, approximately 30 to 70 g / l, or for example, approximately 50 g / l.

[0162] In some embodiments, a water- and oil-containing emulsion (preferably an oil-in-water emulsion) is, - A therapeutically effective dose of laquinimod or a pharmaceutically acceptable salt thereof, e.g., about 5 to about 100 g / l, about 10 to about 100 g / l, about 20 to about 80 g / l, or about 50 g / l of laquinimod, or a corresponding amount of a pharmaceutically acceptable salt thereof; - Sodium carboxymethylcellulose in approximately 2 to 10 g / l, for example, approximately 3 to 8 g / l, or approximately 4 to 6 g / l, and / or carbomer copolymer (e.g., carbomer polymer type B) in approximately 0.2 to 1 g / l, for example, approximately 0.3 to 0.8 g / l, or for example, approximately 0.5 g / l; - Mannitol at approximately 1.5-4 g / l, for example, approximately 2.5-3 g / l, for example, approximately 2.7 g / l; - Glycerol of approximately 10-40 g / l, for example, approximately 20-30 g / l, for example, approximately 25 g / l; - Na-EDTA at approximately 0.2-2 g / l, for example, approximately 0.5-1.5 g / l, or approximately 0.8-1.2 g / l; - A pH buffer effective in bringing the pH to 7.0-8.5, for example, 7.4-8.4, or 8.0-8.4, for example, about 8.4, selected from pH buffers such as disodium hydrogen phosphate dihydrate and TRIS (for example, about 1-1.5 g / l of TRIS); - Approximately 0.05 to 0.2 g / l, for example, approximately 0.1 to 0.15 g / l of benzalkonium chloride; - A surfactant of approximately 10 to 50 g / l, for example, approximately 20 to 40 g / l, preferably a nonionic surfactant, such as polysorbate and / or poloxamer, for example, polysorbate 80 and / or poloxamer 407; - Macrogol 15 hydroxystearate in approximately 1 to 5 g / l, for example, approximately 1.5 to 3.5 g / l, for example, approximately 2.5 g / l, or polyoxyl castor oil (e.g., polyoxyl 35 castor oil) in approximately 30 to 70 g / l, for example, approximately 40 to 60 g / l, for example, approximately 50 g / l; and - Contains vegetable oils such as castor oil, at a concentration of approximately 20 to 100 g / l, for example, approximately 30 to 70 g / l, or for example, approximately 50 g / l.

[0163] Some further emulsion formulations provided herein are shown in Tables 1 to 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 any pharmaceutically acceptable salt thereof; - A viscosity agent such as a carbomer copolymer, hydroxypropyl methylcellulose, polyvinyl alcohol, and / or sodium carboxymethylcellulose, in a concentration sufficient to produce a viscosity within the range indicated herein; - Isotonic agents such as mannitol; - Moisturizers such as glycerol; - Antioxidants such as Na-EDTA; - A pH buffer that provides 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, preservatives such as benzalkonium chloride; - Optionally, surfactants such as polysorbate (e.g., polysorbate 80) and / or poloxamer (e.g., poloxamer 188, or poloxamer 407); and - Optionally, it may contain solubilizers such as macrogol 15-hydroxystearate or polyvinylpyrrolidone.

[0177] In some embodiments, the gel formulation is - Laquinimod or any pharmaceutically acceptable salt thereof; - A viscosity agent such as a carbomer copolymer, hydroxypropyl methylcellulose, polyvinyl alcohol, and / or sodium carboxymethylcellulose, in a concentration sufficient to produce a viscosity within the range indicated herein; - Isotonic agents such as mannitol; - Moisturizers such as glycerol; - Antioxidants such as Na-EDTA; - Preservatives such as benzalkonium chloride; - A pH buffer that provides 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, it may contain a solubilizer such as macrogol 15-hydroxystearate, polyvinylpyrrolidone, or polyoxyl castor oil.

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

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

[0180] In some embodiments, the gel formulation is - A therapeutically effective dose of laquinimod or a pharmaceutically acceptable salt thereof; - Sodium carboxymethylcellulose, and / or carbomer copolymers (e.g., carbomer polymer type B); - isotonic agent; - Moisturizer; - Antioxidant; - A pH buffer effective in bringing the pH to 6.8-8.5, or 7.0-8.5, for example, 7.4-8.4, 7.4-8.0, or 8.0-8.4, for example, about 8.0; - Preservatives; - Optionally, surfactants, such as nonionic surfactants; and - Optionally, include macrogol 15-hydroxystearate, polyoxyl castor oil (e.g., polyoxyl 35-castor oil), or polyvinylpyrrolidone.

[0181] In some embodiments, the gel formulation is - A therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof, e.g., 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 pharmaceutically acceptable salt thereof; - Sodium carboxymethylcellulose in approximately 1 to 10 g / l, for example, approximately 2 to 8 g / l, or approximately 3 to 5 g / l, and / or carbomer copolymer (e.g., carbomer polymer type B) in approximately 0.5 to 6 g / l, for example, approximately 1 to 5 g / l, for example, approximately 1.5 to 3 g / l; - isotonic agent; - Moisturizer; - Antioxidant; - A pH buffer effective in bringing the pH to 6.8-8.5, or 7.0-8.5, for example, 7.4-8.4, 7.4-8.0, or 8.0-8.4, for example, about 8.0; - Preservatives; - Optionally, surfactants, such as nonionic surfactants; and - Optionally, approximately 1 to 5 g / l of macrogol 15 hydroxystearate, for example approximately 1.5 to 3.5 g / l, or approximately 2.5 g / l of polyoxyl castor oil (e.g., polyoxyl 35 castor oil) in amounts of approximately 30 to 70 g / l, for example approximately 40 to 60 g / l, or approximately 50 g / l of polyoxyl castor oil, or approximately 5 to 20 g / l, for example approximately 8 to 15 g / l, or approximately 10 g / l of polyvinylpyrrolidone.

[0182] In some embodiments, the gel formulation is - A therapeutically effective dose, e.g., approximately 10-100 g / l of laquinimod or a pharmaceutically acceptable salt thereof; - Carbomer copolymers (e.g., carbomer polymer type B) containing approximately 1 to 10 g / l and / or approximately 0.5 to 6 g / l; - isotonic agent; - Moisturizer; - Antioxidant; - A pH buffer effective in bringing the pH to 6.8-8.5, or 7.0-8.5, for example, 7.4-8.4, 7.4-8.0, or 8.0-8.4, for example, about 8.0; - Preservatives; - Optionally, surfactants, such as nonionic surfactants; and - Optionally, it may contain approximately 1 to 5 g / l of macrogol 15 hydroxystearate, or approximately 30 to 70 g / l of polyoxyl castor oil (e.g., polyoxyl 35 castor oil), or approximately 5 to 20 g / l of polyvinylpyrrolidone.

[0183] In some embodiments, the gel formulation is - A therapeutically effective dose, e.g., approximately 10-100 g / l of laquinimod or a pharmaceutically acceptable salt thereof; - Carbomer copolymers (e.g., carbomer polymer type B) containing approximately 1 to 10 g / l and / or approximately 0.5 to 6 g / l; - Approximately 1.5-4 g / l of mannitol; - Approximately 10-40 g / l of glycerol; - Approximately 0.2-2 g / l of Na-EDTA; - A pH buffer effective in bringing the pH to 6.8-8.5, or 7.0-8.5, for example, 7.4-8.4, 7.4-8.0, or 8.0-8.4, for example, about 8.0; - Approximately 0.05 to 0.2 g / l of benzalkonium chloride; - Optionally, a surfactant, such as a nonionic surfactant, such as a surfactant of about 0.1 to about 5 g / l, preferably a nonionic surfactant; and - Optionally, it may contain approximately 1 to 5 g / l of macrogol 15 hydroxystearate, or approximately 30 to 70 g / l of polyoxyl castor oil (e.g., polyoxyl 35 castor oil), or approximately 5 to 20 g / l of polyvinylpyrrolidone.

[0184] In some embodiments, the gel formulation is - A therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof, e.g., 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 pharmaceutically acceptable salt thereof; - Sodium carboxymethylcellulose in approximately 1 to 10 g / l, for example, approximately 2 to 8 g / l, or approximately 3 to 5 g / l, and / or carbomer copolymer (e.g., carbomer polymer type B) in approximately 0.5 to 6 g / l, for example, approximately 1 to 5 g / l, for example, approximately 1.5 to 3 g / l; - Mannitol at approximately 1.5-4 g / l, for example, approximately 2.5-3 g / l, for example, approximately 2.7 g / l; - Glycerol of approximately 10-40 g / l, for example, approximately 20-30 g / l, for example, approximately 25 g / l; - Na-EDTA at approximately 0.2-2 g / l, for example, approximately 0.5-1.5 g / l, or approximately 0.8-1.2 g / l; - A pH buffer effective in bringing the pH to 6.8-8.5, or 7.0-8.5, for example, 7.4-8.4, 7.4-8.0, or 8.0-8.4, for example, about 8.0, selected from pH buffers such as disodium hydrogen phosphate dihydrate and TRIS (for example, about 1-1.5 g / l of TRIS); - Approximately 0.05 to 0.2 g / l, for example, approximately 0.1 to 0.15 g / l of benzalkonium chloride; - Optionally, surfactants, such as nonionic surfactants, such as about 0.1 to about 5 g / l, such as about 0.2 to about 3 g / l, or about 0.5 to about 2 g / l, preferably nonionic surfactants, such as polysorbate and / or poloxamer, such as polysorbate 80 or poloxamer 407; and - Contains approximately 1 to 5 g / l of macrogol 15 hydroxystearate, for example, approximately 1.5 to 3.5 g / l, or approximately 2.5 g / l of polyoxyl castor oil (e.g., polyoxyl 35 castor oil) in approximately 30 to 70 g / l, for example, approximately 40 to 60 g / l, or approximately 50 g / l of polyoxyl castor oil, or approximately 5 to 20 g / l, for example, approximately 8 to 15 g / l, or approximately 10 g / l of polyvinylpyrrolidone.

[0185] In some embodiments, the gel formulation is - A therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof, e.g., about 10 to about 100 g / l, about 20 to about 80 g / l, or about 20 to about 50 g / l of laquinimod, or a corresponding amount of a pharmaceutically acceptable salt thereof; - Sodium carboxymethylcellulose in approximately 1 to 10 g / l, for example, approximately 2 to 8 g / l, or approximately 3 to 5 g / l, and / or carbomer copolymer (e.g., carbomer polymer type B) in approximately 0.5 to 6 g / l, for example, approximately 1 to 5 g / l, for example, approximately 1.5 to 3 g / l; - Mannitol at approximately 1.5-4 g / l, for example, approximately 2.5-3 g / l, for example, approximately 2.7 g / l; - Glycerol of approximately 10-40 g / l, for example, approximately 20-30 g / l, for example, approximately 25 g / l; - Na-EDTA at approximately 0.2-2 g / l, for example, approximately 0.5-1.5 g / l, or approximately 0.8-1.2 g / l; - A pH buffer effective in bringing the pH to 6.8-8.5, or 7.0-8.5, for example, 7.4-8.4, 7.4-8.0, or 8.0-8.4, for example, about 8.0, selected from pH buffers such as disodium hydrogen phosphate dihydrate and TRIS (e.g., about 1-1.5 g / l of TRIS, or about 1.5-2 g / l of disodium hydrogen phosphate dihydrate); In addition, optionally, - Pharmaceutically acceptable preservatives, e.g., benzalkonium chloride in concentrations of approximately 0.05 to 0.2 g / l, e.g., approximately 0.1 to 0.15 g / l; - A pharmaceutically acceptable surfactant, such as a nonionic surfactant, such as a surfactant of about 0.1 to about 5 g / l, such as about 0.2 to about 3 g / l, or about 0.5 to about 2 g / l, such as about 1 g / l, preferably a nonionic surfactant, such as polysorbate, such as polysorbate 80; and - A pharmaceutically acceptable solubilizer, e.g., macrogol 15 hydroxystearate in concentrations of approximately 1 to 5 g / l, e.g., approximately 1.5 to 3.5 g / l, e.g., approximately 2.5 g / l. It contains one or more components selected from the following.

[0186] In some embodiments, the gel formulation is - A therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof, e.g., about 10 to about 100 g / l, about 20 to about 80 g / l, or about 20 to about 50 g / l of laquinimod, or a corresponding amount of a pharmaceutically acceptable salt thereof; - Sodium carboxymethylcellulose in approximately 1 to 10 g / l, for example, approximately 2 to 8 g / l, or approximately 3 to 5 g / l, and / or carbomer copolymer (e.g., carbomer polymer type B) in approximately 0.5 to 6 g / l, for example, approximately 1 to 5 g / l, for example, approximately 1.5 to 3 g / l; - about 1.5 to 4 g / l, for example about 2.5 to 3 g / l, for example about 2.7 g / l of mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l of glycerol; - about 0.2 to 2 g / l, for example about 0.5 to 1.5 g / l, or about 0.8 to 1.2 g / l of Na-EDTA; - a pH buffering agent 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, wherein the pH buffering agent is 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 pharmaceutically 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; and - a pharmaceutically acceptable solubilizer, for example macrogol 15 hydroxystearate at about 1 to about 5 g / l, for example about 1.5 to about 3.5 g / l, for example about 2.5 g / l comprises one or more components selected from the above.

[0187] In some embodiments, the gel formulation is - a therapeutically effective amount of rakinimod or a pharmaceutically acceptable salt thereof, for example about 10 to about 100 g / l, about 20 to 80 g / l, or about 20 to about 50 g / l of rakinimod, or a corresponding amount of a pharmaceutically acceptable salt thereof; - about 1 to about 10 g / l, for example about 2 to about 8 g / l, or about 3 to about 5 g / l of sodium carboxymethyl cellulose, and / or about 0.5 to about 6 g / l, for example about 1 to about 5 g / l, for example about 1.5 to about 3 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 of mannitol; - about 10 to 40 g / l, for example about 20 to about 30 g / l, for example about 25 g / l of glycerol; - Na-EDTA at approximately 0.2-2 g / l, for example, approximately 0.5-1.5 g / l, or approximately 0.8-1.2 g / l; - A pH buffer effective in bringing the pH to 6.8-8.5, or 7.0-8.5, for example, 7.4-8.4, 7.4-8.0, or 8.0-8.4, for example, about 8.0, selected from pH buffers such as disodium hydrogen phosphate dihydrate and TRIS (for example, about 1-1.5 g / l of TRIS); In addition, optionally, - Pharmaceutically acceptable preservatives, e.g., benzalkonium chloride in concentrations of approximately 0.05 to 0.2 g / l, e.g., approximately 0.1 to 0.15 g / l; and - A pharmaceutically acceptable surfactant, such as a nonionic surfactant, for example, a surfactant of about 0.1 to about 5 g / l, for example, about 0.2 to about 3 g / l, or about 0.5 to about 2 g / l, for example, about 1 g / l, preferably a nonionic surfactant, for example, polysorbate, for example, polysorbate 80 It contains one or more components selected from the following.

[0188] In some embodiments, the gel formulation is - A therapeutically effective amount of laquinimod or a pharmaceutically 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 pharmaceutically acceptable salt thereof, e.g., the sodium salt of laquinimod; - Sodium carboxymethylcellulose in approximately 1 to 10 g / l, for example, approximately 2 to 8 g / l, or approximately 3 to 5 g / l, and / or carbomer copolymer (e.g., carbomer polymer type B) in approximately 0.5 to 6 g / l, for example, approximately 1 to 5 g / l, for example, approximately 1.5 to 3 g / l; - Mannitol at approximately 1.5-4 g / l, for example, approximately 2.5-3 g / l, for example, approximately 2.7 g / l; - Glycerol of approximately 10-40 g / l, for example, approximately 10-30 g / l, or approximately 15-20 g / l; - Na-EDTA at approximately 0.2-2 g / l, for example, approximately 0.5-1.5 g / l, or approximately 0.8-1.2 g / l; - A pH buffer in an amount effective to produce 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 buffer selected from disodium hydrogen phosphate dihydrate and TRIS (for example, about 1 to 1.5 g / l of TRIS, or about 1.5 to 2 g / l of disodium hydrogen phosphate dihydrate); In addition, optionally, - Pharmaceutically acceptable preservatives, e.g., benzalkonium chloride in concentrations of approximately 0.05 to 0.2 g / l, e.g., approximately 0.1 to 0.15 g / l; and - A pharmaceutically acceptable surfactant, such as a nonionic surfactant, for example, a surfactant of about 0.1 to about 5 g / l, for example, about 0.2 to about 3 g / l, or about 0.5 to about 2 g / l, for example, about 1 g / l, preferably a nonionic surfactant, for example, polysorbate, for example, polysorbate 80 It contains one or more components selected from the following.

[0189] In some embodiments, the gel formulation is - A therapeutically effective amount of laquinimod or a pharmaceutically 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 pharmaceutically acceptable salt thereof, e.g., the sodium salt of laquinimod; - Sodium carboxymethylcellulose in approximately 1 to 10 g / l, for example, approximately 2 to 8 g / l, or approximately 3 to 5 g / l, and carbomer copolymer (e.g., carbomer polymer type B) in approximately 0.5 to 6 g / l, for example, approximately 1 to 5 g / l, for example, approximately 1.5 to 3 g / l; - Mannitol at approximately 1.5-4 g / l, for example, approximately 2.5-3 g / l, for example, approximately 2.7 g / l; - Glycerol of approximately 10-40 g / l, for example, approximately 10-30 g / l, or approximately 15-20 g / l; - Na-EDTA at approximately 0.2-2 g / l, for example, approximately 0.5-1.5 g / l, or approximately 0.8-1.2 g / l; - A pH buffer in an amount effective to produce 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 buffer selected from disodium hydrogen phosphate dihydrate and TRIS (for example, about 1 to 1.5 g / l of TRIS, or about 1.5 to 2 g / l of disodium hydrogen phosphate dihydrate); In addition, optionally, - Pharmaceutically acceptable preservatives, e.g., benzalkonium chloride in concentrations of approximately 0.05 to 0.2 g / l, e.g., approximately 0.1 to 0.15 g / l; and - A pharmaceutically acceptable surfactant, such as a nonionic surfactant, for example, a surfactant of about 0.1 to about 5 g / l, for example, about 0.2 to about 3 g / l, or about 0.5 to about 2 g / l, for example, about 1 g / l, preferably a nonionic surfactant, for example, polysorbate, for example, polysorbate 80 It contains one or more components selected from the following.

[0190] In some embodiments, the gel formulation is - A therapeutically effective amount of laquinimod or a pharmaceutically 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 pharmaceutically acceptable salt thereof, e.g., the sodium salt of laquinimod; - Approximately 3 to 5 g / l of sodium carboxymethylcellulose, and approximately 1.5 to 3 g / l of carbomer copolymer (e.g., carbomer polymer type B); - Approximately 2.5 to 3 g / l of mannitol; - Approximately 15-20 g / l of glycerol; - Approximately 0.8-1.2 g / l of Na-EDTA; - An amount of pH buffer effective to achieve a pH of 6.8 to 8.0, for example, approximately 7.4 (e.g., approximately 1.5 to 2 g / l of disodium hydrogen phosphate dihydrate); Furthermore, preferably, - Approximately 0.1 to 0.15 g / l of benzalkonium chloride; and - Polysorbate 80 at approximately 0.5 to 1.5 g / l It contains one or more (e.g., both) components selected from the following.

[0191] In some embodiments, the gel formulation is (i) a therapeutically effective dose of laquinimod or a pharmaceutically acceptable salt thereof as the active ingredient; (ii) A pharmaceutically acceptable thickening agent, selected from cellulose derivatives such as carbomer copolymers (e.g., type B) and / or sodium carboxymethylcellulose, in an amount sufficient to give a viscosity as defined herein, preferably about 2 to 50 mPas, about 2 to 40 mPas, about 2 to 30 mPas, about 10 to about 10 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 pharmaceutically acceptable isotonic agent, such as a nonionic isotonic agent such as mannitol, in an amount sufficient to produce an osmotic pressure as specified 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) pharmaceutically acceptable humectants, such as polyols including glycerol; (v) pharmaceutically acceptable antioxidants, e.g., Na-EDTA; and (vi) a pharmaceutically acceptable pH adjuster, such as a basic buffer such as TRIS or disodium hydrogen phosphate dihydrate, in an amount sufficient to bring about 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 8.0, 6.8 to about 8.0, about 7.0 to about 8.0, or about 7.4 to 8.0; and optionally, (vii) Pharmacopoecially acceptable preservatives, e.g., benzalkonium chloride; (viii) pharmaceutically acceptable surfactants, such as polysorbates including polysorbate 80; and (ix) a pharmaceutically acceptable solubilizer, for example macrogol 15 hydroxystearate which comprises one or more components selected from the above.

[0192] In some further embodiments, the gel formulation: (i) 10 to 100 g / l of racinimod, or a corresponding amount of a pharmaceutically acceptable salt of racinimod; (ii) 1 to 10 g / l of sodium carboxymethyl cellulose, and / or 0.5 to about 6 g / l of a carbomer copolymer; (iii) 1.5 to 4 g / l of mannitol; (iv) 10 to 40 g / l of glycerol; (v) 0.2 to 2 g / l of Na-EDTA; and (vi) a pH adjuster 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, for example topical ocular administration: (i) 10 to 12 g / l of racinimod, or a corresponding amount of a pharmaceutically acceptable salt of racinimod, for example a sodium salt of racinimod; (ii) 2 to 4 g / l of sodium carboxymethyl cellulose and 1 to 2 g / l of a carbomer copolymer; (iii) 2 to 3 g / l of mannitol; (iv) 15 to 20 g / l of glycerol; (v) 0.5 to 1.5 g / l of Na-EDTA; and (vi) a pH adjuster in an amount effective to provide a pH in the range of 6.8 to 8.0, for example about 7.4.

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

[0195] In some embodiments, the gel formulation is (i) 10-12 g / l of laquinimod, or a corresponding amount of a pharmaceutically acceptable salt of laquinimod, such as the sodium salt of laquinimod; (ii) 2-4 g / l of sodium carboxymethylcellulose and 1-2 g / l of carbomer copolymer; (iii) 2-3 g / l of mannitol; (iv) 15-20 g / l of glycerol; (v) 0.5-1.5 g / l of Na-EDTA; (vi) A pH adjusting agent effective in producing a pH in the range of 6.8 to 8.0, for example, about 7.4; (vii) Benzalkonium chloride in a concentration of 0.05 to 0.1 g / l; 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 surfactants. In some embodiments, the gel formulations provided herein do not contain solubilizers. In some embodiments, the gel formulations provided herein do not contain preservatives. In some embodiments, the gel formulations provided herein do not contain any of the optional components (vii) to (ix).

[0197] Some further gel formulations provided herein are shown in Tables 13 to 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, roughly (1) A step of mixing excipients other than the viscosity-enhancing agent with water to obtain an aqueous solution, (2) Mix the viscosity-concentrating agent(s) with the aqueous solution and stir 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, add water to adjust the volume of the viscous solution. (5) Mixing raquinimod with the viscous solution, while mechanically dispersing it as needed. (6) In the case of an oil-in-water emulsion, methods are also provided herein which, if necessary, include the step of further adjusting the volume of the aqueous phase and mixing a pharmaceutically acceptable oil with the aqueous phase.

[0224] Use of preparations The formulations provided herein are administered partially, preferably topically, to a patient's eye from a dose container that allows for the instillation of small amounts of the formulation, such as 1 to 10 drops having a droplet volume of, for example, 10 to 100 μl, 10 to 50 μl, or 10 to 40 μl, or 20 to 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 incorporating PureFlow® technology, such as the Novelia® multi-dose eye dropper sold by Nemera (France).

[0225] Therefore, in some embodiments, the formulations of the present invention, which are advantageously preservative-free, are provided in a multi-dose container having a valve structure that can effectively protect the formulation from microbial contamination, such as the Novelia® multi-dose eye dropper.

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

[0227] Preferably, the formulations provided herein are administered regularly 1 to 6 times a day, for example 1 to 5 times a day, 1 to 3 times a day, or 1 to 2 times a day. In some embodiments, the regular administration is once a day. In some embodiments, the regular administration is twice a day. In some embodiments, the regular administration is three times a day. In some embodiments, the regular administration is once every two days. In some embodiments, the formulation is administered once a week.

[0228] In some embodiments, the formulation is administered once daily for 2 to 14 days, or for a longer period, for example, 1 to 6 months, 2 to 6 months, or 3 to 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 to 14 days. In some embodiments, the formulation is administered once daily for 10 to 14 days. In some embodiments, the formulation is administered once daily for approximately 7 days. In some embodiments, the formulation is administered for 1 to 12 months, or 1 to 6 months, or 1 to 3 months, for example, once a week for 3 to 6 months. However, the exact dosage regimen and duration of treatment are usually determined by the treating physician.

[0229] Further embodiments include dosage containers containing the laquinimod formulations provided herein. The dosage containers may include integrated means for administering 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 the instillation of an appropriate dose of the formulation into 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 are preservative-free.

[0230] Further embodiments include kits (sometimes also called kits of parts) comprising dosage containers and instructions for use, as disclosed herein. In some embodiments, such kits also include one or more additional containers containing further instruments or materials useful in connection with the administration of the formulation, such as washing, wiping, or other means of administration.

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

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

[0233] In some embodiments, the eye 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, eyelids, cornea, retina, or optic nerve pathway.

[0234] In some embodiments, the OID is selected from uveitis, acute conjunctivitis, viral conjunctivitis, non-gonococcal 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, OID is uveitis. Uveitis is inflammation of the uvea or uveal duct, which includes the iris, ciliary body, and choroidal portion of the eye. Inflammation of the retina, called retinitis, and inflammation of the optic nerve, called optic neuritis, may or may not occur with uveitis. Anatomically, uveitis can be classified as anterior, intermediate, posterior, or diffuse, depending on which part of the uveal duct is affected. Anterior uveitis is mainly localized to the anterior part of the eye and includes iritis and iridocyclitis. Intermediate uveitis, also called peripheral uveitis, focuses on the ciliary body and squamous epithelium region just behind the iris and lens. For this reason, it is sometimes called "cyclitis" and "squamitis." Posterior uveitis refers to one of several forms, such as retinitis, choroiditis, or optic neuritis. Diffuse uveitis refers to inflammation affecting all parts of the eyeball, including the anterior, intermediate, and posterior structures (The Merck Manual, 1999). Inflammation caused by uveitis can lead to a variety of other eye conditions, including glaucoma, cataracts, and cystic macular edema, and can ultimately result in permanent vision loss.

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

[0237] In some embodiments, OID is conjunctivitis. In some embodiments, OID is associated with autoimmune diseases, such as multiple sclerosis, autoimmune hemolytic anemia, autoimmune oophoritis, autoimmune thyroiditis, autoimmune uveoretinitis, Crohn's disease, chronic immunothrombocytopenic purpura, colitis, contact sensitivity disease, diabetes mellitus, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, idiopathic myxedema, myasthenia gravis, psoriasis, pemphigus vulgaris, rheumatoid arthritis, or systemic lupus erythematosus. In some embodiments, OID is associated with Crohn's disease.

[0238] In some embodiments, eye diseases involve excessive (or harmful) vascularization of the eye, for example, in response to external stimuli to the eye or as a natural consequence of aging. The eyeball consists of many different tissues, such as the cornea, iris, ciliary body, choroid, retina, and macula, and these tissues may undergo harmful vascularization. In some embodiments, eye diseases involve excessive vascularization of the cornea, iris, ciliary body, choroid, retina, and / or macula. In some embodiments, eye diseases involve excessive vascularization of the anterior tissues of the eyeball, such as the cornea, iris, and ciliary body.

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

[0240] Furthermore, in some embodiments, the eye disease is accompanied by excessive vascularization of the posterior tissues of the eyeball, such as the choroid, retina, and macula.

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

[0242] The following abbreviations may be used below in this specification. β-CD β-cyclodextrin EP (European Pharmacopoeia) HPLC (High-Performance Liquid Chromatography) HPMC (Hydroxypropyl Methylcellulose) kDa (kilodaltons, kg / mol) MFI Microflow Imaging NaCMC (NaCMC) Carboxymethylcellulose Sodium PA Pro Analysis PVA (Polyvinyl Alcohol) PVDF (Polyvinylidene Fluoride) rH / RH Relative humidity RP-HPLC (Reverse-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 a quality conforming to the United States Pharmacopeia (USP) and / or European Pharmacopeia (EP). The excipients were selected for ophthalmic administration. All chemicals used in the analytical methods were of a quality appropriate for each individual analytical method (e.g., professional analysis).

[0244] Preparation of gel and emulsion formulations The formulations were prepared as follows: weighing of excipients, dissolution overnight in water for injection (WFI) at 2–8°C using a magnetic stirrer to approximately 80% of the final volume, pH adjustment of the formulations at a temperature-controlled 23–25°C, volume increase to the final volume, and dissolution of laquinimod. pH adjustment of the high-viscosity formulations was performed on day 2, and dispensing of the formulations and commencement of accelerated degradation testing were performed on day 3.

[0245] The excipients were weighed in an order according to their solubility. That is, easily soluble excipients were added to the formulation first, and less soluble excipients, i.e., gelling agents, were added last. In detail, the process was as follows: Water (Aqua B. Braun, manufactured by Braun) was placed in a non-sterile 0.5 L PP beaker (manufactured by Sarstedt), and the excipients were added in stages as described above, while stirring the formulation with a magnetic bar of a stirrer (CIMARECi Poly, manufactured by Thermo Scientific) between additions, until the final volume reached approximately 80%.

[0246] pH adjustment requires the complete dissolution of all excipients. However, some formulations contained excipients with low solubility, such as carbomer type B, making complete dissolution difficult even after overnight stirring. Therefore, after overnight stirring, the formulations were visually inspected, and if incomplete dissolution of excipients was observed, a high-performance rod disperser (T 18 digital ULTRA-TURRAX®, manufactured by IKA) equipped with a dispersion tool (S 18 N - 19 G, manufactured by IKA) was applied to the formulation.

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

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

[0249] pH adjustment The final pH adjustment of all formulations and buffers, and the pH measurement of the resulting formulations, were performed at a temperature of 23°C to 25°C using a calibrated pH electrode (VWR) connected to a SevenEasy pH-Meter (Mettler Toledo) (compliant with both EP and USP standards).

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

[0251] [Table 38]

[0252] Measurement of osmotic pressure Osmotic pressure was measured using an osmometer (Osmomat 3000, Gonotec) by freezing point depression. The osmotic pressure of the entire aqueous solution was determined by comparing the freezing points of pure water and the aqueous solution. Each measurement was performed using a 50 μl aliquot after calibration with sodium chloride standard solution (600 mOsm / kg) and purified water. Gels and emulsions were measured using two copies, and if the deviation between two measurements exceeded 10%, three copies were measured. The arithmetic mean and standard deviation were then calculated.

[0253] Particle size measurement Particle size was determined by flow imaging analysis using a FlowCam 8100 system with a 10x objective lens (ANASYSTA) and 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) measurement are defined as follows: no more than 20 particles larger than 25 μm, no more than 2 particles larger than 50 μm, and no particles larger than 90 μm per 10 μg of laquinimod (PhEur monograph "Eye preparations" dose form monograph no. 1163, version 01 / 2008). Results were reported as particles / 10 μg of laquinimod for each of the described particle filter groups.

[0254] Sample preparation for particle size measurement involved diluting the sample 1:10 with a buffer of the same pH to which lacinimod had been added to a supersaturated state. Sodium phosphate buffers at pH 6.8 and 7.4, and Tris buffers at pH 8.0 and 8.4 were prepared, lacinimod was added to the supersaturation point, and the solutions were centrifuged at 2000xg for 3 minutes. The supernatant was used for sample dilution. Before diluting the sample, 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 then with a 4% surfactant (Hellmanex®, Hellma Analytics) to prevent cross-contamination and ensure reproducibility between measurements.

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

[0256] Save the sample During characterization, all samples (replicas) were stored in the dark for up to two weeks at 5°C, 25°C, 30°C, and 40°C. Further testing was performed at 5°C, 30°C, and 40°C. Samples stored at 5±3°C were kept in a refrigerator and their temperature was monitored externally. Samples subjected to accelerated degradation were stored in cabinets (manufactured by Memmert) with humidity controlled to 25±2°C / 60±5% relative humidity (RH), 30±2°C / 65±5% RH, and 40±2°C / 75±5% RH (ICH Q1 guidelines), respectively. Temperature was monitored throughout the entire storage period.

[0257] Density measurement Sample density was measured at room temperature (RT) with a sample volume of 1.103 ml using a Gay-Lussac pycnometer (Carl Roth). The weight of the pycnometer was measured using a chemical 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 (Anton Paar), with capillaries of different diameters, at both 20°C and at both 20°C and 37°C. The dynamic viscosity η of each sample was given by the known sphere density (ρb = 7.66 g / cm³). 3 Based on the measured sample density (ρs) and the characteristic constant of the capillary (C1), it was calculated according to the following formula.

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

[0260] Table 39 shows the materials used in Examples 1 to 7, as well as the suppliers and part numbers of each material.

[0261] [Table 39-1]

[0262] [Table 39-2]

[0263] Example 1 Ten different formulations, namely two emulsions (E1 and E2) and eight gels (S1-S8), were prepared using the method described herein. 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 week and 2 weeks, and at 40°C for 2 weeks, respectively. A very low degree of degradation of 0.03% (average) was observed after 2 weeks at 30°C, but the degree of degradation was slightly higher at 40°C (average 0.34%). The highest degree of degradation (based on RP-HPLC peak area) was observed in emulsion formulations E1 and E2, where the main peak relative area decreased by more than 0.9% compared to the initial concentration (t=0) (Table 41).

[0266] [Table 41]

[0267] Stability of the formulation against particle formation, sedimentation, and creaming. Slight 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 fraction of the total amount of lakinimod in the formulation. Therefore, it was concluded that either the lakinimod in the supernatant was dissolved, or the suspended particles of lakinimod were small enough not to precipitate. It was hypothesized that the precipitation was due to an interaction between the carbomer and lakinimod and was affected by pH. When formulation S1 was titrated from pH 7.4 to pH 8.0, the precipitate disappeared. This supported the hypothesis of a pH-dependent interaction between the carbomer and lakinimod.

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

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

[0272] Precipitation was observed in all gel formulations except S3. S1 showed the most precipitate, followed by S2 and S8. Little to no precipitation was observed in formulations S4, S5, S6, and S7. Precipitation could not be completely resuspended in formulations S5 and S6, but the other gel formulations were homogeneous after resuspending. The almost complete absence of precipitation in formulations S4 and S7 suggests that β-cyclodextrin in formulation S4 and polysorbate in formulation S7 have a stabilizing effect on raquinimod.

[0273] Following pH Eur 10.0 "Eye preparations," particle sizes were measured in three classes: over 25 μm, over 50 μm, and over 90 μm. The number of particles per 10 μg of laquinimod was calculated for each class. Particles were observed in formulations E1, E2, S1, S2, and S8. Cylindrical particles were detected in the suspension (gel), while mainly oil droplets were detected in the emulsion (Figure 5). It was observed that increasing pH resulted in a decrease in particle count.

[0274] Osmotic pressure The osmotic pressures of formulations E1, E2, and S1-S8 were measured, and for comparison, the osmotic pressure of a similar formulation ("empty" formulation) that did not contain laquinimod was also measured. The theoretical and measured osmotic pressures of these formulations and the laquinimod-free "empty" formulation are shown in Table 43.

[0275] [Table 43]

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

[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 raquinimod was completely dissolved.

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

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

[0281] [Table 45]

[0282] [Table 46-1]

[0283] [Table 46-2]

[0284] The chemical stability of raquinimod Samples of all formulations were stored at 5°C, 30°C, and 40°C for up to two weeks, and then analyzed by RP-HPLC. No significant decrease in main peak relative area was detected during storage at 5°C and 30°C, but a slight decrease was observed after two 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 the formulation against particle formation, sedimentation, and creaming. The appearance of all deteriorated formulation samples was examined using the same method as described for Example 1, and similar results were obtained.

[0288] Osmotic pressure The osmotic pressures of formulations E2-0 to E2-4 and S3-0 to S3-10 were measured in the same manner as the osmotic pressures of similar formulations ("empty" formulations), except that they did not contain laquinimod.

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

[0290] [Table 49]

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

[0292] In addition to measurements at 20°C, viscosity was also measured at 37°C to more closely simulate conditions inside the eye. The results are shown in Table 50.

[0293] [Table 50]

[0294] Example 3 Using formulation S7 as a starting material, a further gel formulation, formulation S7-1, was prepared by adding an additional viscosity-enhancing agent. The contents of formulations S7 (for comparison) and S7-1 are shown in Table 51.

[0295] [Table 51]

[0296] When measured using the same viscosity measurement system as described above, the viscosity of formulation S7-1 at 20°C was 17.6 mPas.

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

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

[0299] Bovine eyeballs were supplied by ABP (Ruthvenfield Road, Inveralmond Industrial Estate, Perth, PH1 3XB, UK). The eyeballs were collected from cattle immediately after slaughter and placed in containers with cold Hank's HBSS solution. During transport to the testing facility, the eyeballs were kept cool using cool packs.

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

[0301] Overview of the experimental design Six replicas were treated with each formulation for 4 hours of exposure. Permeation samples were collected only from corneas treated with the test substance, immediately before administration and at 30-minute intervals after administration. The final sample was collected 4 hours after administration (a total of 9 samples were collected from each cornea). Corneal opacity was measured before administration and after the final permeation sample collection. Laquinimod concentrations in the permeation samples were measured throughout the entire exposure period.

[0302] Test system setup The cornea was detached from a fresh eyeball. Upon arrival, the eyeball was washed in an HBSS and then examined for any obvious defects or signs of damage (e.g., scratches, opacity, neovascularization). The cornea of ​​an undamaged eyeball was removed, leaving a scleral margin of approximately 3 mm. The harvested cornea was placed in an HBSS with the epithelial side down and stored at room temperature until needed. Subsequently, the cornea was mounted with the epithelial side facing forward in a specially designed corneal holder manufactured by 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 insertion, both chambers of each corneal holder were filled with pre-warmed minimal essential medium (MEM) that did not contain phenol red. To encourage the cornea to return to its original curvature, the posterior chamber was filled first, taking care to prevent air bubbles from entering the medium. Subsequently, before administration, the holders were equilibrated in an incubator maintained at 32°C for at least one hour.

[0304] After the equilibration period, the culture medium in both chambers was replaced with fresh, pre-warmed MEM that did not contain phenol red. Baseline turbidity was then measured, and any damaged corneas or those with turbidity exceeding 7 opacity units were excluded from further use. Corneas that passed these tests were assigned to the test treatment group. The MEM in the posterior chamber was replaced with pre-warmed receptor solution using a syringe, allowing for measurement of the volume of solution added to the posterior chamber. The volume of the posterior chamber was recorded.

[0305] Pre-administration treatment MEM was removed from the anterior chamber immediately before administration. Pre-administration samples of receptor fluid were collected from each test substance-treated cornea. Receptor fluid samples were not collected from the vehicle control cornea. To prevent leakage during the incubation period, the access port to the posterior chamber was sealed with tape.

[0306] Administration Laquinimod and a saline control were administered undiluted. Before administration, the corneal holder was tilted forward to avoid contact between the administration solution and the corneal epithelium. The dose (approximately 750 μl) was administered via the anterior chamber access port using a syringe. Each dose was administered to six replicated corneas and exposed for 4 hours. Before retrieving the dose from the vial, the vial was gently swirled to resuspend the preparation.

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

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

[0309] Cleaning After the final receptor fluid was collected, the administered solution was removed from the anterior chamber, and the cornea was washed with MEM containing phenol red (approximately 5 ml per wash). Corneal washing was performed at least three times in both the anterior and posterior chambers, or until no residue of the test substance was visually detected. After washing was complete, one more wash was performed with MEM without phenol red to remove the phenol red and prevent interference with subsequent optical measurements. Then, before proceeding, both chambers were refilled with MEM without phenol red.

[0310] Measurement of turbidity After cleaning, the opacity of all corneal holders was measured by placing each corneal holder into an opacitometer supplied by Duratec Analysentechnik GmbH and recording the subsequent lux values.

[0311] Analysis of transmission samples Samples were stored in a freezer maintained at -20°C until analysis. A 10 µl aliquot of a calibration standard (ranging from 50.0 to 25000 ng / ml), a quality control sample, or a 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. The 96-round well plate was then capped, vortexed, and centrifuged at 2400 g for 5 minutes at 4°C. Thereafter, the sample was injected into a Sciex API4000™ mass spectrometer coupled with a Waters Acquity UPLC® system to generate laquinimod at known concentrations.

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

[0313] Detector responses were plotted against laquinimod concentration, and a calibration curve excluding the origin was constructed by regression analysis. The measured concentration of each prepared standard used to construct 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 criterion. The concentration measured in at least 67% of bracketed QC samples should be within 100±20% of the nominal concentration, and at least 50% of QC samples at each concentration level should meet this criterion.

[0314] Test samples whose measured concentration exceeded the analytical range of the assay were remeasured after dilution. Test samples whose measured concentration was below the analytical range were reported as <LLOQ (not quantifiable).

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

[0316] Save the sample The receptor fluid samples were stored in a -20°C freezer until analysis.

[0317] Computer system Table 52 shows the computer systems used in this study and the data collected and / or analyzed by these systems.

[0318] [Table 52]

[0319] result Statistical analysis was limited to calculating the mean, standard deviation, and coefficient of variation as needed.

[0320] turbidity Turbidity was calculated using the following formula.

[0321]

number

[0322] (In the formula, I0 = MEM is the opacitometer measurement value (lux) of a corneal holder containing only MEM. I = Measured value (lux) of the holder containing the cornea (either baseline or post-administration). The turbidity change and corrected turbidity change were calculated as follows. Turbidity change = Turbidity after administration - Baseline turbidity Corrected turbidity change = Turbidity change (test substance) - Turbidity change (physiological saline) Table 53 shows the results of turbidity measurements before and after administration.

[0323] [Table 53]

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

[0325] The permeability of Lakinimod The total amount of raquinimod transmitted was calculated from the results obtained by LC-MS / MS analysis.

[0326] The cumulative absorption of raquinimod (μg / cm³) through bovine corneas (n=6) after exposure to formulations S3, S4, and S7, respectively. 2 The transmission results are shown in Tables 54 to 56 and Figures 6 to 8.

[0327] [Table 54]

[0328] [Table 55]

[0329] [Table 56]

[0330] The cumulative absorption of laquinimod increased throughout the entire exposure period for each formulation of the present invention. The results of all three formulations were similar and followed the same general pattern. Formulation S4 showed the lowest laquinimod permeability and was the most consistent across different corneas. Formulations S3 and S7 showed higher laquinimod permeability, but the results were more corneal inconsistent.

[0331] Example 5 Formulations E2-2A, S3-3A, and S3-8A were prepared with pH values ​​and compositions as shown 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, were found to be 15.7 mPa.s, 21.5 mPa.s, and 23.7 mPa.s, respectively.

[0334] Example 6 The corneal turbidity changes 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-administration turbidity measurements for different formulations and a 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 to no change in turbidity. The results were similar to those of the control group. Little to no signs of damage were detected in the corneas treated with any of the formulations. Formulation S3-6 showed the greatest increase in turbidity (2.74 ± 2.36), but this treatment group also showed the greatest variability in the change in turbidity after administration, ranging from 0.71 to 6.93.

[0338] The cumulative absorption of raquinimod (μg / cm³) through bovine corneas (n=6) after exposure to formulations E2-2A, S3-1, S3-3A, S3-6, S3-7, and S3-8A, respectively. 2 The transmission 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, the corneal opacity change and bovine corneal permeability were measured in vitro after a single 4-hour exposure to formulations S3-3A and S7-1, as well as 50 mg / ml of raquinimod in pH 8 saline (PBS).

[0346] Six duplicate corneas were treated with each formulation or physiological saline (negative control) for 4 hours of exposure. Transmission samples were taken only from the corneas treated with the test substance, immediately before administration and at 30-minute intervals after administration. The final sample was taken 4 hours after administration (a total of 9 samples were taken from each cornea). Corneal turbidity was measured before administration and after the final transmission sample was taken. The concentration of the active ingredient was measured by LC-MS / MS in transmission samples taken throughout the entire exposure period. The results of turbidity measurements before and after administration are shown in Table 65.

[0347] [Table 65]

[0348] The results shown in Table 65 indicate that all treatments caused little to no change in turbidity.

[0349] The cumulative absorption of raquinimod (μg / cm³) through bovine corneas (n=6) after exposure to preparations S3-3A, S71, and raquinimod in physiological saline, respectively. 2 The transmission results 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 to 69 indicate that the cumulative absorption of laquinimod increased throughout the entire exposure period for each formulation. Four hours after administration, the formulations could be ranked in the following order from highest to lowest permeability: Formulation S7-1 > Formulation S3-3A > Laquinimod in PBS.

[0355] Example 8 The efficacy of the formulation 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 photoreceptor-retinoid binding protein peptide 161-180 (IRBP161-180) in an incomplete Freund's adjuvant (IFA) supplemented with Mycobacterium tuberculosis H37Ra.

[0357] Oral laquinimod was prepared in physiological saline solution. The ophthalmic formulation was prepared as eye drops. The composition of the ophthalmic formulation was S3-3A (containing 50 mg / ml of laquinimod), and the corresponding vehicle control was the S3-3A formulation without laquinimod. The treatment was carried out according to the schedule shown in Table 70.

[0358] [Table 70]

[0359] From day 0 until the end of the experiment, animals were scored weekly for clinical signs of uveitis. Retinal images were taken in unanesthetized, restrained animals using topical endoscopy fundus imaging (TEFI) 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 eyeball.

[0361] [Table 71]

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

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

[0364] [Table 72]

[0365] No difference was observed between the two vehicle groups. Administration of the ophthalmic formulation of raquinimod to the eye significantly suppressed the disease progression compared to control animals treated with the vehicle alone (Figure 19).

[0366] Example 9 A gel formulation containing 10.62 g / l of laquinimod sodium (10 g / l of 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 osmotic pressure, pH, viscosity, and relative density. The methods and results are shown in Table 74.

[0369] [Table 74]

[0370] When the droplet size was tested, a droplet with a volume of approximately 34 μl was obtained.

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

[0372] Example 11 For the formulation of Example 9, stability tests were performed on the pharmaceutical product packaged in a semipermeable container under the specified conditions (long-term storage conditions: 2°C to 8°C, accelerated conditions: 25°C / RH40%) in accordance with ICH Guide Q1A(R2). The results of droplet volume, osmotic pressure, pH, viscosity, and raquinimod assay after storage times 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 white gel throughout the entire test period. As can be seen from Tables 75 and 76 above, the formulation of the present invention showed no significant changes in any of its test properties under any of the test conditions. Therefore, based on the stability data obtained, the shelf life of the formulation of the present invention, when stored at 2°C to 8°C, is considered to be 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 with a pH of 7.4 and the components shown in Table 77 was prepared.

[0377] [Table 77]

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

[0379] Example 13 Using the formulation from Example 12, a study was conducted to measure the intraocular distribution of laquinimod after single and repeated administration to rabbits, followed by local ocular administration. Briefly, this study was conducted over a 10-day period using seven male New Zealand white rabbits weighing approximately 2.3–3.0 kg at the time of administration. The animals were housed and managed 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 formulation was stored at 4°C until use.

[0380] Of the seven test animals, six were administered the formulation from Example 12, and one animal was administered the same amount of placebo formulation, which had the same composition as the formulation from Example 12 except that it did not contain laquinimod. Each animal was treated as follows: On day 1, a single local ocular dose was administered to each eye; no administration was performed on days 2 and 3; from days 4 to 9, three local ocular doses were administered to each eye at 2-hour intervals; and on day 10, a single local ocular dose was administered to each eye. Before administration, the animals were removed from their housing cages and appropriately restrained. Then, using a pipette, the local ocular dose was administered directly to the cornea of ​​each eye of each animal. The dose was 30 μl per eye in each administration session. After administration, the animals were returned to their housing cages. Details of the study are summarized in Table 78.

[0381] [Table 78]

[0382] On day 10, the animals were euthanized 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after the final local administration to the eye. Immediately afterward, the eyeballs were rapidly excised along with the surrounding eyelid tissue, embedded in tragacanth gum, and flash-frozen with isopentane cooled with dry ice. The resulting isolated eyeballs were stored in a freezer kept below -65°C.

[0383] For distribution studies, eyeballs (right eye of each animal) were sectioned using a cryostat at -20°C. For each tissue sample, 10 μm thick sections were collected on indium-tin oxide (ITO) coated glass slides for mass spectrometry imaging (MSI). Analysis was performed using a Bruker Daltonix SolariX mass spectrometer with matrix-assisted laser desorption / ionization using Fourier transform ion cyclotron resonance (MALDI-FTICR). All analyses were performed with a spatial resolution of 60 μm using 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 m / z observed in rakinimod 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 extratissue 30 minutes after topical administration of the formulation in Example 12. Although the concentrations of laquinimod in the cornea and extratissue were lower at 4 and 8 hours, at these later time points, laquinimod could be detected in the posterior part of the eye, i.e., the retina / choroid and sclera. Specific embodiments of the present invention are as follows. [Aspect 1] A formulation for ocular administration, in which the aqueous phase (i) Laquinimod or a pharmaceutically acceptable salt thereof as an active ingredient, (ii) Pharmaceutically acceptable viscosity modifiers, (iii) Pharmaceutically acceptable isotonic agents, (iv) Pharmaceutically acceptable humectants, (v) pharmaceutically acceptable antioxidants, and (vi) A preparation containing a pharmaceutically acceptable pH adjuster. [Aspect 2] The formulation according to embodiment 1, wherein the pharmaceutically acceptable viscosifying agent is present in an amount sufficient to yield a dynamic viscosity of 2 to 200 mPas when measured at 20°C. [Aspect 3] The formulation according to embodiment 2, wherein the pharmaceutically acceptable viscosifying agent is present in an amount sufficient to yield a dynamic viscosity of 15 to 45 mPas when measured at 20°C. [Aspect 4] The formulation according to any one of embodiments 1 to 3, wherein the pharmaceutically acceptable thickening agent comprises one or more from the group consisting of polyvinyl alcohol, poly(acrylic acid) homopolymer or copolymer (carbomer), polyvinylpyrrolidone, and cellulose derivatives, such as hydroxypropyl methylcellulose and carboxymethylcellulose sodium. [Aspect 5] The preparation according to any one of embodiments 1 to 4, wherein the pharmaceutically acceptable isotonic agent is present in an amount sufficient to produce an osmotic pressure of 200 to 600 mOsm / kg. [Aspect 6] The formulation according to embodiment 5, wherein the pharmaceutically acceptable isotonic agent is present in an amount sufficient to produce an osmotic pressure of 250 to 375 mOsm / kg. [Aspect 7] The formulation according to any one of embodiments 1 to 6, wherein the pharmaceutically acceptable isotonic agent is a nonionic isotonic agent. [Aspect 8] The formulation according to embodiment 7, wherein the nonionic isotonic agent is mannitol. [Aspect 9] The formulation according to any one of embodiments 1 to 8, wherein the pharmaceutically acceptable humectant is a nonionic polyol. [Aspect 10] The formulation according to embodiment 9, wherein the nonionic polyol is glycerol. [Aspect 11] The formulation according to any one of embodiments 1 to 10, wherein the pharmaceutically acceptable pH adjusting agent is present in an amount sufficient to produce a pH in the range of 6.8 to 8.5. [Aspect 12] The formulation according to embodiment 11, wherein the pharmaceutically acceptable pH adjusting agent is present in an amount sufficient to produce a pH in the range of 6.8 to 8.0. [Aspect 13] (vii) The preparation according to any one of embodiments 1 to 12, further comprising a pharmaceutically acceptable preservative. [Aspect 14] The formulation according to embodiment 13, wherein the pharmaceutically acceptable preservative is benzalkonium chloride. [Aspect 15] (viii) The formulation according to any one of embodiments 1 to 14, further comprising a pharmaceutically acceptable surfactant. [Aspect 16] The formulation according to embodiment 15, wherein the pharmaceutically acceptable surfactant is a nonionic surfactant. [Aspect 17] (ix) The preparation according to any one of embodiments 1 to 16, further comprising a pharmaceutically acceptable solubilizer. [Aspect 18] A formulation according to any one of embodiments 1 to 17, which is in the form of a gel. [Aspect 19] (i) 5-100 g / l of laquinimod, or a corresponding amount of pharmaceutically 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) 1.5-4 g / l of mannitol, (iv) 10-40 g / l glycerol, (v) 0.2~2 g / l of Na-EDTA, and (vi) The formulation according to embodiment 18, comprising an amount of pH buffering agent effective in providing a pH in the range of 6.8 to 8.5, preferably in the range of 6.8 to 8.0. [Aspect 20] The formulation according to embodiment 19, further comprising 0.1 to 5 g / l of polysorbate. [Aspect 21] A formulation according to any one of embodiments 1 to 17, which is in the form of a water- and oil-containing emulsion, preferably an oil-in-water emulsion. [Aspect 22] The preparation according to any one of embodiments 1 to 21, wherein the ocular administration is local ocular administration. [Aspect 23] A preparation according to any one of embodiments 1 to 22, for use in the treatment of eye disorders. [Aspect 24] The formulation according to embodiment 23, wherein the eye disorder is selected from glaucoma, inflammatory eye disease, and disease involving excessive vascularization of the eye. [Aspect 25] A dosage container containing the preparation described in any one of the embodiments 1 to 24. [Aspect 26] Use of a preparation described in any one of embodiments 1 to 22 in the manufacture of a pharmaceutical product for treating eye disorders. [Aspect 27] The use according to embodiment 26, wherein the eye disorder is selected from glaucoma, inflammatory eye diseases, and diseases involving excessive vascularization of the eye. [Aspect 28] A method for treating eye disorders by administering a preparation described in any one of embodiments 1 to 22 in a therapeutically effective amount to a mammal in need of treatment. [Aspect 29] The method according to embodiment 28, wherein the eye disorder is selected from glaucoma, inflammatory eye diseases, and diseases involving excessive vascularization of the eye.

Claims

1. A formulation for ocular administration, in which the aqueous phase (i) A therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof as an active ingredient, (ii) A pharmaceutically acceptable viscous agent in an amount sufficient to yield a dynamic viscosity of 2–200 mPas when measured at 20°C. (iii) A pharmaceutically acceptable isotonic agent in an amount sufficient to produce an osmotic pressure of 200–600 mOsm / kg. (iv) Pharmaceutically acceptable moisturizers, (v) pharmaceutically acceptable antioxidants, and (vi) A preparation containing a pharmaceutically acceptable pH adjuster.

2. The formulation according to claim 1, wherein the pharmaceutically acceptable viscosifying agent is present in an amount sufficient to yield a dynamic viscosity of 5 to 100 mPas when measured at 20°C.

3. The formulation according to claim 2, wherein the pharmaceutically acceptable viscosifying agent is present in an amount sufficient to yield a dynamic viscosity of 10 to 50 mPas when measured at 20°C.

4. The formulation according to any one of claims 1 to 3, wherein the pharmaceutically acceptable thickening agent comprises one or more from the group consisting of polyvinyl alcohol, poly(acrylic acid) homopolymer or copolymer (carbomer), polyvinylpyrrolidone, and cellulose derivatives.

5. The formulation according to any one of claims 1 to 4, wherein the pharmaceutically acceptable isotonic agent is present in an amount sufficient to produce an osmotic pressure of 200 to 500 mOsm / kg.

6. The formulation according to claim 5, wherein the pharmaceutically acceptable isotonic agent is present in an amount sufficient to produce an osmotic pressure of 200 to 400 mOsm / kg.

7. The formulation according to any one of claims 1 to 6, wherein the pharmaceutically acceptable isotonic agent is a nonionic isotonic agent.

8. The formulation according to claim 7, wherein the nonionic isotonic agent is mannitol.

9. The formulation according to any one of claims 1 to 8, wherein the pharmaceutically acceptable humectant is a polyol.

10. The formulation according to claim 9, wherein the polyol is a C3 to C6 polyol.

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

5.

12. The formulation according to claim 11, wherein the pharmaceutically acceptable pH adjusting agent is present in an amount sufficient to produce a pH in the range of 6.8 to 8.

0.

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

14. The formulation according to claim 13, wherein the pharmaceutically acceptable preservative is benzalkonium chloride.

15. (viiii) The formulation according to any one of claims 1 to 14, further comprising a pharmaceutically acceptable surfactant.

16. The formulation according to claim 15, wherein the pharmaceutically acceptable surfactant is a nonionic surfactant.

17. (ix) The formulation according to any one of claims 1 to 16, further comprising a pharmaceutically acceptable solubilizer.

18. The pharmaceutically acceptable thickening agent is present in an amount sufficient to produce a dynamic viscosity of 10–45 mPas when measured at 20°C; The aforementioned pharmaceutically acceptable isotonic agent is present in an amount sufficient to produce an osmotic pressure of 200-400 mOsm / kg; and The formulation according to any one of claims 1 to 17, wherein the pharmaceutically acceptable pH adjusting agent is present in an amount sufficient to produce a pH of 6.8 to 8.

0.

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

20. (i) 5 to 100 g / l of laquinimod, or a corresponding amount of a pharmaceutically 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) 1.5-4 g / l of mannitol, (iv) 10-40 g / l of glycerol, (v) 0.2 to 2 g / l of Na-EDTA, and (vi) The formulation according to claim 19, comprising an amount of pH buffering agent effective in providing a pH in the range of 6.8 to 8.

0.

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

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

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

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

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

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

27. Use of a preparation according to any one of claims 1 to 23 in the manufacture of a pharmaceutical product for treating eye disorders.

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

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