Ophthalmic uses and compositions of margaric acid

Abstract

Herein are provided novel uses and compositions of margaric acid or a pharmaceutical acceptable salt thereof. The compounds herein and compositions thereof have been found to have a positive effect in several ophthalmic conditions, such as increased intraocular pressure, glaucoma, ocular surface conditions, corneal conditions, or dry eye disease.

Description

[0001] TITLE: Ophthalmic uses and compositions of margaric acid

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the field of medicine and, particularly, to compounds and compositions useful as medicaments for the treatment of ophthalmic conditions.

[0004] BACKGROUND ART

[0005] Ophthalmic conditions encompass a broad range of conditions affecting the eyes and vision which can severely impact quality of life. These conditions are prevalent across the globe and have been a major contributor to visual impairment and blindness, particularly in aging populations. As life expectancy increases worldwide, the incidence of ophthalmic conditions is projected to rise, creating an urgent need for innovative therapeutic and diagnostic solutions.

[0006] The management of ophthalmic conditions has advanced significantly over the past few decades. However, despite these improvements, numerous challenges persist in the treatment and management of a wide range of eye conditions e.g., increased intraocular pressure (IOP), glaucoma, tear film instability, or dry eye disease (DED).

[0007] Current therapeutic strategies for the management of increased IOP and glaucoma include eye drops, laser therapies, and surgery. Eye drops include prostaglandin analogs, beta-blockers, and carbonic anhydrase inhibitors, targeted to reduce aqueous humor production orto enhance drainage. However, these medications have several drawbacks, including poor patient compliance due to the need for daily use, potential side effects like eye redness or systemic effects (e.g., bradycardia from beta-blockers), and diminishing effectiveness over time. Laser therapies, such as selective laser trabeculoplasty (SLT), can improve drainage but often lose efficacy, requiring repeating procedures. Surgical interventions (e.g., trabeculectomy) are reserved for severe cases but carry risks of complications, such as infection and hypotony (excessively low IOP).

[0008] Current therapeutic strategies for the management of tear film instability and DED are mainly based in the administration of artificial tears, which provide temporary relief but do not address the underlying causes. Artificial tear films are the first-line treatment for moderate DED. Inflammation may be controlled with prescription eye drops that contain the immune-suppressing medicine cyclosporin, lifitegrast or loteprednol, but they take several weeks to show results and can cause burning sensations or irritation. Corticosteroids are not ideal for long-term use due to potential side effects. Punctal plugs, which block tear drainage, offer longer-term relief but may cause discomfort, irritation, or infection. Other therapeutical options are tear film-stimulating medicines and autologous blood serum drops for severe dry eye. Despite the availability of several agents to treat tear film instability and DED, many patients experience only partial relief from these treatments, indicating a need for more effective, long-term solutions, therefore there is a need for new solutions that improve on current therapeutics (e.g., agents that target inflammation with minimal side effects) and target novel aspects of condition (e.g., agents that address neurosensory abnormalities, meibomian gland dysfunction, microbiome alterations, anatomic issues) with the ultimate goal of enhanced patient outcomes.

[0009] Margaric acid, or heptadecanoic acid, is a saturated fatty acid with molecular formula CH3(CH2)i5CO2H. Margaric acid is described in WO2021 163425A1 for the treatment of mechanical pain by the inhibition of PIEZO2 mechanosensitive ion channels in sensory neurons in vitro. In particular, the document discloses the relation between PIEZO2 channels and allodynia, i.e. when innocuous mechanical sensations become painful.

[0010] As it is known in the art (see, Fernandez-Trillo J. et al. “Piezo2 Mediates Low-Threshold Mechanically Evoked Pain in the Cornea” J.Neurosci. 2020;40(47) 8976-8993), corneal neurons express Piezo2 as a response of comparatively low mechanical forces, evoking sensations of discomfort or pain and triggering protective reflexes.

[0011] For these reasons, there is a need to develop effective pharmacological treatments for ophthalmic conditions e.g., glaucoma, dry eye disease, increased intraocular pressure, and tear film instability, which address their underlying causes, increase effectiveness and its duration, improves patient compliance, and minimize side effects.

[0012] Despite their promising therapeutic potential, the practical application of margaric acid faces significant challenges due to their structure as a long-chain fatty acid and its limited solubility in water and most organic solvents. Consequently, the conventional approach to formulating margaric acid involves its dissolution in oils.

[0013] However, oil formulations for ophthalmic administration have certain disadvantages that limit their use in eye topical treatments e.g., blurred vision due to the oily film that forms over the eye, poor patient compliance because of the discomfort associated with the blurry vision and the oily feel, slower clearance from the eye because oils have longer retention times and will stay longer in the surface of the eye increasing discomfort, slower release of the drug as the oily medium can delay the availability of the drug in the eye, difficult thermal sterilization as the drug can easily suffer degradation when the oil medium is heated, difficult sterilization by filtration since the density and viscosity of the oil solution impairs its filtration through the fine filters, e.g. 0.22 pm, used for sterilization, difficulty in the filing of the final container, the difficulty achieving accurate dosing and potential allergic reactions to the oils or preservatives used in oil solution compositions.

[0014] WO2021163425A1 discloses topical compositions of margaric acid dissolved in a mixture of oils, more specifically a composition of a combination of margaric acid and eicosapentaenoic acid in a mixture of castor oil, paraffin oil, and sesame oil. Considering the shortcomings of the prior art, there exists a need for the development of a formulation containing margaric acid, that can overcome the challenges for ophthalmic administration associated with oils solutions.

[0015] Therefore, there is a need to provide ophthalmic compositions that treat or reduce a sign or symptom of a condition that involves tear film instability and / or increased intraocular pressure in subject. There is also a need to provide such ophthalmic compositions wherein the stability of the pharmaceutically active ingredient, excipients, or phases contained in such ophthalmic composition is maintained in order to maximize the pharmaceutical activity of an ophthalmic composition in each dose administered and to allow its sterilization with a decreased risk of degradation. What is also needed are ophthalmic compositions that treat or prevent ophthalmic conditions e.g., increased intraocular pressure, glaucoma, ocular surface conditions, corneal conditions or dry eye, as well as a sign or symptom thereof, in a subject, which improve patient compliance.

[0016] SUMMARY OF THE INVENTION

[0017] The present invention provides compounds and compositions useful for the treatment and / or prevention of ophthalmic conditions in a subject in need thereof.

[0018] Surprisingly, the inventors have found that margaric acid and its compositions show an outstanding activity in the treatment and prevention of ophthalmic conditions, such as glaucoma and dry eye disease, by decreasing intraocular pressure and improving tear film instability and improving corneal integrity. Margaric acid shows said activity with an excellent ocular tolerability. These findings are supported by the in vivo experimental data provided by the working Examples in the present document which was obtained from studies in an acute glaucoma rabbit model and dry eye disease murine model, and ocular tolerability study in rabbits.

[0019] Accordingly, a first aspect provided herein relates to margaric acid or a pharmaceutical acceptable salt thereof for use in the treatment and / or prevention of ophthalmic conditions in a subject in need thereof.

[0020] In particular, the treatment and / or prevention of ophthalmic conditions comprises the reduction of increased intraocular pressure, improving tear film instability, increasing tear volume, improving corneal surface integrity and / or decreasing deleterious side effects in a subject in the need thereof.

[0021] Other aspects relate to margaric acid or a pharmaceutical acceptable salt thereof for use in the treatment or prevention of a condition selected from the group consisting of increased intraocular pressure and glaucoma; and for use in the treatment of a condition selected from the group consisting of ocular surface conditions, corneal conditions, and dry eye disease.

[0022] These aspects can alternatively be formulated as a method for treating, preventing or ameliorating the conditions defined herein, or symptoms, complications and / or sequelae thereof, comprising administering a therapeutically effective amount of margaric acid or a pharmaceutical acceptable salt thereof to a subject in the need thereof.

[0023] One problem to be solved by the present invention is finding a suitable formulation comprising saturated fatty acids particularly margaric acid. The difficulty lies in the inherent nature of margaric acid as a lipid, which poses challenges to their dissolution in both aqueous and organic solutions, thereby limiting the therapeutic applicability of these compounds.

[0024] The formulation of margaric acid, as a long-chain fatty acid, presents several disadvantages that limit the design, preparation and effectiveness of a pharmaceutical composition thereof. First, due to its long carbon chain, its solubility in water and in many organic solvents is limited, restricting the number of suitable solvents to be used. Often, co-solvents are required to enhance its solubility, in some cases in specific solvent:co-solvent ratios, adding further complexity to the formulation. Additionally, the need to work at or above its melting point to achieve solubilization in the formulation adds complexity to the process and can result in the degradation of margaric acid. Margaric acid also exhibits a tendency to crystallize, particularly at low temperatures, which can negatively affect the stability of the formulation. Furthermore, in some cases, the selection of appropriate surfactants is required to improve both solubility and stability. Therefore, the obtention of a successful pharmaceutical formulation of margaric acid is not a trivial achievement, which requires a thorough understanding of the compound's properties and its potential interactions with other ingredients, along with extensive experimental tests.

[0025] The inventors have developed colloidal liquid compositions of margaric acid or a pharmaceutical acceptable salt thereof which are suitable for ophthalmic administration and are able to overcome the disadvantages of the oil solution compositions present in the prior art.

[0026] The solution is based on the provision of a formulation comprising margaric acid in the form of an aqueous colloidal composition. The formulation can also comprise a lipophilic solvent among other components. This novel formulation aims to facilitate the efficient dissolution and proper delivery of margaric acid, e.g., through topical ophthalmic administration avoiding the undesired effects linked to oil solutions, i.e. blurred vision due to the oily film that forms over the eye, poor patient compliance because of the discomfort associated with the blurry vision and the oily feel, slower clearance from the eye because oils have longer retention times and will stay longer in the surface of the eye increasing discomfort, slower release of the drug as the oily medium can delay the availability of the drug in the eye, difficult thermal sterilization as the drug can easily suffer degradation when the oil medium is heated, difficult sterilization by filtration since the density and viscosity of the oil solution impairs its filtration through the fine filters, e.g. 0.22 pm, used for sterilization, difficulty in the filing of the final container, the difficulty of achieving accurate dosing and the potential allergic reactions to the oils or preservatives used in oil solution compositions. Such a formulation would not only enhance the therapeutic efficacy of margaric acid-based therapies but also improve patient compliance and accessibility if administered topically in the eye, thereby addressing unmet clinical and formulation needs in the management of ophthalmic conditions while maintaining a suitable solubilization, stability and availability of margaric acid and its composition.

[0027] Thus, another aspect relates to a composition of margaric acid or a pharmaceutical acceptable salt in the form of a colloidal composition.

[0028] In another aspect, herein is provided a composition of margaric acid or a pharmaceutical acceptable salt thereof in the form of a colloidal composition as defined above for use as defined in the first aspect.

[0029] Throughout the description and claims the word "comprise" and its variations are not intended to exclude other technical features, additives, components, or steps. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein. The following examples and drawings are provided herein for illustrative purposes, and without intending to be limiting to the present invention.

[0030] DESCRIPTION OF DRAWINGS

[0031] FIG. 1 shows the effect of margaric acid on IOP in acute glaucoma model in NZW rabbits. (A) shows a schematic representation of the experimental protocol used. (B) shows the IOP change normalized to IOP at 1 h as baseline (mmHg) in acute glaucoma model in NZW rabbits after treatment with vehicle or MA at 0.075% as micellar solution. Arrows mark the moment when margaric acid or vehicle were topically administered. Data is expressed as Mean + / - SEM. Vehicle n=16 eyes; Margaric Acid n=16 eyes.

[0032] FIG. 2 shows study design of tear film break-up time (TFBUT), tear volume, corneal fluorescein staining, and lissamine green staining in scopolamine-induced Dry Eye Model in Mice.

[0033] FIG. 3 shows the effect of margaric acid 0.075% w / v on tear film break-up time (TFBUT) on day 7 in scopolamine-induced dry eye model in mice. Vehicle (n=8 mice; 16 eyes), Margaric acid (n=8 mice; 16 eyes). Margaric acid vs Vehicle had significant differences (****p<0.0001 ; One-way ANOVA / Dun nett's test).

[0034] FIG. 4 shows the effect of margaric acid 0.075% w / v on tear volume on day 7 in scopolamine-induced dry eye model in mice. Vehicle (n=8 mice; 16 eyes), Margaric acid (n=8 mice; 16 eyes). Margaric acid vs Vehicle had significant differences (*p<0.05; One-way ANOVA / Dunnett's test). FIG. 5 shows the effect of margaric acid 0.075% w / v on corneal fluorescein staining in scopolamine- induced dry eye model in mice. Vehicle (n=8 mice; 16 eyes), margaric acid (n=8 mice; 16 eyes). On day 14, Margaric acid vs Vehicle had significant differences (****p<0.0001 ; Kruskal-Wallis test / Dun nett's).

[0035] FIG. 6 shows the effect of margaric acid 0.075% w / v on lissamine green staining in scopolamine- induced dry eye model in mice. Vehicle (n=8 mice; 16 eyes), margaric acid (n=8 mice; 16 eyes). On day 14, Margaric acid vs Vehicle had significant differences (*p<0.05; Kruskal- Wallis test / Dun nett's).

[0036] DETAILED DESCRIPTION OF THE INVENTION

[0037] Definitions

[0038] Condition: The term "condition" refers to any physiological or pathological state affecting an organism, encompassing diseases, disorders, syndromes, or abnormalities that impair normal functioning of the body, including both acute and chronic manifestations and risk factors thereof.

[0039] Excipient: The terms "excipient" and "carrier" are used interchangeably and refer to an inert substance added to a e.g., pharmaceutical composition, to further facilitate administration of a compound of the present invention.

[0040] Subject: The terms "subject", "patient", "individual", "host" and variants thereof are used interchangeably herein and refer to any mammalian subject, particularly humans, but also including without limitation, humans, domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like), and laboratory animals (e.g., monkey, rats, mice, rabbits, guinea pigs and the like) for whom diagnosis, treatment, or therapy is desired. The compositions and methods described herein are applicable to both human therapy and veterinary applications.

[0041] Subject in need thereof: As used herein, "subject in need thereof includes subjects, such as mammalian subjects, that would benefit from the administration of the compounds provided herein.

[0042] Therapeutically effective amount: As used herein the term "therapeutically effective amount" is the amount of a compound / composition of the present invention that is enough to produce a desired therapeutic effect, pharmacological and / or physiological effect on a subject in need thereof.

[0043] Treatment: The terms "treat", "treatment", and "therapy" as used herein refer to, e.g., the reduction in severity of a disease or condition disclosed herein; the amelioration or elimination of one or more symptoms, complications, or sequelae associated with a disease or condition disclosed herein; the provision of beneficial effects to a subject with a condition / disease disclosed herein, without necessarily curing the disease or condition. The term also includes prophylaxis or prevention of a disease or condition or symptoms, complications, or sequelae thereof. The term refers to a clinical or nutritional intervention to prevent the disease or condition; cure the disease or condition; delay onset of the disease or condition; delay onset of a symptom, complication or sequela; reduce the seriousness of the disease or condition; reduce the seriousness of a symptom, complication, or sequela; improve one or more symptoms; improve one or more complications; improve one or more sequelae; prevent one or more symptoms; prevent one or more complications; prevent one or more sequelae; delay one or more symptoms; delay one or more symptoms; delay one or more complications; delay one or more sequelae; ameliorate one or more symptoms; ameliorate one or more complications; ameliorate one or more sequelae; shorten the duration of one or more symptoms; shorten the duration of one or more complications; shorten the duration of one or more sequelae; reduce the frequency of one or more symptoms; reduce the frequency of one or more complications; reduce the frequency of one or more sequelae; reduce the severity of one or more symptoms; reduce the severity of one or more complications; reduce the severity of one or more sequelae; improve the quality of life; increase survival; prevent a recurrence of the disease or condition; delay a recurrence of the disease or condition; or any combination thereof, e.g., with respect to what is expected in the absence of the treatment with the compound / composition of the present invention.

[0044] Prevent: The terms "prevent", "preventing", "prophylaxis" and variants thereof as used herein, refer, e.g., to partially or completely delaying the onset of a disease, disorder and / or condition disclosed herein; partially or completely delaying the onset of one or more symptoms, features, or clinical manifestations, complications, or sequelae of a particular disease, disorder, and / or condition disclosed herein;

[0045] (i) partially or completely delaying the onset of one or more symptoms, features, or manifestations, complications, or sequelae of a particular disease, disorder, and / or condition disclosed herein;

[0046] (ii) partially or completely delaying progression from a particular disease, disorder and / or condition disclosed herein; and / or

[0047] (iii) decreasing the risk of developing pathology associated with the disease, disorder, and / or condition disclosed herein.

[0048] Symptom: As used herein, the term "symptom" refers to subjective or physical sign, indication, or evidence of disease / condition or physical disturbance observed by the subject. In general, the term refers to any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by the patient and indicative of condition. Symptoms are felt or noticed by the individual experiencing the symptom but may not easily be noticed by others. In some aspects, a symptom can be a mild symptom, a moderate symptom, or a severe symptom. As used herein, the term "mild symptom" refers to a symptom that is not life threatening and does not require, e.g., intensive care treatment (e.g., at a hospital ICU). As used herein, the term "moderate symptom" refers to a symptom that requires monitoring because it may become life threatening and may require, e.g., hospitalization. As used herein, the term "severe symptom" refers to a symptom that is life threatening and requires, e.g., intensive care treatment (e.g., at a hospital ICU).

[0049] Complication: As used herein, the term "complication" refers to a pathological process or event occurring during a disease or condition that is not an essential part of the disease or condition; where it may result from the disease / condition or from independent causes. Accordingly, the term complication refers to medical / clinical problems that are observed in subjects diagnosed with a disease or condition disclosed herein, e.g., increased intraocular pressure, glaucoma, dry eye disease or tear film instability. In some aspects, a complication can be temporary. In some aspects, a complication can be chronic or permanent.

[0050] Sequela: As used herein, the term "sequela" refers to a long-term, chronic, or permanent complication.

[0051] Pharmaceutically acceptable salt: As used herein, the term “pharmaceutically acceptable salt” refers to that the salt derived from the corresponding compound is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the condition and necessity of the treatment.

[0052] Uses of margaric acid

[0053] All the methods and uses described herein can be formulated as margaric acid or a pharmaceutical acceptable salt thereof for use in treating and / or preventing ophthalmic conditions and the other uses described herein. Alternatively, this can be formulated as the use of margaric acid or a pharmaceutical acceptable salt thereof for the manufacture of a composition, a nutraceutical composition, a veterinary composition, a food product or a personal care product for the treatment and / or prevention of ophthalmic conditions and the other uses disclosed herein. This can be also alternatively formulated as methods of treating and / or preventing ophthalmic conditions or symptoms, complications and / or sequelae thereof and the other uses described herein in a subject in need thereof comprising administering a therapeutically effective amount of the compounds herein.

[0054] The examples of the present invention provide evidence of the activity of margaric acid as a therapy of ophthalmic conditions. Thus, the present invention describes the positive effect of margaric acid or a pharmaceutical acceptable salt thereof in the treatment, prevention and amelioration of ophthalmic conditions, symptoms, complications and / or sequelae thereof.

[0055] According to the present invention, ophthalmic conditions encompass a range of diseases and / or conditions affecting the eyes, with key categories including those related to tear film stability and to increased intraocular pressure (IOP).

[0056] Examples of ophthalmic conditions include meibomian gland disorder, keratitis, allergic keratoconjunctivitis, contact lens discomfort, increased intraocular pressure, glaucoma, ocular surface conditions, corneal conditions, tear film instability or dry eye disease.

[0057] In an aspect, herein is provided margaric acid or a pharmaceutical salt thereof for use in the treatment and / or prevention of ophthalmic conditions selected from the group consisting of ocular surface conditions, corneal conditions, dry eye disease (DED), tear film instability, glaucoma, and increased intraocular pressure. More specifically, ophthalmic conditions are selected from the group consisting of dry eye disease and glaucoma. Alternatively, ophthalmic disorders are selected from the group consisting of increased intraocular pressure and tear film instability. In another alternative aspect the ophthalmic disorder is selected from the group consisting of ocular surface conditions, corneal conditions, dry eye disease (DED), and tear film instability, particularly dry eye disease (DED), and tear film instability, more particularly dry eye disease. In another alternative aspect the ophthalmic disorder is selected from the group consisting of increased intraocular pressure and glaucoma, particularly glaucoma.

[0058] In some embodiments, the administration of margaric acid or a pharmaceutical salt thereof results in at least one outcome (i.e., effect) selected, but not limited to, from the group consisting of:

[0059] - decrease of intraocular pressure,

[0060] - increase of tear film stability, more particularly an increase in the tear film break-up time,

[0061] - improving corneal integrity, and

[0062] - increased ocular tolerability, for instance decreasing side effects.

[0063] More particularly, the outcome (i.e., effect) is selected, but not limited to, from the group consisting of:

[0064] - a decrease of intraocular pressure, and

[0065] - increased ocular tolerability, for instance decreasing side effects.

[0066] In some embodiments, the outcome (i.e., effect) is selected, but not limited to, from the group consisting of:

[0067] - increase of tear film stability, more particularly an increase in the tear film break-up time,

[0068] - improving corneal integrity, and

[0069] - increased ocular tolerability, more particularly a decrease of side effects.

[0070] In one aspect it is provided margaric acid or a pharmaceutical salt thereof for use in decreasing intraocular pressure.

[0071] Another aspect relates to margaric acid or a pharmaceutical salt thereof for use in increasing tear film stability, in particular tear film break-up time.

[0072] In one aspect, margaric acid or a pharmaceutical salt thereof is provided for use in improving corneal integrity. In one aspect, margaric acid or a pharmaceutical salt thereof is provided for use in increasing ocular tolerability, more particularly a decrease of side effects.

[0073] The present invention provides margaric acid or a pharmaceutical salt thereof for use to avoid complications of glaucoma such as loss of peripheral vision, vision impairment in central vision, headache, eye pain, nausea, vomiting, blurred vision, halos or colored rings around lights, eye redness, avoid or reduce hospitalization, reduce (shorten) treatment time, delay the need for treatment, eliminate the need for treatment, reduce patient blindness rate, reduce patient’s chance of blindness, increase patient’s chance of recovery, reduce the severity of at least one symptom, reduce the severity of at least one complication, reduce the severity of at least one sequela, reduce the duration of at least one symptom, reduce the duration of at least one complication, reduce the duration of at least one sequela, or any combination thereof in a subject, said methods comprising administering margaric acid or a pharmaceutical salt thereof to a subject in need thereof.

[0074] The present invention provides margaric acid or a pharmaceutical salt thereof for use to avoid complications of ocular surface condition, in particular dry eye disease, such as eye redness, eye mucus, light sensitivity, difficulty wearing contact lenses, difficulty with night vision, watery eyes, blurred vision, eye fatigue, avoid or reduce hospitalization, reduce (shorten) treatment time, delay the need for treatment, eliminate the need for treatment, reduce patient blindness rate, reduce patient’s chance of blindness, increase patient’s chance of recovery, reduce the severity of at least one symptom, reduce the severity of at least one complication, reduce the severity of at least one sequela, reduce the duration of at least one symptom, reduce the duration of at least one complication, reduce the duration of at least one sequela, or any combination thereof in a subject, said methods comprising administering margaric acid or a pharmaceutical salt thereof to a subject in need thereof.

[0075] As said, the compound for the indicated uses can be alternatively formulated as the provision of the use of the compound for the manufacture of a composition and other compositions for such uses and the provision of methods comprising the administration of margaric acid or a pharmaceutical salt thereof to a subject in need thereof.

[0076] As used herein, the subject is a mammal, in particular a human, at risk of developing, or already having, ophthalmic conditions, in particular increased intraocular pressure, glaucoma, tear film instability, ocular surface condition, and / or dry eye disease.

[0077] Increased intraocular pressure

[0078] In an embodiment, the condition is increased IOP. Thus, in an aspect, it is provided margaric acid or a pharmaceutical salt thereof for use in the treatment and / or prevention of increased intraocular pressure.

[0079] IOP is the pressure exerted by the fluid (aqueous humor) inside the eye. Normally, aqueous humor is produced and drained in a balanced manner, maintaining a healthy eye pressure. However, when the drainage system becomes blocked or impaired, the fluid builds up, leading to elevated IOP.

[0080] IOP plays a central role in the development and progression of glaucoma, a group of eye conditions that damage the optic nerve and can lead to vision loss or blindness.

[0081] Glaucoma, also known as glaucomatous optic neuropathy, is a group of eye disorders characterized by progressive optic nerve damage and loss of retinal ganglion cells resulting in visual field loss and ultimately leading to blindness.

[0082] Elevated IOP is the most significant modifiable risk factor for open-angle glaucoma and angle-closure glaucoma, two of the most common types of glaucoma. In open-angle glaucoma, the drainage angle remains open, but fluid drains too slowly, causing a gradual rise in pressure. In angle-closure glaucoma, the drainage angle is physically blocked, leading to a more sudden and severe increase in IOP. High IOP exerts mechanical stress on the optic nerve, particularly at the optic nerve head (the point where the optic nerve exits the eye). Over time, this pressure damages the nerve fibers, leading to the characteristic vision loss associated with glaucoma.

[0083] Glaucoma is commonly classified into two categories: primary or secondary, depending on the underlying cause of the condition.

[0084] Primary glaucoma can be further divided into two subtypes: primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), which are distinguished by the anatomical features of the anterior chamber.

[0085] In secondary glaucoma, another eye condition or health issue such as injury, cataract, tumour, inflammation, or certain medications is causing the condition. Secondary forms of glaucoma include neovascular glaucoma, pigmentary glaucoma, exfoliation glaucoma and traumatic glaucoma.

[0086] Primary Open-Angle Glaucoma (POAG) is the most common form of glaucoma, caused by increased IOP that damages the optic nerve. Angle-Closure Glaucoma is an acute form of glaucoma where the drainage angle is blocked, causing a rapid rise in IOP.

[0087] In an embodiment, margaric acid or a pharmaceutical salt thereof is for use in the treatment and / or prevention of glaucoma. Thus, in an aspect, it is provided margaric acid or a pharmaceutical salt thereof for use in the treatment and / or prevention of glaucoma. Particularly glaucoma is selected from the group consisting of Primary Open-Angle Glaucoma (POAG), Angle-Closure Glaucoma and / or glaucomatous optic neuropathy. More particularly, the glaucoma is selected from the group consisting of Primary Open-Angle Glaucoma (POAG), and / or Angle-Closure Glaucoma.

[0088] Ocular surface conditions Ocular surface conditions encompass a range of disorders affecting the cornea, conjunctiva, and other structures essential for a healthy ocular environment, for example. Among these, corneal conditions are particularly concerning, as they can compromise the integrity and function of the corneal epithelium, leading to discomfort, impaired vision, and a heightened risk of infection. Examples of corneal conditions include e.g. dry eye disease (also known as keratoconjunctivitis sicca), meibomian gland disorder, keratitis, allergic keratoconjunctivitis, or contact lens discomfort.

[0089] A critical factor in the onset and progression of many corneal conditions is tear film quality and stability, which is commonly assessed by Tear Film Break-Up Time (TFBUT). TFBUT measures the time it takes for the tear film to break up after a blink, indicating tear film stability. Shortened TFBUT is a hallmark of tear film instability and is frequently observed in many ocular surface conditions, in particular corneal conditions and more specifically in dry eye disease (DED), a prevalent ocular surface disorder characterized by insufficient tear production or excessive tear evaporation. Tear film instability, reflected in a reduced TFBUT, results in increased osmolarity and inflammation, leading to epithelial damage and persistent corneal irritation.

[0090] Corneal conditions often share a common pathophysiology with DED, in which tear film instability — manifested by a low TFBUT — leads to corneal dryness, erosions, and cellular damage. Maintaining an optimal tear film composition, including a stable balance of lipids, aqueous, and mucin layers, is essential to prolong TFBUT, ensuring adequate corneal hydration and protection of the cornea. Therapeutic interventions that improve TFBUT are therefore critical for effectively managing both corneal disorders and dry eye disease.

[0091] In an embodiment, margaric acid or a pharmaceutical salt thereof is provided for use in the treatment and / or prevention of ocular surface conditions. Thus, in an aspect, margaric acid or a pharmaceutical salt thereof is provided for use in the treatment and / or prevention of ocular surface conditions. Particularly, ocular surface conditions are associated with tear film instability and / or decreased TFBUT.

[0092] Another embodiment relates to margaric acid or a pharmaceutical salt thereof for use in the treatment and / or prevention of corneal conditions. In particular the corneal conditions are associated with tear film instability and / or decreased Tear Film Break-Up Time (TFBUT).

[0093] In an embodiment, margaric acid or a pharmaceutical salt thereof is provided herein for use in the treatment and / or prevention oftearfilm instability, in particular for the treatment of decreased TFBUT.

[0094] In an embodiment, the ocular surface condition is selected from the group consisting of dry eye disease, meibomian gland disorder, keratitis, allergic keratoconjunctivitis, and contact lens discomfort. More particularly, the condition is dry eye disease. Thus, an aspect of the present invention relates to margaric acid or a pharmaceutical salt thereof for use in the treatment and / or prevention of dry eye disease. DED is a multifactorial condition of the ocular surface characterized by a loss of homeostasis of the tear film, in which tear film instability and hyperosmolarity play etiological roles. Symptoms of DED include dryness, irritation, visual complaints (e.g., blurred, fluctuating), redness, and tearing which are driven by ocular surface abnormalities, including poor tear film quality, epithelial disruption, and anatomic disturbances.

[0095] The core mechanism of DED is tear film hyperosmolarity, which is the hallmark of the condition. Epithelial cell damage, lipid layer and blinking abnormalities, defective glycocalyx, loss of gel mucin and reduction in tear film volume may result in loss of lubrication between the globe and eyelids.

[0096] Topical and systemic medications, contact lenses, ophthalmic surgeries, and non-surgical procedures can cause DED. Preservatives such as benzalkonium chloride in ophthalmic formulations can exacerbate DED through toxic and pro-inflammatory effects. Systemic medications can result in decreased tear film production, altered sensory input, and reflex tear film secretion. Refractive and corneal surgeries can cause or aggravate DED due to the transection of corneal nerves or through the use of post-operative topical medications. Cosmetic and functional eyelid surgeries, botulinum toxin injections, and even cataract surgery, along with their post-procedure topical medications, can lead to DED.

[0097] Diagnostic screening questionnaires for the diagnosis of DED, such as the 5-item Dry Eye Questionnaire (DEQ-5) or the Ocular Surface Disease Index (OSDI), include tear film break-up time, tear osmolarity determination, and ocular surface staining (that includes the cornea, conjunctiva and lid margin) with fluorescein and lissamine green. Said tests lead to the identification of a disruption in tear film homeostasis, allowing the diagnosis of dry eye disease.

[0098] The invention also encompasses margaric acid or a pharmaceutical salt thereof for use in the treatment of ocular surface conditions, particularly dry eye disease, susceptible to ameliorate or to be prevented by an increase of tear film stability, more particularly an increase in the tear film breakup time, and / or a decrease corneal tissue lesions and / or cicatrized tissue.

[0099] The invention also encompasses margaric acid or a pharmaceutical salt thereof for use in the treatment, prevention and / or amelioration of dry eye disease, symptoms, complications and / or sequelae thereof by increasing tear film stability.

[0100] Compounds, pharmaceutical salts and preparation processes thereof

[0101] Margaric acid and its salts are commercially available from several suppliers. The synthesis and purification of margaric acid or a pharmaceutical salt thereof can be carried out by conventional synthetic methods for saturated fatty acids known in the art, e.g., from natural occurring stearic acid through its conversion to the corresponding halogen acid, the substitution of the halogen by an hydroxyl group and its subsequent oxidation to render margaric acid as disclosed in US1529946A, which is incorporated herein by reference in its entirety.

[0102] In some embodiments, the invention relates to pharmaceutically acceptable salts of margaric acid. As used herein the expression “pharmaceutically acceptable salt” designates any salt which, upon administration to the subject, is capable of providing (directly or indirectly) a compound as described herein. For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from margaric acid, which contains an acidic moiety, by conventional chemical methods. Generally, such salts are, e.g., prepared by reacting the free acid form of margaric acid with a stoichiometric amount of the appropriate base in water or in an organic solvent or in a mixture of both. Generally, non-aqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred. Examples of alkali addition salts include inorganic salts such as, e.g., sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, e.g., tromethamine, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine and basic amino acid salts.

[0103] In some embodiments, the salt is sodium, potassium, calcium, magnesium, ammonium, tromethamine, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, and triethanolamine, particularly sodium, potassium, magnesium, and ammonium.

[0104] Compositions

[0105] Margaric acid or a pharmaceutical salt thereof for the uses herein described can be administered via any route normally used to administer a medicament for the treatment of ophthalmic conditions, specifically for the treatment of increased intraocular pressure, glaucoma, ocular surface conditions, corneal conditions, tear film instability or dry eye disease. Suitable routes include topical or intraocular routes, particularly the instillation of a composition on the ocular surface.

[0106] In an aspect, herein is provided a composition of margaric acid or a pharmaceutical salt thereof for use in the treatment and / or prevention of ophthalmic conditions. In particularthe ophthalmic condition is increased intraocular pressure, more particularly glaucoma, and more particularly Primary Open- Angle Glaucoma (POAG), and / or Angle-Closure Glaucoma. In an embodiment, the ophthalmic condition is ocular surface condition, more particularly a corneal condition, and more particularly tear film instability and / or dry eye disease.

[0107] An aspect relates to the composition of margaric acid or a pharmaceutical acceptable salt thereof disclosed in the present document as an ophthalmic composition. As described herein, an ophthalmic composition is a formulation designed to the administration into, around or on the surface of the eye and includes, but is not limited to, topical and injectable compositions.

[0108] An injectable ophthalmic composition, as described herein, is a sterile formulation designed for administration via injection into or around the eye to deliver margaric acid or a pharmaceutical salt thereof directly to ocular tissues. A topical ophthalmic composition, as referred to herein, is a sterile formulation intended for direct application to the surface of the eye e.g., solutions, suspensions, emulsions, or gels.

[0109] An embodiment relates to the composition of margaric acid or a pharmaceutical acceptable salt thereof which is a topical ophthalmic composition. Particularly, the composition of margaric acid or a pharmaceutical acceptable salt thereof is a topical liquid composition, more particularly in the form of drops.

[0110] In an embodiment herein provided, the composition is selected from the group consisting of a mineral oil solution and a colloidal composition, particularly the composition is a colloidal composition.

[0111] As disclosed herein, the term “colloidal composition” refers to compositions in which therapeutic agents are encapsulated, dispersed, solubilized, or carried within colloidal-sized particles, droplets, micelles, or globules typically ranging from 1 nm to 1 pm. Said systems are designed to maintain a dispersed phase of small particles, droplets, micelles or globules within a continuous phase, i.e. a liquid.

[0112] Colloidal compositions can be formulated from various materials, including lipids, surfactants, polymers, or proteins, and include, but not limited to, compositions comprising liposomes, polymeric nanoparticles, micelles, emulsions and nanoemulsions.

[0113] In an aspect herein, the composition of margaric acid or a pharmaceutical salt thereof disclosed herein is in the form of a micellar solution or an emulsion, particularly an emulsion. In an embodiment, the composition is in the form of a micellar solution.

[0114] The composition described herein can be formulated as an emulsion, which consists of two immiscible liquid phases, typically an oil phase and an aqueous phase, where one phase is dispersed as fine droplets within the other. The emulsion structure enables the encapsulation and stabilization of lipophilic (oil-soluble) and hydrophilic (water-soluble) compounds within a single formulation, enhancing bioavailability of the active ingredient.

[0115] In an embodiment, it is provided a composition, e.g., an emulsion or a micellar solution, comprising margaric acid or a pharmaceutical acceptable salt thereof, a surfactant and a solvent. Particularly, the composition comprises margaric acid or a pharmaceutical acceptable salt thereof in an amount from about 0.01 to about 1 % w / v, from about 0.05 to about 0.5 % w / v, or from about 0.07% to about 0.3%w / v, more particularly from about 0.07% to 0.3% w / v.

[0116] In this description, the concentration of the compound in the composition is expressed as %w / v (weight per volume), representing the weight of margaric acid as a free acid relative to the total volume of the solution. The composition ranges provided for the active compound in this description are referenced to the free acid form of the compound. When using a pharmaceutically acceptable salt of the active compound, the composition range is adjusted according to the molecular weight of the specific salt form and its solubility to achieve an equivalent amount of the free acid, as is standard practice in the art. Such adjusted composition ranges for a pharmaceutically acceptable salt are considered within the scope of this description and claims.

[0117] Surfactants stabilize the emulsion by reducing the interfacial tension between the oil and aqueous phases, thereby preventing the coalescence of dispersed droplets. Surfactants align at the oil-water interface to create a stable colloidal structure. Surfactants may be non-ionic, anionic, or amphoteric,

[0118] In an embodiment the composition comprises a surfactant in an amount from about 1 % to about 40% w / v, from about 2% to about 20% w / v, or from about 4% to about 15% w / v, particularly from about 4% to about 15% w / v.

[0119] In an embodiment, the surfactant of the composition is selected from the group consisting of polyoxyl 40 stearate, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, polyoxyl 20 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, polyoxyethylene (10) cetyl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylated (23) lauric alcohol, D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS), and mixtures thereof. In particular the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil and mixtures thereof. More particularly the surfactant is polysorbate 80.

[0120] In an embodiment, the solvent in the composition is water. In an alternative embodiment the solvent is a mixture of water and a lipophilic solvent.

[0121] Lipophilic solvents are organic solvents characterized by their ability to dissolve hydrophobic substances, which are generally insoluble or sparingly soluble in water, due to their nonpolar or minimally polar chemical structure. Lipophilic solvents are generally sparingly soluble or insoluble in water due to their nonpolar nature, which does not readily interact with water's polar structure.

[0122] In an embodiment, the lipophilic solvent is selected from the group consisting of mineral oil, vegetable oils such as sesame oil, soya oil, argan oil, cottonseed oil, castor oil, medium chain triglycerides, fluorinated alkanes, semifluorinated alkanes, ethyl oleate, isopropyl myristate, isopropyl palmitate, isopropyl isostearate, isostearyl isostearate, myristyl lactate, ethylhexyl hydroxystearate, ethylhexyl pelargonate, triethylhexanoin, isohexadecane, triisononanoin. More particularly the lipophilic solvent is selected from the group consisting of medium chain triglycerides, castor oil, soya oil, and mixtures thereof.

[0123] In an embodiment, the lipophilic / water solvent ratio is from 0.1 / 0.9 to 0.01 / 0.99 w / w, particularly from 0.08 / 0.92 to 0.01 / 0.99 w / w, more particularly from 0.05 / 0.95 to 0.02 / 0.98 w / w.

[0124] The compositions herein provided can also comprise a pH modifier. A pH modifier is an acidic, basic, or amphoteric substance and their mixtures including buffer solutions, which is used to adjust the pH of the composition to a suitable objective value, either during the preparation of the composition or as a final adjustment to obtain a composition in the form of a colloidal solution, e.g., an emulsion or a micellar solution, and to obtain a composition with a pharmaceutically acceptable pH.

[0125] In embodiment, the pH of the compositions herein described is from about 5 to about 9. Particularly, the composition is an emulsion and the pH is from about 6 to about 8. In an alternate embodiment, the composition is a micellar solution and the pH is from about 7 to about 8.

[0126] In an embodiment herein, the pH modifier is selected from the group consisting of ammonia, diisopropanolamine, triethanolamine, tromethamine, tromethamine hydrochloride, TRIS buffer, phosphate buffer, sodium hydroxide, potassium hydroxide, citric acid, lactic acid, acetic acid, phosphoric acid, hydrochloric acid, tartaric acid and, boric acid, sulphuric acid, nitric acid, carbonic acid, maleic acid and succinic acid, a pharmaceutically acceptable salt thereof, and mixtures thereof. Particularly, the pH modifier is selected from the group consisting oftromethamine, hydrochloric acid, and mixtures thereof.

[0127] Further, the compositions herein provided can also comprise an osmolality modifier. An osmolality modifier is a compound or mixture of compounds added to an ophthalmic liquid composition to adjust its osmolality, thereby achieving an osmotic balance that is compatible with the natural osmolality of tears and the ocular surface. By modifying the osmolality, these agents help to create an isotonic or near-isotonic solution. Suitable osmolality modifiers include inorganic salts (e.g., sodium chloride, potassium chloride) or organic compounds (e.g., sugar alcohols like glycerin, mannitol, or propylene glycol) that help to achieve a target osmolality typically from about 150 to about 500 mOsm / kg, particularly about 200 to about 400 mOsm / kg, more particularly from about 250 to about 350 mOsm / kg, which are similar to physiological tear fluid. The osmolality of the composition herein is measured using methods known in the art, specifically by an osmometer, in accordance with standard procedures for determining the osmolal concentration of solutions

[0128] In embodiment, the composition herein defined comprises an osmolality modifier in an amount from about 0.05% to about 15% w / v, particularly from about 0.1 % to about 10% w / v, more particularly from about 0.15% to about 5 % w / v.

[0129] In alternative embodiment, the composition provided herein shows an osmolality from about 150 to about 500 mOsm / kg, particularly about 200 to about 400 mOsm / kg, more particularly from about 250 to about 350 mOsm / kg.

[0130] In embodiment herein, the osmolality modifier is selected from the group consisting of sorbitol, mannitol, xylitol, glycerin, dextrose, polyethylene glycol, propylene glycol, dextran, sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate, calcium carbonate, sodium lactate, and mixtures thereof. Particularly, the osmolality modifier is selected from the group consisting of sorbitol, mannitol, xylitol, glycerin, dextrose, polyethylene glycol, propylene glycol, dextran and mixtures thereof. More particularly, the osmolality modifier is glycerol.

[0131] An embodiment relates to compositions herein further comprise a pH modifier and an osmolality modifier.

[0132] The compositions herein provided can comprise a viscosity modifier to adjust the thickness of the solution, helping it to adhere to the eye for an extended period.

[0133] In an embodiment, the composition herein provided comprises a viscosity modifier in an amount from about 0% to about 15% w / v, particularly from about 0% to about 10%, more particularly from about 0% to about 5%.

[0134] In an embodiment herein, the viscosity modifier is selected from the group consisting of polyvinylpirrolidone, polyvinyl alcohol, polyethylene glycol, glycerine, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, xanthan gum, guar gum, welan gum, gellan gum, tragacanth gum, ceratonia gum, agar, carrageenan, alginic acid, sodium alginate, potassium alginate, propylene glycol alginate, hyaluronic acid, sodium hyaluronate, poly(acrylic acid) derivatives such as carbomer and polycarbol, poloxamers, chitosan and chitosan derivatives, maltodextrin, and mixtures thereof. Particularly, the viscosity modifier is selected from the group consisting of polyvinylpirrolidone, polyvinyl alcohol, polyethylene glycol, glycerine, hyaluronic acid, sodium hyaluronate, carbomer, polycarbol, and mixtures thereof.

[0135] An embodiment herein provided relates to a composition comprising:

[0136] Margaric acid (or salt equivalent) 0.01 % -1 % w / v

[0137] Surfactant 1 % - 40% w / v pH modifier q.s. pH 5 - 9

[0138] Osmolality modifier 0.05% - 15% w / v (150 - 500 mOsm / Kg)

[0139] Viscosity modifier 0% - 15% w / v

[0140] Solvent q.s 100% w / v; wherein the surfactant is e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate

[0141] 85, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil or mixtures thereof, particularly the surfactant is polysorbate 80; the solvent is e.g., water or a mixture of water and a lipophilic solvent, more specifically the lipophilic solvent is e.g., medium chain triglycerides, castor oil, soya oil, or mixtures thereof; the pH modifier is e.g., tromethamine, hydrochloric acid, TRIS buffer, phosphate buffer or mixtures thereof; the osmolality modifier is e.g., sorbitol, mannitol, xylitol, glycerin, dextrose, polyethylene glycol, propylene glycol, dextran and mixtures thereof, particularly, glycerol; and / or the viscosity modifier is e.g., polyvinylpirrolidone, polyvinyl alcohol, polyethylene glycol, glycerine, hyaluronic acid, sodium hyaluronate, carbomer and polycarbol, or mixtures thereof;

[0142] Specifically, the present invention also relates to a composition comprising:

[0143] Margaric acid (or salt equivalent) 0.05% - 0.5% w / v

[0144] Surfactant 2% - 20% w / v pH modifier q.s. pH 6 - 8

[0145] Osmolality modifier 0.1 % - 10% w / v (200 - 400 mOsm / Kg)

[0146] Viscosity modifier 0% - 10% w / v

[0147] Solvent q.s. 100% w / v;

[0148] More specifically, the present invention also relates to a composition comprising:

[0149] Margaric acid (or salt equivalent) 0.07% - 0.3% w / v

[0150] Surfactant 4% - 15% w / v pH modifier q.s. pH 6.4 - 7.8

[0151] Osmolality modifier 0.15% - 5% w / v (200 - 400 mOsm / Kg)

[0152] Viscosity modifier 0% - 5% w / v

[0153] Solvent q.s. 100% w / v;

[0154] In an embodiment herein is provided a composition of margaric acid or a pharmaceutical salt thereof as defined herein for use in the treatment and / or prevention of ophthalmic conditions. In particular the ophthalmic condition is increased intraocular pressure, more particularly glaucoma, and more particularly Primary Open-Angle Glaucoma (POAG), and / or Angle-Closure Glaucoma. In an alternate particular aspect the ophthalmic condition is ocular surface condition, more particularly a corneal condition, and more particularly tear film instability and / or dry eye disease.

[0155] As will be apparent to those skilled in the art upon reading this description, each of the individual aspects described and illustrated herein have discrete components and features which can be combined with the features of any of the other several aspects without departing from the scope or spirit of the present document.

[0156] Herein is provided a process for the preparation of the compositions of the invention. a) add the osmolality modifier and the pH modifier to water and mix until complete dissolution. b) adjust to suitable pH as required. c) Separately, add the surfactant and optionally the solvent to another vessel under heating and mix until a transparent solution is obtained. d) add margaric acid and stir until completely dissolved. e) heat the aqueous phase and add it slowly to the vessel containing the active ingredient under stirring. Stirring was accelerated progressively to the maximum possible that ensures homogenous mixing. f) Optionally add the viscosity modifier. g) test pH and adjust if required. h) allow the product to come down to room temperature and complete until 100% with water.

[0157] The method can further involve packaging the final solution into vials, which can be designed for either multidose or monodose administration.

[0158] Administration

[0159] A therapeutically effective dose level and administration regime of margaric acid or a pharmaceutical salt thereof herein will depend on many factors. In addition, it is well-known within the skill of the art to start doses of the active composition at relatively low levels and increase the dosage until the desired effect is achieved. Efficacy of the methods provided herein can be determined using any appropriate method. For example, criteria for ophthalmic conditions can be determined and evaluated with any one of several objectives, which include clinical analysis by a physician, which are routinely used by all professional healthcare practitioners.

[0160] Clinicians, physicians, and other health care professionals can administer the compounds provided herein to a subject in need thereof according to a method provided herein. In general, more than one administration of the compound is performed at various intervals (e.g., once a day, twice a day) or according to any other appropriate treatment regimen. The duration of treatment can be a single dose or periodic multiple doses for as long as the administration of the compounds provided herein is tolerated by the subject, even chronically.

[0161] In some embodiments, the compounds provided herein are administered in a single dose or repeated dose at specific time intervals, e.g., can be administered daily for a specific number of days or according to a specific dosing schedule. In an embodiment, the compounds provided herein are administered from about 10 days to about 90 days. More particularly, they are administered during a period from about 10 days to about 60 days or from about 15 to about 45 days, more particularly for about 30 days. In another embodiment, the compounds are administered until the condition is completely treated.

[0162] In an embodiment, margaric acid or a pharmaceutical salt thereof is administered ocularly in the form of an ophthalmic composition. Particularly, is administered topically on the ocular surface. More particularly, the ophthalmic composition is in the form of drops.

[0163] In an embodiment, margaric acid or a pharmaceutical salt thereof are administered topically by instillation of 1 or 2 drops, typically from about 0.2 to about 0.5 ml per drop, of a liquid ophthalmic composition into the eye, once or twice a day.

[0164] Aspects / Embodiments herein provided in so-called claim format

[0165] The first aspect of the invention relates to margaric acid or a pharmaceutical salt thereof for use in the treatment and / or prevention of ophthalmic conditions. Specific aspects are margaric acid or a pharmaceutical salt thereof for use in the treatment and / or prevention of increased intra-ocular pressure; and margaric acid or a pharmaceutical salt thereof for use in the treatment and / or prevention of ocular surface conditions.

[0166] This “claim format” section is divided into 3 sub-sections directed individually to the specific aspects of the first aspect and to the second aspect as discussed herein.

[0167] Embodiments related to the first aspect - Increased intra-ocular pressure

[0168] 1. Margaric acid or a pharmaceutical acceptable salt thereof for use in the treatment and / or prevention of ophthalmic conditions.

[0169] 2. Margaric acid or a pharmaceutical acceptable salt thereof for use according to claim 1 , wherein the condition is increased intra-ocular pressure.

[0170] 3. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of the preceding claims, wherein the condition is glaucoma.

[0171] 4. Margaric acid or a pharmaceutical acceptable salt thereof for use according to claim 3, wherein the glaucoma is selected from the group consisting of Primary Open-Angle Glaucoma (POAG) and Angle-Closure Glaucoma.

[0172] 5. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of the preceding claims, wherein margaric acid is administered ocularly.

[0173] 6. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of the preceding claims, wherein margaric acid is administered topically on the surface of the eye. 7. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of the preceding claims, wherein margaric acid is administered in the form of drops.

[0174] 8. A composition of margaric acid or a pharmaceutical acceptable salt thereof for use as defined in any of the preceding claims.

[0175] 9. The composition according to claim 8 in the form of a colloidal composition.

[0176] 10. The composition according to any of claims 8-9, which is an emulsion or a micellar solution.

[0177] 11 . The composition according to any of claims 8-10, which is a micellar solution.

[0178] 12. The composition according to any of claims 8-11 , comprising margaric acid or a pharmaceutical acceptable salt thereof, a surfactant and a solvent.

[0179] 13. The composition according to any of claims 8-12, wherein margaric acid or a pharmaceutical acceptable salt thereof is present in an amount from about 0.01 to about 1 % w / v.

[0180] 14. The composition according to any of claims 8-14, wherein margaric acid or a pharmaceutical acceptable salt thereof is present in an amount from about 0.05 to about 0.5 % w / v.

[0181] 15. The composition according to any of claims 8-14, wherein margaric acid or a pharmaceutical acceptable salt thereof is present in an amount from about 0.07% to about 0.3%.

[0182] 16. The composition according to any of claims 8-15, wherein the surfactant is in an amount from about 1 % to about 40% w / v.

[0183] 17. The composition according to any of claims 8-16, wherein the surfactant is in an amount from about 2% to about 20% w / v.

[0184] 18. The composition according to any of claims 8-17, wherein the surfactant is in an amount from about 4% to about 15% w / v.

[0185] 19. The composition according to any of claims 8-18, wherein the solvent is water.

[0186] 20. The composition according to any of claims 8-19, wherein the solvent is a mixture of water and a lipophilic solvent.

[0187] 21 . The composition according to claim 20, wherein the lipophilic solvent is selected from the group consisting of medium chain triglycerides, castor oil, soya oil, and mixtures thereof. 22. The composition according to any of claims 12-21 , further comprising a pH modifier and an osmolality modifier.

[0188] 23. The composition according to any of claims 8-22, comprising

[0189] Margaric acid 0.01% - 1% w / v Surfactant 1% - 40% w / v pH modifier q.s. pH 5 - 9 osmolality modifier 0.05% - 15% w / v (150 - 500 mOsm / Kg)

[0190] Viscosity modifier 0% - 15% w / v Solvent q.s 100% w / v

[0191] 24. The composition according to any of claims 8-23, comprising Margaric acid (or salt equivalent) 0.05% - 0.5% w / v Surfactant 2% - 20% w / v pH modifier q.s. pH 6 - 8

[0192] Osmolality modifier 0.1 % - 10% w / v (200 - 400 mOsm / Kg)

[0193] Viscosity modifier 0% - 10% w / v Solvent q.s 100% w / v.

[0194] 25. The composition according to any of claims 8-24, comprising Margaric acid (or salt equivalent) 0.07% - 0.3% w / v Surfactant 4% - 15% w / v pH modifier q.s. pH 6.4 - 7.8

[0195] Osmolality modifier 0.15% - 5% w / v (200 - 400 mOsm / Kg)

[0196] Viscosity modifier 0% - 5% w / v Solvent q.s 100% w / v

[0197] 26. The composition according to any of claims 8-25, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil and mixtures thereof.

[0198] 27. The composition according to any of claims 12-26, wherein the surfactant is polysorbate 80.

[0199] 28. The composition according to any of claims 22-27, wherein the pH modifier is selected from the group consisting of tromethamine, hydrochloric acid, TRIS buffer, phosphate buffer, and mixtures thereof.

[0200] 29. The composition according to any of claims 22-28, wherein the osmolality modifier is selected from the group consisting of sorbitol, mannitol, xylitol, glycerin, dextrose, polyethylene glycol, propylene glycol, dextran, sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate, calcium carbonate, sodium lactate, and mixtures thereof.

[0201] 30. The composition according to any of claims 22-29, wherein the osmolality modifier is glycerol.

[0202] 31 . The composition according to any of claims 8-30, wherein the composition is a topical ophthalmic composition.

[0203] Embodiments related to the first aspect - Ocular surface conditions.

[0204] 1. Margaric acid or a pharmaceutical acceptable salt thereof for use in the treatment and / or prevention of ophthalmic conditions.

[0205] 2. Margaric acid or a pharmaceutical acceptable salt thereof for use according to claim 1 , wherein the condition is an ocular surface condition.

[0206] 3. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of the preceding claims, wherein the condition is corneal.

[0207] 4. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of the preceding claims, wherein the condition is selected from the group consisting of dry eye disease, meibomian gland disorder, keratitis, allergic keratoconjunctivitis, and contact lens discomfort.

[0208] 5. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of the preceding claims, wherein the condition is tear film instability.

[0209] 6. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of the preceding claims, wherein the condition is dry eye disease.

[0210] 7. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of the preceding claims, wherein margaric acid is in the form of an ophthalmic composition.

[0211] 8. Margaric acid or a pharmaceutical acceptable salt thereof for use according to claim 7, wherein the composition is topical.

[0212] 9. Margaric acid or a pharmaceutical acceptable salt thereof for use to claim 8, wherein the composition is in the form of drops.

[0213] 10. A composition of margaric acid or a pharmaceutical acceptable salt thereof for use as defined in any of the preceding claims. 11. The composition according to claim 10 in the form of a colloidal composition.

[0214] 12. The composition according to any of claims 10-11 , which is an emulsion or a micellar solution.

[0215] 13. The composition according to any of claims 10-12, which is a micellar solution.

[0216] 14. The composition according to any of claims 10-13, comprising margaric acid or a pharmaceutical acceptable salt thereof, a surfactant and a solvent.

[0217] 15. The composition according to any of claims 10-14, wherein margaric acid or a pharmaceutical acceptable salt thereof is present in an amount from about 0.01 to about 1 % w / v.

[0218] 16. The composition according to any of claims 10-15, wherein margaric acid or a pharmaceutical acceptable salt thereof is present in an amount from about 0.05 to about 0.5 % w / v.

[0219] 17. The composition according to any of claims 10-16, wherein margaric acid or a pharmaceutical acceptable salt thereof is present in an amount from about 0.07% to about 0.3%.

[0220] 18. The composition according to any of claims 14-17, wherein the surfactant is in an amount from about 1 % to about 40% w / v.

[0221] 19. The composition according to any of claims 14-18, wherein the surfactant is in an amount from about 2% to about 20% w / v.

[0222] 20. The composition according to any of claims 14-19, wherein the surfactant is in an amount from about 4% to about 15% w / v.

[0223] 21 . The composition according to any of claims 14-20, wherein the solvent is water.

[0224] 22. The composition according to any of claims 14-20, wherein the solvent is a mixture of water and a lipophilic solvent.

[0225] 23. The composition according to claim 22, wherein the lipophilic solvent is selected from the group consisting of medium chain triglycerides, castor oil, soya oil, and mixtures thereof.

[0226] 24. The composition according to any of claims 14-23, further comprising a pH modifier and an osmolality modifier.

[0227] 25. The composition according to any of claims 10-24, comprising

[0228] Margaric acid 0.01 % - 1 % w / v

[0229] Surfactant 1 % - 40% w / v pH modifier q.s. pH 5 - 9 osmolality modifier 0.05% - 15% w / v (150 - 500 mOsm / Kg) Viscosity modifier 0% - 15% w / v Solvent q.s 100% w / v

[0230] 26. The composition according to any of claims 10-25, comprising Margaric acid (or salt equivalent) 0.05% - 0.5% w / v Surfactant 2% - 20% w / v pH modifier q.s. pH 6 - 8

[0231] Osmolality modifier 0.1 % - 10% w / v (200 - 400 mOsm / Kg)

[0232] Viscosity modifier 0% - 10% w / v

[0233] Solvent q.s 100% w / v.

[0234] 27. The composition according to any of claims 10-26, comprising Margaric acid (or salt equivalent) 0.07% - 0.3% w / v Surfactant 4% - 15% w / v pH modifier q.s. pH 6.4 - 7.8

[0235] Osmolality modifier 0.15% - 5% w / v (200 - 400 mOsm / Kg)

[0236] Viscosity modifier 0% - 5% w / v

[0237] Solvent q.s 100% w / v

[0238] 28. The composition according to any of claims 14-27, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil and mixtures thereof.

[0239] 29. The composition according to any of claims 14-28, wherein the surfactant is polysorbate 80.

[0240] 30. The composition according to any of claims 24-29, wherein the pH modifier is selected from the group consisting of tromethamine, hydrochloric acid, TRIS buffer, phosphate buffer, and mixtures thereof.

[0241] 31 . The composition according to any of claims 24-30, wherein the osmolality modifier is selected from the group consisting of sorbitol, mannitol, xylitol, glycerin, dextrose, polyethylene glycol, propylene glycol, dextran, sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate, calcium carbonate, sodium lactate, and mixtures thereof.

[0242] 32. The composition according to any of claims 24-31 , wherein the osmolality modifier is glycerol.

[0243] 33. The composition according to any of claims 10-32, wherein the composition is a topical ophthalmic composition. Embodiments related to the second

[0244] 1 . A composition of margaric acid or a pharmaceutical acceptable salt thereof in the form of a colloidal composition.

[0245] 2. The composition according to claim 1 , wherein the composition is selected from the group consisting of an emulsion and a micellar solution, particularly a micellar solution.

[0246] 3. The composition according to any of the preceding claims, comprising margaric acid or a pharmaceutical acceptable salt thereof, a surfactant and a solvent.

[0247] 4. The composition according to any of the preceding claims, wherein margaric acid or a pharmaceutical acceptable salt thereof is present in an amount from about 0.01 to about 1 % w / v

[0248] 5. The composition according to any of the preceding claims, wherein margaric acid or a pharmaceutical acceptable salt thereof is present in an amount from about 0.05 to about 0.5 % w / v.

[0249] 6. The composition according to any of the preceding claims, wherein margaric acid or a pharmaceutical acceptable salt thereof is present in an amount from about 0.07% to about 0.3% w / v.

[0250] 7. The composition according to any of claims 3-6, wherein the surfactant is in an amount from about 1 % to about 40% w / v.

[0251] 8. The composition according to any of claims 3-7, wherein the surfactant is in an amount from about 2% to about 20% w / v.

[0252] 9. The composition according to any of claims 3-8, wherein the surfactant is in an amount from about 4% to about 15% w / v.

[0253] 10. The composition according to any of claims 3-9, wherein the solvent is water.

[0254] 11 . The composition according to any of claims 1-10, wherein the solvent is a mixture of water and a lipophilic solvent.

[0255] 12. The composition according to claim 11 , wherein the lipophilic solvent is selected from the group consisting of medium chain triglycerides, castor oil, soya oil, and mixtures thereof.

[0256] 13. The composition according to any of claims 3-12, further comprising a pH modifier and an osmolality modifier. 14. The composition to any of the preceding claims, comprising

[0257] Margaric acid 0.01 % - 1 % w / v Surfactant 1 % - 40% w / v pH modifier q.s. pH 5 - 9 osmolality modifier 0.05% - 15% w / v (150 - 500 mOsm / Kg)

[0258] Viscosity modifier 0% - 15% w / v Solvent q.s 100% w / v

[0259] 25. The composition to any of the preceding claims, comprising

[0260] Margaric acid (or salt equivalent) 0.05% - 0.5% w / v

[0261] Surfactant 2% - 20% w / v pH modifier q.s. pH 6 - 8

[0262] Osmolality modifier 0.1 % - 10% w / v (200 - 400 mOsm / Kg)

[0263] Viscosity modifier 0% - 10% w / v

[0264] Solvent q.s 100% w / v.

[0265] 16. The composition to any of the preceding claims, comprising

[0266] Margaric acid (or salt equivalent) 0.07% - 0.3% w / v

[0267] Surfactant 4% - 15% w / v pH modifier q.s. pH 6.4 - 7.8

[0268] Osmolality modifier 0.15% - 5% w / v (200 - 400 mOsm / Kg)

[0269] Viscosity modifier 0% - 5% w / v

[0270] Solvent q.s 100% w / v

[0271] 17. The composition to any of claims 3-16, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil and mixtures thereof.

[0272] 18. The composition according to any of claims 3-17, wherein the surfactant is polysorbate 80.

[0273] 19. The composition according to any of claims 3-18, wherein the pH modifier is selected from the group consisting of tromethamine, hydrochloric acid, TRIS buffer, phosphate buffer, and mixtures thereof.

[0274] 20. The composition to any of claims 13-19, wherein the osmolality modifier is selected from the group consisting of sorbitol, mannitol, xylitol, glycerin, dextrose, polyethylene glycol, propylene glycol, dextran, sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate, calcium carbonate, sodium lactate, and mixtures thereof.

[0275] 21 . The composition to any of claims 13-20, wherein the osmolality modifier is glycerol. 22. The composition to any of the preceding claims, wherein the composition is a topical ophthalmic composition.

[0276] 23. The composition of margaric acid or a pharmaceutical acceptable salt thereof according to any of the preceding claims, for use in the treatment and / or prevention of ophthalmic conditions.

[0277] 24. The composition of margaric acid or a pharmaceutical acceptable salt thereof according to any of the preceding claims, for use in the treatment and / or prevention of increased intra-ocular pressure.

[0278] 25. The composition of margaric acid or a pharmaceutical acceptable salt thereof according to any of the preceding claims, for use in the treatment and / or prevention of glaucoma.

[0279] 26. The composition of margaric acid or a pharmaceutical acceptable salt thereof according to claim 25, wherein the glaucoma is selected from the group consisting of Primary Open-Angle Glaucoma (POAG) and Angle-Closure Glaucoma.

[0280] 27. The composition of margaric acid or a pharmaceutical acceptable salt thereof according to any of the claims 1-22, for use in the treatment and / or prevention of ocular surface conditions.

[0281] 28. The composition of margaric acid or a pharmaceutical acceptable salt thereof according to any of the claims 1-22, for use in the treatment and / or prevention of tear film instability.

[0282] 29. The composition of margaric acid or a pharmaceutical acceptable salt thereof according to any of the claims 1-23, for use in the treatment and / or prevention of dry eye disease.

[0283] EXAMPLES

[0284] The following Examples provide data on the effect of the in vivo ophthalmic administration of margaric acid on several factors which are present on ophthalmological conditions. These factors are Intraocular Pressure (IOP), Tear Film break-up time (TFBUT), tear volume, corneal fluorescein staining and lissamine green staining. The Examples also provide compositions of margaric acid.

[0285] EXAMPLE 1 : Compositions

[0286] Micellar solution 0.075% and 0.15%

[0287] Preparation process a) In an appropriate volume vessel, water was weighted and then the osmolality adjustment agent and the pH buffering component were added. b) Mixed until complete dissolution and adjusted to pH 6.4 - 7.8 with HCI as required. c) Separately, the surfactant was added to another vessel and was heated at 65°C. Margaric acid was added and stirred until complete dissolution. d) The aqueous phase was heated at 65°C and added slowly under stirring to the vessel containing the active ingredient. Stirring was accelerated progressively to the maximum possible that ensures homogenous mixing without major splashing on to the walls of the vessel. e) pH was tested and adjusted. f) The composition was allowed to come down to room temperature and completed to 100% with water.

[0288] Mineral oil solution 0.27%

[0289] Preparation process a) In an appropriate volume vessel, mineral oil was weighted and then heated at 65°C. b) Margaric acid was added and stirred until complete dissolution. c) The composition was allowed to come down to room temperature.

[0290] EXAMPLE 2: Margaric acid reduces Intra-Ocular Pressure (IOP) in acute glaucoma model in rabbits.

[0291] For the experiment, sixteen 3-6-month-old male New Zealand White (NZW) rabbits were used (vehicle n=8; margaric acid n=8). Rabbits were housed under standard laboratory conditions, air conditioned with adequate fresh air supply. Environment: temperature 23 ± 3°C, relative humidity 30 - 70%, with approximately 12 hours light and 12 hours dark cycle.

[0292] For the induction of acute glaucoma model, sodium hyaluronate solution at 15 mg / ml (100 pl / eye) was injected bilaterally in the anterior chamber of both eyes. Animals were treated topically (50 pl / eye) with the micellar solution of Example 1 or its corresponding vehicle 1 .5 and 4 hours after model induction. Intraocular pressure (IOP) was measured before and 1 h, 2h, 4h, 8h and 10h after model induction. IOP at 1 h was used as reference and all IOP values were normalized taking IOP at 1 h as the baseline and assessing the IOP reduction compared to that peak.

[0293] In this acute glaucoma model, an increase from baseline of 20-30 mmHg at 1 h after induction was achieved and this was taken as reference value to calculate the IOP reduction in each group. As shown in FIG. 1 treatment with margaric acid results in a clear IOP reduction at 2, 8 and 10h after model induction when compared to Vehicle (p<0.0001 , at 2h, 8h and 10h, margaric acid vs vehicle had significant differences (one-way ANOVA / Dunnett’s)).

[0294] No adverse effect was observed after the corneal topical administration of margaric acid in acute glaucoma model rabbits.

[0295] EXAMPLE 3: Margaric acid improves Dry Eye Disease (DED) signs in murine model

[0296] For the experiment sixteen 6-8 weeks old BALB / C mice were used (Vehicle n=8; Margaric acid n=8). Mice were housed under a 12 h light dark cycle at a temperature of 23±3°C and granted access to food and water ad libitum.

[0297] For model induction, mice were placed in a controlled environment chamber (relative humidity < 40%) and were subcutaneously injected with 0.25% scopolamine hydrobromide solution three times a day for 14 days. Treatment with the micellar solution of Example 1 or its corresponding vehicle was topically administered twice a day (5 pl / eye / time) for 14 days.

[0298] FIG. 2 shows the study design used to evaluate the Tear film break-up time (TFBUT), tear volume, corneal fluorescein staining and lissamine green staining in the scopolamine-induced dry eye model in mice.

[0299] Tear film break-up time (TFBUT)

[0300] At baseline and on day 7 and day 14, the tear film breakup time (TFBUT) of all mice was recorded. Fluorescein solution at 0.5% was applied onto the ocular surface and the eyelid was gently closed. After a blink response, TFBUT was determined with slit-lamp biomicroscope by using cobalt blue light in triplicate. TFBUT was reduced on day 7 to around one third of baseline values.

[0301] FIG. 3 shows that topical ocular administration of margaric acid in the form of the micellar solution of Example 1 significantly increased TFBUT when compared with the group treated with vehicle.

[0302] Tear volume

[0303] At baseline and on day 7 and day 14, tear volume was assessed in all mice measured by phenol red thread. Microforceps were used to insert the cotton thread into the tear film meniscus without touching the eyelid orthe ocular surface. After 30s, the thread was removed, and the entire wet (Red) portion was measured using a calliper. Tear volume was reduced on day 7 to more than one third of baseline values.

[0304] FIG. 4 shows that topical ocular administration of margaric acid in the form of the micellar solution of Example 1 significantly increased tear volume when compared with vehicle.

[0305] Corneal fluorescein staining

[0306] At baseline and on day 7 and day 14, corneal fluorescence staining which is indicative of epithelial lesion was scored in all mice (16 total points in four quadrants). Fluorescein solution at 0.5% was applied topically into the upper conjunctival sac and the eyelid gently closed. After 90 seconds, the excess of fluorescein on the corneal surface was rinsed with saline. The corneal staining was observed and scored under slit-lamp (0= absent; 1 = slightly punctate staining; 2= strong punctate staining but not diffuse; 3 = small positive plaque areas; 4 = large area fluorescein plaque). Corneal fluorescein staining was increased both on day 7 and day 14 which is indicative of epithelial lesion.

[0307] FIG. 5 shows that topical ocular administration of margaric acid in the form of the micellar solution of Example 1 significantly reduced corneal fluorescein staining when compared with vehicle on day 14.

[0308] Lissamine green staining

[0309] At baseline and on day 7 and day 14, lissamine green dye (1 %) was applied topically on the ocular surface and then lissamine green staining which is indicative of keratinized and devitalized epithelial cells was scored in all eyes (0= absent; 1 = less than 25% of cornea stained with scattered punctate staining; 2= 25%-50% of cornea stained with diffuse punctate staining; 3 =50%-75% of cornea stained with punctate staining and apparent epithelial defects; 4 = more than 75% of cornea stained with abundant punctate staining and large epithelial defects). Lissamine green staining was increased both on day 7 and day 14 which is indicative of keratinized and devitalized epithelial cells on the ocular surface.

[0310] FIG. 6 shows that topical ocular administration of margaric acid the micellar solution of Example 1 significantly decreased lissamine green staining when compared with vehicle on day14.

[0311] FIG. 5 and FIG. 6 show that topical ocular administration of margaric acid significantly decreased fluorescein and lissamine green staining, thus supporting the effect of margaric acid in improving integrity of the corneal tissue.

[0312] EXAMPLE 4: Ocular tolerability of Margaric acid in rabbits.

[0313] Micellar solution For the experiment, twenty-one 2-3-month-old male New Zealand White (NZW) rabbits were used (vehicle n=3; margaric acid at 0.075% n=9; margaric acid at 0.15% n=9. Rabbits were housed under standard laboratory conditions, air conditioned with adequate fresh air supply. Environment: temperature 22 ± 3°C, relative humidity 30 - 70%, with approximately 12 hours light and 12 hours dark cycle.

[0314] Animals were treated topically (50 pl / eye) with the micellar solution of Example 1 or its corresponding vehicle twice a day for 14 days.

[0315] No adverse effect was observed after the corneal topical administration of margaric acid in rabbits. Margaric acid was well tolerated with no clinical signs of local or systemic toxicity observed for the complete study duration. There were no adverse effects on the ocular tolerability parameters on cornea, iris, and conjunctiva, assessed by Draize scoring system, direct & indirect ophthalmoscopy, intraocular pressure, and ocular examination (McDonald-Shadduck’s scoring system).

[0316] Mineral oil solution

[0317] For the experiment, twenty-one 2-3-month-old male New Zealand White (NZW) rabbits were used (vehicle n=3; margaric acid at 0.27% n=6). Rabbits were housed under standard laboratory conditions, air conditioned with adequate fresh air supply. Environment: temperature 22 ± 3°C, relative humidity 30 - 70%, with approximately 12 hours light and 12 hours dark cycle.

[0318] Animals were treated topically (50 pl / eye) with the mineral oil solution of Example 1 or its corresponding vehicle thrice a day for 7 days.

[0319] No adverse effect was observed after the corneal topical administration of margaric acid in rabbits. Margaric acid was well tolerated with no clinical signs of local or systemic toxicity observed for the complete study duration. There were no adverse effects on the ocular tolerability parameters on cornea, iris, and conjunctiva, assessed by Draize scoring system, direct & indirect ophthalmoscopy, intraocular pressure, and ocular examination (McDonald-Shadduck’s scoring system).

[0320] REFERENCES

[0321] WO2021163425A1

[0322] US1529946A

[0323] Fernandez-Trillo J. et al. “Piezo2 Mediates Low-Threshold Mechanically Evoked Pain in the Cornea J.Neurosci. 2020,40(47) 8976-8993.

Claims

CLAIMS1. Margaric acid or a pharmaceutical acceptable salt thereof for use in the treatment and / or prevention of increased intra-ocular pressure.

2. Margaric acid or a pharmaceutical acceptable salt thereof for use according to claim 1 , wherein the condition is glaucoma.

3. Margaric acid or a pharmaceutical acceptable salt thereof for use according to claim 2, wherein the glaucoma is selected from the group consisting of Primary Open-Angle Glaucoma (POAG) and Angle-Closure Glaucoma.

4. Margaric acid or a pharmaceutical acceptable salt thereof for use in the treatment and / or prevention of an ocular surface condition.

5. Margaric acid or a pharmaceutical acceptable salt thereof for use according to claim 4, wherein the condition is corneal.

6. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of claims 4-5, wherein the condition is tear film instability.

7. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of claims 4-6, wherein the condition is dry eye disease.

8. Margaric acid or a pharmaceutical acceptable salt thereof for use according to any of claims 1 -7, wherein margaric acid is in the form of ophthalmic composition.

9. Margaric acid or a pharmaceutical acceptable salt thereof for use according to claim 8, wherein the composition is topical.

10. Margaric acid or a pharmaceutical acceptable salt thereof for use according to claim 9, wherein the composition is in the form of drops.11 . A composition of margaric acid or a pharmaceutical acceptable salt thereof in the form of a colloidal composition.

12. The composition according to claim 11 , which is an emulsion or a micellar solution, particularly a micellar solution.

13. The composition according to any of claims 11-12, comprising margaric acid or a pharmaceutical acceptable salt thereof, a surfactant and a solvent.

14. The composition according to any of claims 11-13, wherein margaric acid or the pharmaceutical acceptable salt thereof is present in an amount from about 0.01 to about 1 % w / v, from about 0.05 to about 0.5 % w / v, or from about 0.07% to about 0.3% w / v.

15. The composition according to any of claims 13-14, wherein the surfactant is in an amount from about 1 % to about 40% w / v, from about 2% to about 20% w / v, or from about 4% to about 15% w / v.

16. The composition according to any of claims 11-15, wherein the solvent is water.

17. The composition according to any of claims 11-15, wherein the solvent is a mixture of water and a lipophilic solvent, in particular the lipophilic solvent is selected from the group consisting of medium chain triglycerides, castor oil, soya oil, and mixtures thereof.

18. The composition according to any of claims 11-17, further comprising a pH modifier and an osmolality modifier.

19. The composition according to any of claims 11-18, comprising:Margaric acid 0.01 % - 1 % w / v Surfactant 1 % - 40% w / v pH modifier q.s. pH 5 - 9 osmolality modifier 0.05% - 15% w / v (150 - 500 mOsm / Kg)Viscosity modifier 0% - 15% w / v Solvent q.s 100% w / v20. The composition according to any of claims 13-19, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil and mixtures thereof.21 . The composition according to any of claims 18-20, wherein the pH modifier is selected from the group consisting of tromethamine, hydrochloric acid, TRIS buffer, phosphate buffer, and mixtures thereof.

22. The composition according to any of claims 18-21 , wherein the osmolality modifier is selected from the group consisting of sorbitol, mannitol, xylitol, glycerin, dextrose, polyethylene glycol, propylene glycol, dextran, sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate, calcium carbonate, sodium lactate, and mixtures thereof.

23. The composition according to any of claims 18-22, wherein the osmolality modifier is glycerol.

24. The composition according to any of claims 11-23, wherein the composition is a topical ophthalmic composition.

25. Composition of margaric acid or a pharmaceutical acceptable salt thereof according to any of claims 11-24, for use as defined in any of claims 1-10.

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