WO2026017754A1 - Maresin formulation - Google Patents

Abstract

It is provided a novel formulation comprising a specialized pro-resolving lipid mediator, particularly maresin, a first cosolvent which is an alcohol, and a second cosolvent, all dissolved in water. The formulations of the invention have an efficient dissolution and can be administered orally. Further, they have a positive effect in several conditions, such as a neurodegenerative diseases, autoimmune diseases and injuries to the nervous system. It is also provided a method of preparing the compositions.

Description

TITLE: MARESIN FO MULATION

FIELD OF THE INVENTION

The present invention relates to the field of compositions for specialized pro-resolving lipid mediators, particularly maresin, and their medical uses.

BACKGROUND ART

Specialized pro-resolving lipid mediators (SPMs) are a diverse group of bioactive lipids synthesized from polyunsaturated fatty acids (PUFAs), notably omega-3 and omega-6 fatty acids. Among the SPMs, maresin represents a potent mediator involved in the resolution of inflammation and the promotion of tissue repair processes. These lipid molecules exert their effects by modulating various cellular pathways, including the regulation of leukocyte trafficking, the clearance of apoptotic cells, and the enhancement of tissue regeneration.

Despite their promising therapeutic potential, the practical application of SPMs, particularly maresin, faces significant challenges due to their intricate lipid structure and limited solubility in aqueous solutions. Consequently, the conventional approach to administering SPMs involves parenteral delivery methods, such as intravenous injection, which may not be optimal for chronic or widespread conditions.

W02013170006A2 discloses different natural oil fractions containing SPM and SPM precursors in small amounts. It demonstrates that the fractions enriched in SPM or SPM precursors mediate antiinflammatory actions after the injection of a lipopolysaccharide and an inflammatory agent. This document focuses on the role of these fractions in modulating inflammatory processes.

WO2018134230A1 specifically discloses the therapeutic use of SPMs, particularly maresin, in the treatment of autoimmune and neurodegenerative diseases; and W02019016580A1 discloses the therapeutic use of SPMs, particularly maresin, in the treatment of central nervous system injuries. The formulations described in these disclosures are intraperitoneal saline solutions.

In light of the shortcomings of the prior art, there exists a need for the development of a formulation containing SPMs, in particular maresin, that can overcome the challenges associated with poor solubility. Such a formulation would not only enhance the bioavailability and therapeutic efficacy of SPM- based therapies but also improve patient compliance and accessibility if administered orally, thereby addressing unmet clinical needs in the management of inflammatory and degenerative diseases.

SUMMARY OF THE INVENTION One problem to be solved by the present invention is finding a suitable formulation comprising specialized pro-resolving lipid mediators (SPMs), particularly maresin. The difficulty lies in the inherent nature of SPMs and maresin as lipids, which poses challenges to their dissolution in aqueous solutions, thereby limiting the therapeutic applicability of these compounds.

The solution is based on the provision of a formulation comprising a SPM, in particular maresin, and two organic cosolvents, all dissolved in water. The formulation can also comprise antioxidants and preservatives, among other components. This novel formulation aims to facilitate the efficient dissolution and proper delivery of SPMs, e.g., through oral administration.

Maresin is a lipid that has difficulties dissolving. Even though it may initially appear to dissolve properly, this must be evaluated over time as it may eventually precipitate. Inventors found that maresin precipitates over time if dissolved solely in water and alcohol. Surprisingly, the inventors observed that the addition of a second cosolvent, such as a glycol, enabled maresin to remain dissolved for a period of time, e.g., a year. This result is unexpected because the inventors discovered that despite being a lipidic molecule, the addition of two cosolvents was sufficient to prevent maresin from precipitating.

Another advantage of this new formulation is that it lacks any phase or component that would make scaling up difficult or impossible. This means that the manufacturing process can be easily adjusted to increase production volume without encountering any limitations.

Surprisingly, inventors further demonstrated that the oral administration of the new maresin formulation improved functional outcomes in experimental autoimmune encephalomyelitis (EAE) mice, i.e., amelioration of neurological decline, as compared to mice treated with vehicle (placebo group) as well as to those treated with maresin saline solution (see Figure 1), concluding that the oral administration of maresin conferred protection against EAE and that the new maresin formulation enhances the therapeutic actions of maresin.

This new oral formulation was also tested in SOD1-G93A mice, demonstrating its therapeutic potential in amyotrophic lateral sclerosis (ALS) (see Figure 2).

Accordingly, a first aspect of the invention relates to a composition comprising a specialized proresolving lipid mediator, a first cosolvent which is an alcohol, a second cosolvent, and water. Particularly, the composition further comprises at least one antioxidant and/or at least one preservative; and the composition is an oral composition. Another aspect refers to a composition as defined in the first aspect of the invention, for use as a medicament.

Other aspects relates to a composition as defined in the first aspect of the invention, for use in the treatment of a neurological disease; or for use in the treatment of a neurodegenerative disease; or for use in the treatment of an autoimmune disease; or for use in the treatment of an injury to the nervous system; or for use in the treatment of other diseases, such as inflammation, inflammation- related diseases or conditions, chronic pain, neuropathic pain, and depression concomitant with depression. These aspects can be alternatively formulated as a method for treating a neurological disease; or a neurodegenerative disease; or an autoimmune disease; or an injury to the nervous system; or other diseases such as inflammation, inflammation-related diseases or conditions, chronic pain, neuropathic pain, and depression concomitant with depression, in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a composition as defined in the first aspect of the invention.

Another aspect refers to a method of preparing a composition comprising: (a) preparing a solution by mixing a second cosolvent (e.g., propylene glycol) with a solution of a SPM (e.g., maresin) in a first cosolvent (e.g., alcohol); and (b) adding the desired volume of a solvent (e.g., deionized water) to the solution obtained in (a).

DESCRIPTION OF DRAWINGS

Figure 1 shows the effects of oral administration of maresin-1 on neurological deficits. Graphs show the clinical score of EAE mice treated with maresin saline solution, maresin new formulation and vehicle.

Figure 2 shows the effects of oral administration of maresin-1 in ALS mice. (A) Graph showing functional progression of neurological deficits represented by the latency to fall of the rotarod test. (B) Graph showing the effects of maresin-1 in the lifespan of ALS mice. n=8 for the vehicle group and n=11 for maresin-1 group.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

In order that the present description can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

Neurological diseases: the terms "neurological diseases" or "neurological disorders" as used herein refer to a broad range of conditions that affect the nervous system, which includes the brain, spinal cord, and peripheral nerves. These diseases can result from genetic factors, infections, trauma, autoimmune reactions, or degenerative processes. They are characterized by disruptions in the normal functioning of the nervous system, leading to a wide array of symptoms and impairments in sensory functions (e.g., numbness, tingling, pain, changes in sensation, and vision or hearing disturbances), motor functions (e.g., muscle weakness, tremors, difficulty with movement or coordination, or muscle stiffness), autonomic functions (e.g., blood pressure, temperature control, digestion, bladder function and even sexual function) and cognitive functions (e.g., memory loss, confusion, difficulty concentrating, or changes in behavior or personality). Neurological diseases can affect various aspects of nervous system function, including sensory perception, motor control, cognition, and behavior. They may manifest as chronic conditions or acute episodes, and their severity can range from mild to debilitating. Examples of neurological diseases include Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, migraine, and amyotrophic lateral sclerosis (ALS).

Neurodegenerative diseases: the term "neurodegenerative diseases" as used herein refers to a subset of neurological disorders characterized by the progressive degeneration or death of nerve cells (neurons) in the central nervous system (brain and spinal cord) or peripheral nervous system. These diseases typically result in a gradual decline in cognitive function (e.g., memory loss, impaired reasoning, difficulty with language, or changes in behavior or personality), motor skills (e.g., muscle weakness, tremors, rigidity, difficulty with coordination and balance, or problems with walking or fine motor skills), or both, leading to disabilities and eventually impacting daily functioning. Neurodegenerative diseases involve the gradual loss of structure and function in neurons, which can be caused by various factors including genetic mutations, protein misfolding, oxidative stress, and inflammation. As nerve cells degenerate, they lose their ability to communicate effectively with other cells, leading to disruptions in neural circuits and the emergence of symptoms such as memory loss, movement disorders, and cognitive impairment. Examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Lewi body disease, spinal muscular atrophy, primary lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, monomelic amyotrophy, Leigh syndrome, multiple sclerosis, prion diseases, and multiple system atrophy, among others.

Autoimmune diseases: the term "autoimmune diseases" as used herein refers to those diseases that arise when the body's immune system mistakenly attacks its own tissues, leading to inflammation, tissue damage, and dysfunction of affected organs or systems. These diseases can affect virtually any part of the body and may be localized or systemic, depending on the specific autoimmune response involved. Autoimmune diseases can be triggered by genetic predisposition, environmental factors, infections, or hormonal changes. Examples of autoimmune diseases include multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), psoriasis, Graves' disease, and Hashimoto's thyroiditis. Spinal cord injury (SCi . the term "spinal cord injury" or "SCI" as used herein refers to any injury, wound, ischemia or damage to the spinal cord that results in a loss of function, such as mobility or feeling. Frequent causes of damage are trauma (e.g., by car accident, gunshot, falls) or disease (e.g., polio, spina bifida, Friedreich's Ataxia). The spinal cord does not have to be severe in order for a loss of functioning to occur. In most individuals with SCI, the spinal cord is intact, but the damage results in loss of function. Besides a loss of sensation or motor function, individuals with SCI may also experience symptoms, conditions, or impairments including dysfunction of the bowel and bladder, sexual and fertility dysfunction, inability to regulate blood pressure effectively, reduced control of body temperature, inability to sweat below the level of injury, and chronic pain. A patient with SCI can have any level of SCI, as typically defined by the level of the damage (e.g., at or below any of the eight cervical vertebrae or the twelve thoracic vertebrae). Very high injuries (C-1 , C-2) can result in a loss of many involuntary functions including the ability to breathe, necessitating breathing aids such as mechanical ventilators or diaphragmatic pacemakers.

Traumatic brain injury (TBI)-. the term "traumatic brain injury" or "TBI", also termed as "intracranial injury" refers to any injury, wound, or damage caused by any type of trauma to the head, such as impact to the head or shaking. More specifically, TBI is an acquired injury to the brain caused by an external physical force, resulting in total or partial functional disability or psychosocial impairment, or both. The term applies to open and closed head injuries resulting in impairments in one or more areas, such as cognition; language; memory; attention; reasoning; abstract thinking; judgment; problem-solving; sensory, perceptual, and motor abilities; psychosocial behavior; physical functions; information processing; and speech. The term typically does not apply to brain injuries that are congenital or degenerative, or brain injuries induced by birth trauma. TBI can result in a variety of physiological and psychological symptoms, conditions or impairments, including physical impairments (e.g., speech, vision, hearing and other sensory impairment; headaches; lack of fine motor coordination; spasticity of muscles; paresis or paralysis of one or both sides and seizure disorders; balance impairments; and other gait impairments), cognitive impairments (e.g., short- and long-term memory deficits, impaired concentration, slowness of thinking and limited attention span, as well as impairments of perception, communication, reading and writing skills, planning, sequencing, and judgment), and psychosocial- behavioral-emotional impairments (e.g., fatigue, mood swings, denial, self- centeredness, anxiety, depression, lowered self-esteem, sexual dysfunction, restlessness, lack of motivation, inability to self-monitor, difficulty with emotional control, inability to cope, agitation, excessive laughing or crying, and difficulty relating to others).

Treatment: the terms "treat", "treatment", or "therapy", as used herein refer to a clinical intervention to cure the disease or condition; delay the onset of the disease or condition (e.g., ALS); reduce the seriousness or severity of the disease or condition (e.g., ALS or multiple sclerosis); ameliorate or eliminate one or more symptoms or sequelae associated with a disease or condition (e.g., ALS or multiple sclerosis); or the provision of beneficial effects to a subject with a disease or condition, without necessarily curing the disease or condition.

In some embodiments, the term refers to a clinical intervention to improve one or more symptoms; improve one or more sequelae; delay one or more symptoms; delay one or more sequelae; ameliorate one or more symptoms; ameliorate one or more sequelae; shorten the duration one or more symptoms; shorten the duration of one or more sequelae; reduce the frequency of one or more symptoms; reduce the frequency of one or more sequelae; reduce the severity of one or more symptoms; reduce the severity of one or more sequelae; improve the quality of life; increase survival; delay a recurrence of the disease or condition; reduce the severity of the disease; or any combination thereof, e.g., with respect to what is expected in the absence of treatment.

Prophylaxis or prevention-, as used herein, the terms "prophylaxis", "prevent" or "prevention" (e.g., suppression, inhibition or delay) of a disease or condition or its symptoms or sequelae thereof refer to clinical interventions administered to a subject who is not yet diagnosed with the disease or condition but may be at risk of developing it. Such interventions aim to prevent, inhibit, suppress, reduce the risk, reduce the occurrence or delay the onset of a disease or condition, or to prevent, inhibit, suppress, or delay a symptom associated with a disease or condition.

Effective amount: as used herein, the term "effective amount" of an agent, e.g., the composition of the present invention, is that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an "effective amount" depends upon the context in which it is being applied. For example, in the context of administering an agent that treats a neurodegenerative disease, or ameliorates or prevents the sequelae and/or symptoms associated with a neurodegenerative disease, an effective amount of an agent is an amount sufficient to reduce or decrease e.g., cognitive decline (e.g., memory loss) or motor disfunction (e.g., muscle weakness) in a subject, or any combination thereof as compared to the response obtained without administration of the agent. The term "effective amount" can be used interchangeably with "effective dose", "therapeutically effective amount", or "therapeutically effective dose."

About. The term "about" is used herein to mean approximately, roughly, around, or in the regions of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" can modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower). As used herein, the terms "about" or "at least about" when applied to a series of values or range, apply equally to all member of the list. Accordingly, "at least about 1 , 2, 3, 4..." would be interchangeable with "at least about 1 , at least about 2, at least about 3, at least about 4...". Composition

An aspect of the present invention is directed to a composition (e.g., oral composition) comprising a specialized pro-resolving lipid mediator, a first cosolvent which is an alcohol, a second cosolvent and water. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises a preservative.

The composition of the present invention is a pharmaceutical composition that comprises pharmaceutically acceptable excipients. The term "pharmaceutically acceptable" is art-recognized, and includes excipients, compounds, materials, compositions, carriers, vehicles and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be “acceptable" in the sense of being compatible with the other ingredients of the formulation. Therefore, the components of the composition described herein are pharmaceutically acceptable.

The composition of the present invention can also be in the form of a nutraceutical composition, a food ingredient or supplement, a nutritional supplement, a food formula, a functional food, and the composition comprises appropriate amounts of acceptable excipients. Suitable carriers, excipients, etc. can be found in standard nutraceutical/food/pharmaceutical texts, i.e., the excipients are pharmaceutically acceptable excipients, nutraceutical acceptable excipients or food/edible acceptable excipients. The excipients mentioned in this description are suitable for the compositions of the present invention regardless of the form of the composition.

The product can adopt different forms or names depending on the product approval route and also depending on the country. In an embodiment, the composition is in the form of pharmaceutical composition, and particularly in the form of medicament. In another embodiment, the composition is in the form of medical food. The terms “medical food” or “food for special medical purposes (FSMP)” are used in some countries to refer to a food specially formulated and intended for the dietary management of a disease that has distinctive nutritional needs that cannot be met by normal diet alone. They are defined in regulations such as the Food and Drug Administration's 1988 Orphan Drug Act Amendments in the United States, and the Commission Directive 1999/21 /EC in Europe.

A food supplement is also known as dietary supplement or nutritional supplement. This is a preparation or product intended to supplement the diet, made from compounds usually used in foodstuffs, which provide nutrients or beneficial ingredients that are not usually ingested in the normal diet or may not be consumed in sufficient quantities. Food supplements are usually sold “over the counter”, i.e., without prescription. The compositions provided by the present invention can be administered to a subject by means of any suitable administration route. In some embodiments, the pharmaceutical composition can be administered via oral, rectal, topical, vaginal, parenteral (e.g., intravenous, intraperitoneal, intramuscular, intraarterial, or subcutaneous administration), intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transfermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intrapulmonary, instranasal, intrasternal injection, and infusion. Particularly, said composition is to be administered by oral or parenteral route, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active product used. More particularly, the oral composition is administered orally.

In a particular embodiment, the composition is an oral composition.

The term “oral composition” as used herein may also be referred in this description to as an “oral solution” or a “liquid composition”. In particular, the composition is liquid, having a density and viscosity similar to that of water, which is the predominant component. These terms are used to distinguish the composition from other types of formulations with higher viscosity, such as topical preparations such as creams, ointments or gels. The liquid nature of the composition allows it to be administered orally in the form of a solution, ensuring rapid and uniform dispersion in the oral cavity or gastrointestinal tract. Accordingly, in an embodiment, the composition is a liquid composition. In another embodiment, the composition is an oral solution.

Alternatively, the aspect can also be formulated as a composition for oral administration comprising a specialized pro-resolving lipid mediator, a first cosolvent which is an alcohol, a second cosolvent and water, and optionally an antioxidant and/or a preservative.

The composition is in the form of a liquid solution. Particularly, the composition (e.g., oral composition) is in the form of single-use vials, multiple-use vials, ampoules, syringes, syrups, oral drops, oral elixirs, solutions filled into soft or hard capsules, or gelatin capsules. In a particular embodiment, the composition (e.g., oral composition) is in the form of single-use vials. In a particular embodiment, the composition (e.g., oral composition) is in the form of multiple-use vials.

The composition according to the invention can be administered as such, can be mixed with a suitable drinkable liquid, such as water, yoghurt, milk or fruit juice, or can be mixed with solid or liquid food.

Particularly for the compositions of the invention, the frequency of administration is daily, and the duration of treatment can be from one day to the number of days necessary to observe an improvement in the quality of life. Additionally, the administration can be chronic or intermittent, as deemed appropriate by the supervising practitioner, particularly in view of any change in the disease state or any undesirable side effects. "Chronic" administration refers to administration of the composition in a continuous manner while "intermittent" administration refers to treatment that is done with interruption.

Specialized pro-resolving lipid mediators

As used herein, the term "Specialized pro-resolving lipid mediator" (SPM, also termed "specialized pro-resolving mediator") refers to a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFAs) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes.

In some embodiments, the SPM is selected from the group consisting of a maresin, a n-3-docosa- pentaenoic acid-derived maresin, a D-series resolvin, a E-series resolvin, a n-3 docosapentaenoic acid-derived resolvin, a protectin, a lipoxin, and a combination thereof.

In an embodiment, the SPM is a maresin. In a particular embodiment, the maresin is selected from the group consisting of maresin 1 , maresin 2, 7-epi-maresin 1 , maresin- like-1 and maresin like-2. Maresin 1 (MaR1) is 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid generated from docosahexaenoic acid (DHA) by 12- and 15- lipoxygenase and a soluble epoxide hydrolase. Maresin 2 (MaR2) is 13R,14S-dihydroxy-4Z,7Z,9E,11 E,16Z,19Z-docosahexaenoic acid, also generated by the same enzymes than MaR1 . 7-epi-Maresin 1 (7-epi-MaR1) is the 7S-12E isomer of MaR1 , 7S,14S-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid. Maresin- like-1 (MaR1-L1) is 14S,22-dihydroxy 4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid. Maresin- like-2 (MaR-L2) is 14R,22-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid. MaR-L1 and MaR-L2 are 4S-hy- droxy and 14R-hydroxy metabolites of docosahexaenoic acid. These hydroxy metabolites can be converted by an unidentified cytochrome P450 enzyme to MaR-L1 and MaR-L2 by omega oxidation. Alternatively, DHA may be first metabolized to 22-hydroxy-docosahexaenoic acid by CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2E1 , or CYP3A4 and then metabolized through the cited epoxide- forming pathways to Mar-L1 and MaR-L2. In the context of the present application, the term “maresin” include MaR1 , MaR2, 7-epi-MaR1 , MaR-L1 and MaR-L2. In a particular embodiment, the maresin is maresin-1. In another embodiment, the maresin is maresin-2.

In an embodiment, the SPM is a n-3-docosapentaenoic acid-derived (n-3-DPA) maresin. In a particular embodiment, the n-3-DPA-maresin is selected from the group consisting of maresin 1 n-3, maresin 2 n-3, and maresin 3 n-3. Maresin 1 n-3 (MaR1 n-3) is 7S,14S-dihydroxy- 8E,10E,12Z,16Z,19Z-docosapentaenoic acid. Maresin 2 n-3 (MaR2n-3) is 13,14-dihydroxy- 7Z,9E,11 E,16Z,19Z-docosapentaenoic acid. Maresin 3 n-3 (MaR3n-3) is 4,21-dihydroxy- 7Z,10Z,12E,16Z,19Z-docosapentaenoic acid.

In an embodiment, the SPM is a D-series resolvin. In a particular embodiment, the D-series resolvin is selected from the group consisting of resolvin D1 , resolvin D2, resolvin D3 , resolvin D4, resolvin D5, resolvin D6, 17R-resolvin D1 , 17R-resolvin D2, 17R-resolvin D3 , 17R-Resolvin D4, 17R-Resol- vin D5 and 17R-Resolvin D6. Resolvin D1 (RvD1) is 7S,8R,17S-trihydroxy-4Z,9E,11 E,13Z,15E,19Z- docosahexaenoic acid. Resolvin D2 (RvD2) is 7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-do- cosahexaenoic acid. Resolvin D3 (RvD3) is 4S,11 R,17S-trihydroxy-5Z,7E,9E,13Z,15E,19Z-do- cosahexaenoic acid. Resolvin D4 (RvD4) is 4S,5R,17S-trihydroxy-6E,8E,10Z,13Z,15E,19Z-do- cosahexaenoic acid. Resolvin D5 (RvD5) is 7S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahex- aenoic acid. Resolvin D6 (RvD6) is 4S,17S-dihydroxy-5E,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid. These six D-series resolvins possess a 17S-hydroxy residue; however, if aspirin-treated cy- clooxygenase-2 is the initiating enzyme, they contain a 17R-hydroxy residue and are termed 17R- Resolvin D series or aspirin-triggered (AT)-resolving D series 1 thru 6. 17R-Resolvin D1 (17R-RvD1 ; AT-RvD1) is 7S,8R,17R-trihydroxy-4Z,9E,1 1 E,13Z,15E,19Z-docosahexaenoic acid. 17R-Resolvin D2 (17R-RvD2; AT-RvD2) is 7S,16R,17R-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid. 17R-Resolvin D3 (17R-RvD3; AT-RvD3) is 4S,11 R,17R-trihydroxy-5Z,7E,9E,13Z,15E,19Z-do- cosahexaenoic acid. 17R-Resolvin D4 (17R-RvD4; AT-RvD4) is 4S,5R,17R-trihydroxy- 6E,8E,10Z,13Z,15E,19Z-docosahexaenoic acid. 17R-Resolvin D5 (17R-RvD5; AT-RvD5) is 7S,17R- dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid. 17R-Resolvin D6 (17R-RvD6; AT-RvD6) is 4S,17R-dihydroxy-5E,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid.

In an embodiment, the SPM is a E-series resolvin. In a particular embodiment, the E-series resolvin is selected from the group consisting of resolvin E1 , 18S-resolvin E1 , resolvin E2 and resolvin E3. Resolvin E1 (RvE1) is 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid. 18S-re- solvin E1 (18S-RvE1) is 5S,12R,18S-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid. Resolvin E2 (RvE2) is 5S,18-dihydroxy-eicosa-6E,8Z,11Z,14Z,16E-eicosapentaenoic acid. Resolvin E3 (RvE3) is 17R,18R/S-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid.

In an embodiment, the SPM is a n-3 docosapentaenoic acid-derived (n-3 DPA) resolvin. In a particular embodiment, the n-3 DPA-resolvin is selected from the group consisting of resolvin T1 , resolvin T2, resolvin T3, resolvin T4, n-3 DPA resolvin D1 , n-3 DPA resolvin D2, and n-3 DPA resolvin D5. Resolvin T1 (RvT1) is 7S,13R,20S-trihydroxy-8E,10Z,14E,16Z,18E-docosapentaenoic acid. Resolvin T2 (RvT2) 7S,12R,13S-trihydroxy-8Z,10E,14E,16Z,19Z-docosapentaenoic acid. Resolvin T3 (RvT3) is 7S,8R,13S-trihydroxy-9E,1 1 E,14E,16Z,19Z-docosapentaenoic acid. Resolvin T4 (RvT4) 7S,13R-dihydroxy-8E,10Z,14E,16Z,19Z-docosapentaenoic acid, n-3 NPA Resolvin D1 (RvD1 n-3) is 7S,8R,17S-trihydroxy-9E,1 1 E,13Z,15E,19Z-docosapentaenoic acid, n-3 NPA Resolvin D2 (RvD2n- 3) is 7S,16R,17S-trihydroxy-8E,10Z,12E,14E,19Z-docosapentaenoic acid, n-3 NPA Resolvin D5 (RvD5n-3) is 7S,17S-dihydroxy-8E,10Z,13Z,15E,19Z-docosapentaenoic acid.

In an embodiment, the SPM is a protectin. In a particular embodiment, the protectin is selected from the group consisting of protectin D1 (also known as neuroprotectin D1), protectin DX, 22-hydroxy protectin D1 , 17-epi-protectin D1 , and 10-epi-protectin D1. Protectin or neuroprotectin D1 (PD1 or NPD1) is 10R,17S-dihydroxy-4Z,7Z,11 E,13E,15Z,19Z-docosahexaenoic acid. Protectin DX (PDX) is 10S,17S-dihydroxy-4Z,7Z,11 E,13Z,15E,19Z-docosahexaenoic acid. 22-hydroxy protectin D1 (22- hydroxy-PD1) is 10R,17S,22-trihydroxy-4Z,7Z,11 E,13E,15Z,19Z-docosahexaenoic acid. 17-epi-pro- tectin D1 (17-epi-PD1) also known as aspirin-triggered protectin D1 (AT-PD1) is 10R,17R-dihydroxy- 4Z,7Z,11 E,13E,15Z,19Z-docosahexaenoic acid. 10-epi-protectin D1 (10-epi-PD1) is 10S,17S-dihy- droxy-4Z,7Z,11 E,13E,15Z,19Z-docosahexaenoic acid.

In an embodiment, the SPM is a lipoxin. In a particular embodiment, the lipoxin is selected from the group consisting of lipoxin A4, lipoxin B4 and aspirin -triggered lipoxins (A4 and B4). Lipoxin A4 (LXA4) is 5S,6R,15S-trihydroxy-eicosa-7E,9E,11 Z,13E-eicosatetraenoic acid. Lipoxin B4 (LXB4) is 5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid. Aspirin-triggered lipoxins (AT-LXs) are a group of SPMs that are generated through the aspirin-acetylation of the enzyme cyclooxygen- ase-2 (COX-2), leading to the production of 15R-hydroxyeicosatetraenoic acid (15R-HETE), which subsequently undergoes transformation by 5-lipoxygenase (5-LOX) to form the aspirin-triggered lipoxins. Aspirin-triggered lipoxin A4 (AT-LXA4 or 15-epi-LXA4) is 5S,6R,15R-trihydroxy- 7E,9E,11 Z,13E-eicosatetraenoic acid. Aspirin-triggered lipoxin B4 (AT-LXB4 or 15-epi-LXB4) is 5S,14R,15R-trihydroxy-6E,8Z,10E,12E-eicosatrienoic acid.

In some embodiments, the SPM (e.g., maresin) is present in the composition in an amount from about 0.5 pg/ml to about 200 pg/ml, or from about 1 pg/ml to about 200 pg/ml, or from about 2 pg/ml to about 200 pg/ml, or from about 2 pg/ml to about 100 pg/ml, or from about 2 pg/ml to about 75 pg/ml, or from about 1 pg/ml to about 50 pg/ml, or from about 2 pg/ml to about 50 pg/ml, or from about 2 pg/ml to about 25 pg/ml, or from about 2 pg/ml to about 10 pg/ml. Particularly, the SPM (e.g., maresin) is present in an amount of about 2 pg/ml.

The dose to be administered will vary depending upon the age, weight, and general condition of the subject as well as the severity of the condition being treated, and the judgment of the health care professional. Therapeutically effective amounts can be determined by those skilled in the art and will be adjusted to the particular requirements of each particular case. For example, daily dosage may be higher during the treatment of active symptoms or may be lower for maintenance or prophylactic purposes. In some embodiments, the pharmaceutical composition comprises an effective amount of the SPM, particularly maresin. In some embodiments, SPM (e.g., maresin) is administered to the subject at a dosage from about 0.5 pg/kg to about 500 pg/kg, particularly of about 25 pg/kg per dose (e.g., in mouse).

In some embodiments, SPM (e.g., maresin) is administered to the subject at a dosage from about 0.01 pg/kg to about 50 pg/kg, or from about 0.05 pg/kg to about 40.5 pg/kg, and particularly of about 2 pg/kg per dose (e.g., in humans).

Solvent and cosolvents

The composition of the present invention comprises water as a solvent, and other substances to form a homogenous solution. In an embodiment, the water is selected from the group consisting of deionized water, purified water, distilled water and sterile water. In a particular embodiment, the water is deionized water.

The composition also comprises two organic solvents, which can also be referred to as cosolvents (i.e., first and second cosolvents). A cosolvent is a solvent that is added to a solution to enhance the solubility of a substance that is poorly soluble in the primary solvent, in this case, water. They are commonly used in pharmaceutical formulations, particularly in the preparation of oral dosage forms. Non-limiting examples of cosolvents commonly used in pharmaceutical formulations include alcohols (e.g., ethanol), glycols (e.g., propylene glycol), glycerin and its derivatives, sorbitol, dimethyl sulfoxide (DMSO), dimethylacetamide, almond oil, castor oil, corn oil (maize), cottonseed oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower oil, ethyl lactate, ethyl oleate, medium-chain triglycerides, triacetin, triethyl citrate, and triolein, among others.

As mentioned, the first cosolvent is an alcohol (e.g., ethanol, isopropanol, butanol). In a particular embodiment, the alcohol is ethanol.

In some embodiments, the second cosolvent is selected from the group consisting of a glycol, glycerin or its derivatives, sorbitol, and DMSO.

In an embodiment, the second cosolvent is a glycol. Particularly, the glycol is selected from the group consisting of propylene glycol, polyethylene glycol (PEG), butylene glycol, diethylene glycol (DEG), triethylene glycol (TEG), tetraethylene glycol (TTEG), dipropylene glycol (DPG) and polypropylene glycol (PPG).

In a particular embodiment, the glycol is propylene glycol. In another particular embodiment, the glycol is PEG. Particularly, the PEG is selected from the group consisting of PEG 200, PEG 300, PEG 400, and PEG 600. In a more particular embodiment, the PEG is PEG 400.

In an embodiment, the second cosolvent is glycerin or its derivatives. Non-limiting examples of derivatives are glycerol formal, isopropylidene glycerol, and methylene glycerol.

In a particular embodiment, the first cosolvent is an alcohol and the second cosolvent is a glycol, and more particularly, the first cosolvent is ethanol and the second cosolvent is propylene glycol.

In some embodiments, the first cosolvent and the second cosolvent are present in a volume ratio of about 1 :4 (i.e., 1 :4 alcohol:second cosolvent).

The oral composition of Example 1 .2 comprises 0.5 ml of ethanol 96° and 2 ml of propylene glycol in a total volume of 110 ml. Therefore, the ethanol 96° represents 0.45% v/v (volume fraction), while the propylene glycol represents 1 .82% v/v of the oral composition.

Accordingly, in some embodiments, the first cosolvent is present up to a maximum of about 50% v/v of the total volume. In some embodiments, the first cosolvent is present in an amount of between about 0.01 % v/v and about 50% v/v, between about 0.01 % v/v and about 20% v/v, or between about 0.05% v/v and about 20% v/v, or between about 0.1 % v/v and about 20% v/v, or between about 0.1 % v/v and about 10% v/v, or between about 0.02% v/v and about 5% v/v, or between about 0.02% v/v and about 2.5% v/v.

In some embodiments, the first cosolvent is present in an amount of about: 0.01 %, 0.05%, 0.1 %, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4% , 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1 .1 %, 1.15%, 1.2%, 1 .25%, 1.3%, 1.35%, 1 .4% , 1 .45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, 2.0%, 2.1 %, 2.15%, 2.2%, 2.25%, 2.3%, 2.35%, 2.4% , 2.45%, or 2.5% v/v. In a particular embodiment, the first cosolvent is present in an amount of about 0.45% v/v. In another particular embodiment, the first cosolvent is present in an amount of about 2.5% v/v.

In some embodiments, the second cosolvent is present up to a maximum of about 60% v/v of the total volume. In some embodiments, the second cosolvent is present in an amount of between about 0.1 % v/v and about 60% v/v, or between about 0.5% v/v and about 50% v/v, or between about 1 % v/v and about 40% v/v, or between about 1 % v/v and about 30% v/v, or between about 1 .5% v/v and about 20% v/v, or between about 1 .5% v/v and about 10% v/v, or between 1 .5% v/v and about 5% v/v, or between 1 .5% v/v and about 3% v/v, or between about 0.1 % v/v to about 6% v/v. In some embodiments, the second cosolvent is present in an amount of about: 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9% v/v, or 3.0% v/v. In a particular embodiment, the first cosolvent is in an amount of about 1.8% v/v. In a particular embodiment, the first cosolvent is in an amount of about 3% v/v.

In some embodiments, the first and second cosolvents are present up to a maximum of about 80% v/v. Particularly, the first cosolvent is present up to a maximum of about 50% v/v, or about 20% v/v, and the second cosolvent is present up to a maximum of about 60% v/v. In a particular embodiment, the sum of the volume ratio of the first cosolvent and the second cosolvent does not exceed 100% v/v of the total volume. In some embodiments, the first and second cosolvents are present in an amount of between about 1 % v/v and about 80% v/v, or between about 2% v/v and about 50% v/v. Particularly, the first and second cosolvents are present in an amount of about 1 % v/v, about 2.5% v/v, about 5% v/v, or about 10% v/v, particularly of about 2.5% v/v.

In another embodiment, the sum of the volume ratio of the solvent, the first cosolvent and the second cosolvent does not exceed 100% v/v of the total volume.

Antioxidants

In some embodiments, the composition further comprises at least one antioxidant. An antioxidant is a substance that helps prevent or inhibit oxidation reactions to ensure well preservation of a product. Sulfites are among the most effective antioxidants for the purpose of the present invention, but other compounds can also be used, such as hydroquinone, phenolic antioxidants, nordihydroguaiaretic acid (NDEA), gallates or gallato compounds, benzoic acid or benzoates, vitamin antioxidants (e.g., vitamin C, vitamin E), citric acid or citrates, among others.

In some embodiments, the antioxidant is selected from the group consisting of a sulfite, hydroquinone, a phenolic antioxidant, nordihydroguaiaretic acid (NDEA), a gallates or a gallato compound (e.g., gallic ester), benzoic acid or a benzoate, vitamin antioxidants, and citric acid or a citrate.

In a particular embodiment, the antioxidant is a sulfite. In some embodiments, the sulfite is selected from the group consisting of a sulfite, a bisulfite, a metabisulfite, and a salt thereof. Particularly, the salt is formed with a monovalent or divalent cation, more particularly with sodium, potassium or calcium. In a particular embodiment, the sulfite salt is selected from the group consisting of a sodium salt (e.g., sodium sulfite Na2SOs, sodium bisulfite NaHSCh, sodium metabisulfite N32S2O5), a potassium salt (e.g., potassium sulfite K2SO3, potassium metabisulfite K2S2O5), a calcium salt (e.g., calcium sulfite CaSOs, calcium metabisulfite CaS2C>5), or a magnesium salt. In a particular embodiment, the antioxidant is sodium metabisulfite. In another particular embodiment, the antioxidant is sodium bisulfite.

In some embodiments, the composition comprises a combination of antioxidants. In a particular embodiment, the antioxidant is sodium metabisulfite and sodium bisulfite.

In a particular embodiment, the antioxidant is a phenolic antioxidant. In an embodiment, the phenolic antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and propyl gallate. Particularly, the antioxidant is BHA or BHT.

In a particular embodiment, the antioxidant is a gallate or a gallato compound. In an embodiment, the gallate or gallato compound is selected from the group consisting of gallic acid, ethyl gallate, propyl gallate, octyl gallate, dodecyl gallate, lauryl gallate, stearyl gallate, tetradecyl gallate, pentadecyl gallate and hexadecyl gallate.

In a particular embodiment, the antioxidant is benzoic acid or its salts (benzoates). In an embodiment, the benzoate is selected from the group consisting of sodium benzoate, potassium benzoate, benzyl benzoate, and a parahydrozybenzoate.

In a particular embodiment, the antioxidant is citric acid or its salts (citrates). In an embodiment, the citrate is selected from the group consisting of sodium citrate, potassium citrate, calcium citrate, magnesium citrate, and citric acid monohydrate.

In a particular embodiment, the antioxidant is a vitamin antioxidant. In an embodiment, the vitamin is ascorbic acid (vitamin C) or its derivatives; or vitamin E or its derivatives. In an embodiment, vitamin C derivatives can include ascorbyl palmitate and sodium ascorbate. In an embodiment, vitamin E can be tocopherol (alpha tocopherol, beta tocopherol, gamma tocopherol, delta tocopherol), vitamin E polyethylene glycol succinate or vitamin E acetate.

In some embodiments, the antioxidant can also be selected from the group consisting of malic acid, fumaric acid, phosphoric acid, propionic acid, carbon dioxide, chelating agents, ethyl oleate, sodium formaldehyde sulfoxylate, sodium thiosulfate, sulfur dioxide, erythorbic acid, methionine, monothioglycerol, synergists (like citric acid monohydrate and tartaric acid), and thymol.

The oral composition of Example 1.2 comprises 0.1 g of sodium metabisulfite and 0.1 g of sodium bisulfite in a total volume of 110 ml. Therefore, the sodium metabisulfite represents 0.09% w/v (weight/volume, expressed in g/ml), while the propylene glycol represents 0.09% w/v of the oral composition. Accordingly, in some embodiments, the antioxidant is present up to a maximum of about 1 % w/v.

In some embodiments, the antioxidant is present in an amount of between about 0.01 % w/v and about 1 % w/v, or between about 0.05% w/v and about 1 % w/v, or between about 0.1% w/v and about 1 % w/v, or between about 0.2% w/v and about 1 % w/v.

In some embodiments, the antioxidant is present in an amount of about: 0.01 %, 0.05%, 0.1 %, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, or 1.0% w/v. In a particular embodiment, the antioxidant is present in an amount of about 0.18% w/v.

Preservatives

In some embodiments, the composition further comprises at least one preservative. Preservatives are substances added to pharmaceutical formulations to prevent microbial growth and maintain product stability over time. They are used in multidose formulations to ensure that the solution remains sterile and safe for repeated use.

If the composition is in the form of monodose, preservatives become dispensable. Instead, an alternative approach could involve saturating the product's atmosphere with nitrogen gas (N2). This method creates a low-oxygen environment, inhibiting microbial growth and maintaining the sterility and stability of the monodose solution without the need for preservatives.

In some embodiments, the preservative is an antifungal preservative, an antimicrobial preservative, or a combination thereof.

Various types of preservatives are commonly used in pharmaceutical solutions. In some embodiments, the preservative is selected from the group consisting of benzoic acid or its salts (benzoates) (e.g., sodium benzoate or potassium benzoate), benzylic acid, benzyl compounds (e.g., benzalkonium chloride), sorbic acid or its salts (sorbates) (e.g., potassium sorbate), a parahydroxybenzoate (e.g., methylparaben or propylparaben) or its salts, chlorohexidine, chlorobutanol, chloroxylenol, thimerosal, sulfites or its salts, and xylitol, among others.

In a particular embodiment, the preservative is a parahydroxybenzoate. In an embodiment, the parahydroxybenzoate is selected from the group consisting of methylparaben (also referred to as methyl arahydroxybenzoate, e.g., Nipagin M), ethylparaben, propylparaben (also referred to as propyl parahydroxybenzoate, e.g., Nipasol M), butylparaben, isobutylparaben, and a salt thereof. Particularly, the salt is formed with a monovalent cation, more particularly with sodium or potassium. In a partic- ular embodiment, the salts of a parahydroxybenzoate can be sodium salts (e.g., sodium methylparaben, sodium ethylparaben, sodium propylparaben, sodium butylparaben, sodium isobutylparaben) or potassium salts (e.g., potassium methylparaben, potassium ethylparaben, potassium propylparaben, potassium butylparaben, potassium isobutylparaben). In a more particular embodiment, the parahydroxybenzoate is methylparaben. In another embodiment, the parahydroxybenzoate is propylparaben.

In some embodiments, the composition comprises a combination of preservatives. In a particular embodiment, the preservatives are methylparaben and propylparaben.

In a particular embodiment, the preservative is benzoic acid or its salts (benzoates). In an embodiment, the benzoate is selected from the group consisting of sodium benzoate, potassium benzoate, benzyl benzoate, and a parahydroxybenzoate.

In a particular embodiment, the preservative is a benzyl compound. In an embodiment, the benzyl compound is selected from the group consisting of benzyl alcohol, benzalkonium chloride, and ben- zethonium chloride.

In a particular embodiment, the preservative is sorbic acid or its salts (sorbates). In an embodiment, the sorbate is selected from the group consisting of potassium sorbate, calcium sorbate, and sodium sorbate.

The oral composition of Example 1 .2 comprises 0.2 g of Nipagin M and 0.02 g of Nipasol M in a total volume of 110 ml. Therefore, Nipagin M represents 0.18% w/v (weight/volume, expressed in g/ml), while Nipasol M represents 0.018% w/v of the oral composition.

Accordingly, in some embodiments, the preservative is present in an amount of about: 0.01 % 0.05%, 0.1 %, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, or 1 .0% w/v. In a particular embodiment, the preservative is present in an amount of about 0.2% w/v.

In some embodiments, the preservative is present in an amount of between about 0.01 % w/v and about 1 % w/v, or between about 0.05% w/v and about 1 % w/v, or between about 0.1% w/v and about 1 % w/v.

In some embodiments, the preservative is present up to a maximum of about 1 % w/v. Particularly, the total amount of antioxidants and preservatives is present up to a maximum of about 1 % w/v.

Other components In some embodiments, the composition of the present invention further comprises other components selected from the group consisting of a surfactant, a chelating agent, a buffer, a precipitation inhibitor agent, a permeability enhancer, a stabilizing agent, a pH modifier, and a complexation agent.

In an embodiment, the composition further comprises at least one surfactant. Surfactants can be used to aid solubilization in formulations by acting on the specific surface of the substance so that it can dissolve in a solvent (e.g., water). Non-limiting examples of surfactants can be sorbitan fatty acid esters; polysorbates prepared from lauric, palmitic, stearic, and oleic acids; polyoxyethylene monoesters such as polyoxyethyl ethylene monostearate, polyoxyethylene monolaurate, and polyoxyethylene monooleate; glycerol monostearate; sorbitan esters; polysorbate 80; polyoxyethylene sorbitan monooleate; polyoxyl stearate macrogol ethers; polyoxyethylene; macrogolglycerol esters; caprylocaproyl macrogol-8 glycerides; PEG-8 caprylic/capric glycerides; macrogol glycerol hydroxystearate; polyoxyl 35 castor oil; macrogol glycerolhydroxystearate; polyoxyl 40 hydrogenated castor oil; macrogolglycerides such as caprylocaproyl polyoxylglycerides, lauroyl polyoxylglycerides such as hydrogenated coconut oil PEG 1500 esters, Gelucire 44/14; stearoyl polyoxylglycerides; PEG-8 beeswax; polyethyleneglycol derivatives; polyoxyethylene castor oil derivatives; polyoxyethylene alkyl ethers; polyoxyethylene stearates; mixture of glycerol monostearate and PEG-75 stearate beeswax; and glyceryl monostearate polyoxylethylene stearates; among others.

In an embodiment, the surfactant can be an ionic surfactant (anionic or cationic surfactant) or a nonionic surfactant. Particularly, the non-ionic surfactant is selected from the group consisting of alkyl polyglucosides (e.g., decyl glucoside, lauryl glucoside), polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), c/-a-tocopherol polyethylene glycol 1000 succinate (TPGS), Solutol HS-15, sorbitan mono-oleate (Span 80), polyoxyl 40 stearate, and a polyglycolyzed glyceride (e.g., Labrafil M- 1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, and Softigen 767). More particularly, the non-ionic surfactant is polyoxyl castor oil.

In some embodiments, the composition further comprises a chelating agent and includes, but is not limited to, ethylenediaminetetraacetic acid (EDTA), disodium EDTA, calcium disodium edetate, tartaric acid, malic acid and citric acid.

In some embodiments, the composition further comprises a buffer such as an acetate, a citrate and a phosphate.

In some embodiments, the composition further comprises a precipitation inhibitor agent and includes, but is not limited to, hypromellose (HPMC), hypromellose acetate succinate, hypromellose phthalate, poloxamer and their derivatives, cyclodextrin and their derivatives, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, vinylpyrrolidone-vinyl acetate copolymer, and mixtures thereof.

In some embodiments, the composition further comprises other excipients like permeability enhancers, stabilizing agents, pH modifiers, and complexation agents. Examples of suitable permeability enhancer include, but are not limited to, phospholipid and their derivatives, phosphatidylcholine, lecithin and their derivatives and mixtures thereof. Examples of suitable stabilizing agents are cyclodextrins, which can increase the equilibrium solubility of some hydrophobic molecules. Non-limiting examples of cyclodextrins are alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, hydroxypropyl cyclodextrins, methylated cyclodextrins, and sulfobutylether cyclodextrins. Examples of suitable pH modifier include, but are not limited to, megulamine and their derivatives, sodium hydroxide and their derivatives, sodium bicarbonate and their derivatives, hydrochloric acid, and mixtures thereof. Examples of suitable complexation agents include, but are not limited to, cyclodextrin and derivatives, phospholipids and derivatives and mixtures thereof.

Particular embodiments

As will be apparent to those skilled in the art upon reading this description, each of the individual embodiments described and illustrated herein have discrete components and features which can be combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Particular combinations of the above embodiments detailed in different sections are described herein.

The invention relates to a composition comprising a specialized pro-resolving lipid mediator, a first cosolvent which is an alcohol, a second cosolvent and water, wherein:

- the specialized pro-resolving lipid mediator is a maresin, particularly maresin-1 ;

- the water is deionized water;

- the first cosolvent is ethanol; and

- the second cosolvent is a glycol, particularly propylene glycol;

In an embodiment, the composition further comprises at least one antioxidant, particularly a sulfite, and more particularly sodium metabisulfite and/or sodium bisulfite.

In an embodiment, the composition further comprises at least one preservative, particularly a parahydroxybenzoate, more particularly methylparaben and/or propylparaben. Particularly, the first cosolvent and the second cosolvent have a volume ratio of about 1 :4. Particularly, first cosolvent is up to a maximum of about 50% v/v (or 20% v/v), and the second cosolvent is up to a maximum of about 60% v/v. Particularly, the antioxidant and preservative are up to a maximum of about 1 % w/v. In a particular embodiment, the sum of the volume ratio of the first cosolvent and the second cosolvent does not exceed 100% v/v of the total volume. The invention also relates to a composition comprising:

- from about 1 pg/ml to about 200 pg/ml maresin, or from about 2 pg/ml to about 50 pg/ml maresin, particularly 2 pg/ml maresin;

- from about 0.1% v/v to about 20% v/v alcohol (e.g., ethanol);

- from about 1% v/v to about 60% v/v glycol (e.g., propylene glycol); and

- q.s. deionized water.

The invention also relates to a composition comprising:

- from about 1 pg/ml to about 200 pg/ml maresin, particularly 2 pg/ml maresin;

- from about 0.1% v/v to about 20% v/v alcohol (e.g., ethanol);

- from about 1% v/v to about 60% v/v glycol (e.g., propylene glycol);

- from about 0.1 % w/vto about 1% w/v antioxidant (e.g., sodium metabisulfite and sodium bisulfite);

- from about 0.1 % w/vto about 1% w/v preservative (e.g., methylparaben and propylparaben); and

- q.s. deionized water.

The invention also relates to a composition comprising:

- about 2 pg/ml maresin-1 ;

- about 0.45% v/v ethanol;

- about 1 .82% v/v propylene glycol; and

- q.s. deionized water.

The invention also relates to a composition comprising:

- about 2 pg/ml maresin-1 ;

- about 0.45% v/v ethanol;

- about 1 .82% v/v propylene glycol;

- about 0.09% w/v sodium metabisulfite;

- about 0.09% w/v sodium bisulfite;

- about 0.18% w/v methylparaben;

- about 0.018% w/v propylparaben; and

- q.s. deionized water.

In an embodiment, the invention relates to an oral solution comprising:

- maresin-1 in an amount from 1 pg/ml to 50 pg/ml,

- a first cosolvent which is ethanol,

- a second cosolvent consisting of a glycol in an amount from 0.1% v/v to 6% v/v, and

- water. In a particular embodiment, the second cosolvent consists of a glycol selected from the group consisting of ethylene glycol, propylene glycol, polyethylene glycol, butylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol and polypropylene glycol. Particularly, the glycol is propylene glycol. More particularly, wherein the first cosolvent and the second cosolvent are present in a volume ratio of about 1 :4.

In a particular embodiment, the oral solution further comprises at least one antioxidant. Particularly, the antioxidant is selected from the group consisting of a sulfite, hydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, nordihydroguaiaretic acid, a gallate or a gallato compound, benzoic acid or a benzoate, ascorbic acid, vitamin E, and citric acid or a citrate. More particularly, the antioxidant is a sulfite selected from the group consisting of a sulfite, a bisulfite, a metabisulfite, and a salt thereof, wherein the salt is selected from the group consisting of a sodium salt, a potassium salt, and a calcium salt, particularly, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, calcium sulfite, and calcium metabisulphite. Even more particularly, the antioxidant is sodium metabisulfite and sodium bisulfite.

In another particular embodiment, the oral solution further comprises at least one preservative which is an antifungal preservative, an antimicrobial preservative, or a combination thereof. Particularly, the preservative is a parahydroxybenzoate selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, and a salt thereof. More particularly, the preservative is methylparaben and propylparaben.

In a particular embodiment, the oral solution comprises:

- from 1 pg/ml to 50 pg/ml maresin, particularly 2 pg/ml maresin;

- from 0.1 % v/v to 20% v/v ethanol;

- from 0.1 % v/v to 60% v/v propylene glycol;

- from 0.1 % w/v to 1 % w/v sodium metabisulfite and sodium bisulfite;

- from 0.1 % w/v to 1 % w/v methylparaben and propylparaben; and

- water.

More particularly, the oral solution comprises:

- 2 pg/ml maresin-1 ;

- 0.45% v/v ethanol;

- 1 .82% v/v propylene glycol;

- 0.09% w/v sodium metabisulfite and 0.09% w/v sodium bisulfite;

- 0.18% w/v methylparaben and 0.018% w/v propylparaben; and

- water.

Medical uses As discussed previously, Example 2 of the present invention provides evidence of the neurological beneficial effects of the new maresin formulation described herein in a EAE mice model which reproduces multiple sclerosis (MS); and Example 3 in SOD1-G93A mice model which reproduces amyotrophic lateral sclerosis (ALS).

The induction of EAE in control mice leads to demyelination that in turn, causes functional deficits and paralysis of both hind limbs and weakness in front limbs. The EAE mouse model is useful as a model of MS disease, but can be extended to other autoimmune diseases characterized by demyelination. Diseases that meet these characteristics and are similar to MS disease are Guillain-Barre Syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and optic neuritis (ON).

MS and ON are extremely related. In fact, more than half of all people with MS experience ON at some point and the risk of developing MS after one episode of ON is about 50% over a lifetime. GBS, CIDP and ON are autoimmune diseases characterized by demyelination and have the same mechanism as for MS, since it is the immune system that attacks myelin. Indeed, animal models of MS, GBS, CIDP and ON are induced by using similar immunization protocols against different myelin peptides and exhibit similar clinical features.

SOD1-G93A transgenic mice are used as a model of ALS which is representative of other neuro- degenerative diseases characterized by locomotor loss as a consequence of lower motor neuron and/or upper motor neuron death. Diseases that meet these characteristics similar to ALS and are termed as motor neuron diseases are primary lateral sclerosis (PLS), progressive bulbar palsy (PBP), progressive muscular atrophy (PMA) and spinal muscular atrophy (SMA).

Furthermore, possible uses of maresin are described in WO2018134230A1 and W02019016580A1 , which are herein incorporated by reference in their entirety. These patent applications, from which some of the inventors are the same as the present application, demonstrate the use of maresin for neurodegenerative diseases such as amyotrophic lateral sclerosis (SOD1-G93A mice model), autoimmune diseases such as multiple sclerosis (EAE mice model), and central nervous system injuries such as spinal cord injury or traumatic brain injury (e.g., spinal cord contusion injury mice model).

Mice spinal cord contusion injury models are used as a model of SCI injury which is representative of other central nervous system injuries characterized by motor, sensory and autonomic loss due to disruption of ascending and descending axonal pathways in the spinal cord, neuronal and myelin loss. Diseases that meet these characteristics similar to SCI are traumatic brain injury (TBI), brain and spinal cord ischemia and/or hemorrhage and nerve injury, degenerative spine disease, epidural abscesses, and brain and/or spinal cord infections (e.g. herpes virus, HIV, neurosyphilis, etc). The inventors of the present invention have demonstrated that a new oral composition of maresin significantly improves the outcome of multiple sclerosis in a EAE mice model and of amyotrophic lateral sclerosis in a SOD1-G93A transgenic mice. Thus, it is plausible to conclude that the new maresin oral formulation would be equally suitable for neurodegenerative diseases and central nervous system injuries.

Accordingly, another aspect relates to a composition as defined herein, for use as a medicament.

An aspect of the present invention also relates to a composition as defined herein, for use in the treatment of a neurological disease.

Neurological diseases include neurodegenerative diseases, autoimmune diseases, and injuries to the nervous system, among others.

In an embodiment, the neurological disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, schizophrenia, depression, manic depression, neurodevelopmental disorder, autism, migraine, spinal cord injury, traumatic brain injury, stroke, Guillain-Barre syndrome, peripheral neuropathy, muscular dystrophy, Tourette syndrome, spinal muscular atrophy, cerebral palsy, restless legs syndrome, myasthenia gravis, Charcot-Marie-Tooth disease, fibromyalgia, spinocerebellar ataxia, dystonia, Rett syndrome, narcolepsy, chronic inflammatory demyelinating polyneuropathy, polyradiculoneuropathy (CIDP), optic neuritis (ON), neurofibromatosis, Friedreich's ataxia, Batten disease, Creutzfeldt-Jakob disease, Krabbe disease, Machado-Joseph disease, Niemann-Pick disease, prion diseases, Leigh syndrome, Wilson's disease, Alexander disease, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), Landau- Kleffner syndrome, nenign paroxysmal positional vertigo (BPPV), Shy-Drager syndrome, primary lateral sclerosis (PLS), progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), progressive supranuclear palsy (PSP), monomelic amyotrophy, tardive dyskinesia, neurosyphilis, central pontine myelinolysis, opsoclonus-myoclonus syndrome, stiff person syndrome, hyperekplexia, spinocerebellar degeneration, and neurological manifestations of systemic diseases (e.g., lupus, sarcoidosis).

In a particular embodiment, the neurological disease is selected from the group consisting of multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, optic neuritis, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, spinal and bulbar muscular atrophy, monomelic amyotrophy, spinal cord injury, traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, schizophrenia, depression, manic depression, neurodevelopmental disorder, autism, migraine, and stroke. In a more particular embodiment, the neurodegenerative disease is selected from the group consisting of multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury and traumatic brain injury.

An aspect of the present invention also relates to a composition as defined herein, for use in the treatment of a neurodegenerative disease.

In an embodiment, the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, spinal muscular atrophy, spinal bulbar muscular atrophy (SBMA), monomelic amyotrophy, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD), Lewy body dementia (LBD), spinocerebellar ataxia (SCA), Charcot-Marie-Tooth disease (CMT), Friedreich's ataxia, Krabbe disease, Machado-Joseph disease, Niemann-Pick disease, Huntington's disease-like 2 (HDL2), dentatorubral-pallidoluysian atrophy (DRPLA), Lafora disease, Wilson's disease, Batten disease, and lysosomal storage diseases (e.g., Tay-Sachs disease, Gaucher's disease).

In a particular embodiment, the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

In an embodiment, the neurodegenerative disease is characterized by motor neuron degeneration. Particularly the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, primary lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, spinal and bulbar muscular atrophy, and monomelic amyotrophy. In a more particular embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis.

In another embodiment, the administration of the composition of the invention results in at least one outcome (i.e., effect) selected, but not limited to, from the group consisting of:

- reduction of locomotor loss;

- reduction of motor neuron loss (functional loss);

- reduction of electrophysiological loss;

- reduction of paralysis,

- preservation of neuro-muscular integrity; and

- a combination thereof.

Another aspect of the present invention relates to a composition as defined herein, for use in the treatment of an autoimmune disease. In an embodiment, the autoimmune disease is selected from the group consisting of multiple sclerosis (MS), Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), optic neuritis (ON), HIV dementia, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, celiac disease, vitiligo, Sjogren's syndrome, autoimmune hepatitis, Addison's disease, myasthenia gravis, pemphigus vulgaris, autoimmune hemolytic anemia, ankylosing spondylitis, polymyositis, dermatomyositis, and reactive arthritis.

In a particular embodiment, the autoimmune disease is selected from the group consisting of multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, optic neuritis, HIV dementia, inflammatory bowel disease, psoriasis, rheumatoid arthritis and systemic lupus erythematosus.

In an embodiment, the autoimmune disease is characterized by the attack of myelin antigens that lead to demyelination. Particularly, the autoimmune disease is selected from the group consisting of multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy and optic neuritis. Particularly, the autoimmune disease is multiple sclerosis.

In another embodiment, the administration of the composition of the invention results in a reduction of demyelination.

Another aspect of the present invention relates to a composition as defined herein, for use in the treatment of an injury to the nervous system. In a particular embodiment, the injury to the nervous system can be a central nervous system (CNS) injury, a peripheral nervous system injury or an injury related to ischemia.

In an embodiment, the CNS injury is selected from the group consisting of neurological traumas and injuries, surgery related trauma and/or injury, retinal injury and trauma, injury related to epilepsy, spinal cord injury, traumatic brain injury, brain injury, brain surgery, trauma related brain injury, trauma related to spinal cord injury, brain injury related to cancer treatment, spinal cord injury related to cancer treatment, brain injury related to infection, brain injury related to inflammation, spinal cord injury related to infection, spinal cord injury related to inflammation, brain injury related to environmental toxin, and spinal cord injury related to environmental toxin. In a particular embodiment, the CNS injury is a spinal cord injury (SCI) or a traumatic brain injury.

In an embodiment, the peripheral nervous system injury is selected from the group consisting of diabetic neuropathy, peripheral neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, traumatic neuropathy, compression neuropathy, stretch injuries, Guillain-Barre syndrome, multifocal motor neuropathy, chemotherapy-induced neuropathy, alcoholic neuropathy, HIV/AIDS neuropathy, Lyme disease neuropathy, Charcot-Marie-Tooth disease, radiculopathy, sciatica, entrapment neuropathies, and brachial plexus injury.

In an embodiment, the injury related to ischemia is selected from the group consisting of brain ischemia, spinal cord ischemia, and retinal ischemia.

In another embodiment, the administration of the composition of the invention results in at least one outcome (i.e., effect) selected, but not limited to, from the group consisting of:

- increased myelin content at the injury epicenter;

- improved neuronal survival at the injury epicenter;

- improved locomotor recovery;

- reduced demyelination at the injury epicenter;

- reduced axonal damage at the injury epicenter; and

- a combination thereof.

Another aspect of the present invention relates to a composition as defined herein for use in the treatment of other diseases, such as inflammation, inflammation-related diseases or conditions, chronic pain, neuropathic pain, and depression concomitant with depression.

In an aspect, the composition is for use in the treatment of inflammation, or inflammation-related diseases or conditions. In a particular embodiment, the inflammation-related diseases or condition is selected from the group consisting of psoriasis, rheumatoid arthritis, psoriatic arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, lupus, sarcoidosis, atherosclerosis, diabetes, and cancer.

In an embodiment, the administration of the composition of the invention results in the reduction in inflammation, particularly:

- enhanced neutrophil clearance;

- resolution of neutrophil inflammation;

- late macrophages clearance;

- reduced macrophage accumulation;

- reduced chemokine expression; and/or

- attenuation of secondary tissue damage.

In an aspect, the composition is for use in the treatment of chronic pain. Common types of chronic pain include arthritis, fibromyalgia, back pain, cancer pain, headaches (including migraines), inflammatory bowel disease, endometriosis, sciatica, neck pain, or diabetes, among others. In an aspect, the composition is for use in the treatment of neuropathic pain. Common types of neuropathic pain include diabetes, AIDS, stroke, multiple sclerosis, Parkinson's disease, shingles, trauma, lupus, or Guillain-Barre syndrome, among others.

In an aspect, the composition is for use in the treatment of depression concomitant with depression.

In an embodiment, the administration of the composition results in the reduction in pain and/or depression, particularly:

- reduction in pain severity;

- decreased frequency of pain episodes;

- improved functioning (e.g., improved mobility, decreased muscle tension, less fatigue);

- improved emotional well-being (e.g., improved mood, reduced anxiety, better sleep);

- improved cognitive symptoms (e.g., improved concentration);

- reduction in anxiety symptoms, and/or

- increased social engagement.

Alternatively, the invention also encompasses a method of treating a neurological disease; or a neu- rodegenerative disease (e.g., ALS); or an autoimmune disease (e.g., MS); or an injury to the nervous system (e.g., SCI); or other diseases such as inflammation, inflammation-related diseases or conditions, chronic pain, neuropathic pain, and depression concomitant with depression; in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a composition as defined herein.

In addition to the therapeutic applications described herein, the present invention also relates to the composition as defined herein for use in the prophylaxis and/or prevention of the various diseases or conditions described herein (e.g., neurological diseases such as ALS and MS). Accordingly, all aspects and embodiments described in the context of the treatment are equally applicable, mutatis mutandis, to the prophylactic or preventive use of the composition defined herein for the same diseases or conditions.

The invention is focused on human applications, but the subject can also be a different mammalian subject for veterinary purposes, e.g., 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). Therefore, in an embodiment, the subject is a human. In another embodiment, the subject is a mammal. In a particular embodiment, the mammal is a domestic animal, a farm animal or a laboratory animal.

In an embodiment, the invention relates to an oral solution comprising:

- maresin-1 , - a first cosolvent which is ethanol,

- a second cosolvent selected from the group consisting of a glycol, glycerin or its derivatives, sorbitol, and dimethyl sulfoxide, and

- water, for use in the treatment of a neurological disease.

In a particular embodiment, the second cosolvent is a glycol, particularly propylene glycol. Particularly, maresin-1 is present in an amount of 2 pg/ml. More particularly, the first cosolvent and the second cosolvent are present in a volume ratio of about 1 :4.

In a particular embodiment, the neurological disease is selected from the group consisting of multiple sclerosis (MS), Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), optic neuritis (ON), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), spinal and bulbar muscular atrophy (SMA), monomelic amyotrophy, spinal cord injury, traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, schizophrenia, depression, manic depression, neurodevelopmental disorder, autism, migraine, and stroke. Particularly, the neurological disease is amyotrophic lateral sclerosis. Particularly, the neurological disease is multiple sclerosis.

Methods of preparation

Regarding the preparation of the composition of the present invention is within the scope of ordinary person skilled in the art and will depend upon the final dosage formulation.

An aspect of the present invention relates to a method of preparing a composition (e.g., oral composition) comprising: a) preparing a solution by mixing a second cosolvent (e.g., propylene glycol) with a solution of a SPM (e.g., maresin) in a first cosolvent (e.g., alcohol); and b) adding the desired volume of a solvent (e.g., deionized water) to the solution obtained in (a).

In some cases, the composition further comprises at least one antioxidant, which would be added to the solvent solution. Accordingly, in an embodiment, the method of preparing a composition comprises: a) providing a solution of a SPM (e.g., maresin) in a first cosolvent (e.g., alcohol); b) preparing a first solution by homogenizing with agitation a pre-weighed amount of an antioxidant (e.g., sodium metabisulfite and sodium bisulfite) in a solvent (e.g., deionized water); c) adding the desired volume of a second solution with a second cosolvent (e.g., propylene glycol) to the first solution obtained in (b); and d) adding the desired volume of the solution of the SPM in the first cosolvent referred in (a) to the obtained solution (c).

In other cases, the composition further comprises at least one preservative. In this case, it is necessary to heat the second cosolvent. Accordingly, in an embodiment, the method of preparing a composition comprises: a) providing a solution of a SPM (e.g., maresin) in a first cosolvent (e.g., alcohol); b) preparing a first solution by homogenizing with agitation a pre-weighed amount of an antioxidant (e.g., sodium metabisulfite and sodium bisulfite) in a solvent (e.g., deionized water); c) preparing a second solution by heating a second cosolvent (e.g., propylene glycol); d) weighting and adding a preservative (e.g., Nipagin M and Nipasol M) to the heated cosolvent obtained in (c), and stirring the solution until complete dissolution; e) adding the desired volume of the second solution obtained in (d) to the first solution obtained in (b); and d) adding the desired volume of the solution of the SPM in the first cosolvent referred in (a) to the obtained solution (e).

In some embodiments, the heating of step (c) is between about 40°C and about 75°C, particularly about 50°C and about 60°C.

In an embodiment, the specialized pro-resolving lipid mediator is maresin. In another embodiment, the solvent is water, particularly deionized water. In another embodiment, the first cosolvent is an alcohol, particularly ethanol. In another embodiment, the second cosolvent is a glycol, particularly propylene glycol. In another embodiment, the antioxidant is a sulfite, particularly sodium metabisulfite and sodium bisulfite.

As will be apparent to those skilled in the art, each of the individual embodiments described in section "Composition" can be combined with the features of the method of preparation. For example, the first cosolvent and the second cosolvent mentioned in the method of preparation can be in a volume ratio of about 1 :4.

The method can further involve the addition other excipients or ingredients usually employed in the art.

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

A particular embodiment for the method of preparation is detailed in Example 1 .2, which mentions the specific amounts of the compounds. EXAMPLES

EXAMPLE 1. Preparation of the maresin oral solutions and control solution

The objective of this example is the preparation of an oral solution of maresin with a concentration of 2 pg/ml.

1.1 Preparation of the vehicle oral formulation (new formulation), referred herein to as "vehicle" Sodium metabisulfite (0.1 g) and sodium bisulfite (0.1 g) were first weighed. Solution A wasprepared by dissolving the pre-weighed sodium metabisulfite and sodium bisulfite in 105 ml of deionized water with agitation. For the preparation of Solution B, 10 ml of propylene glycol were heated to 50-60°C in a graduated cylinder. Next, 1 g of Nipagin M and 0.1 g of Nipasol M were added, and the mixture was stirred until complete dissolution. Subsequently, 2 ml of Solution B were added to Solution A, followed by the addition of 0.5 ml of 96° ethanol to the formed solution. The final solution was then packaged in clear and colorless 20 ml glass vials. The obtained solution was a clear and transparent solution. The formulation of the obtained vehicle oral solution is presented in Table 1.

Table 1. Formulation of vehicle oral formulation.

1 .2 Preparation of the new maresin oral formulation, referred herein to as "new maresin formulation" Forthe preparation of 110 ml of maresin oral formulation with a concentration of 2 pg/ml, the following steps were carried out. Firstly, sodium metabisulfite (0.1 g) and sodium bisulfite (0.1 g) were weighed. Then, Solution A was prepared by dissolving the pre-weighed sodium metabisulfite and sodium bisulfite in 105 ml of deionized water with agitation. Next, exactly 2 ml of Solution B (the same solution as prepared for the vehicle solution) were added to Solution A using a pipette, followed by the addition of 0.5 ml of ethanolic solution containing 0.1 mg/ml of maresin-1 (Cayman Chemicals) to the formed solution. The volume was adjusted to 110 ml with deionized water. Finally, the final solution was packaged into 10 ml amber glass vials. The obtained solution was clear and transparent. The formulation of the obtained maresin oral solution is presented in Table 2. Table 2. Formulation of 2 pg/ml maresin oral solution.

1.3 Preparation of the maresin oral saline solution, referred herein to as "maresin saline solution" A solution of 2 pg/ml of maresin-1 in saline (0.9% NaCI) was prepared. For this purpose, maresin-1 solution (0.1 pg/pl in ethanol; Cayman Chemicals) was removed from the -80°C freezer. 5 pl of the maresin-1 solution was added in individual Eppendorf tubes containing 245 pl of 0.9% NaCI. This was prepared. Therefore, each tube contained 250 pl of a maresin-1 solution at a concentration of 2 pg/ml.

EXAMPLE 2. Effect of new maresin formulation on experimental autoimmune encephalomyelitis (EAE) mice

The animal model used in this example to reproduce multiple sclerosis (MS) disease is EAE mouse model. EAE is typically induced in animals either by injection of an emulsion containing a fragment of a myelin membrane protein or a homogenate of spinal cord tissue, or by injection of myelin antigenspecific T cells. In our case, EAE was induced by injection of myelin oligodendrocyte glycoprotein (MOG)35-55 peptide emulsified in complete Freund’s Adjuvant supplemented with 4 mg of Mycobacterium tuberculosis H37RA. Immunization with these peptides causes activation and expansion of peripheral myelin-specific encephalitogenic CD4+ T cells, which are shown to be critical for the pathophysiology of the disease induction. These activated encephalitogenic CD4+ T cells migrate into the CNS by crossing the leaky blood-brain barrier and initiate an inflammatory cascade, which ultimately leads to myelin destruction, axonal loss that cause clinical deficits.

2.1 Material and methods

Experiments were performed in adult (8-10 weeks) females C57BI/6J mice. Before the procedure, mice were anesthetized with intramuscular injection of ketamine (22 mg/kg) and xylazine (2.5 mg/kg). EAE was actively induced using a solution containing 3 mg/mL of myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) (ThermoFisher) solved in sterile saline (0.9% NaCI) and 4 mg/mL of Mycobacterium tuberculosis (Difco, Detroit, Ml, USA) solved in Complete Freund’s Adjuvant (CFA) (Difco). After emulsification, two 100 pl were injected subcutaneously in both flaks of the base of the tail. Immediately after induction and 2 days later, animals received an intraperitoneal injection of 400 ng of pertussis toxin (Enzo Life Sciences) solved in 100 pl sterile saline (0.9% NaCI).

EAE mice were treated with maresin-1. Treatment was initiated the first day mice showed the first signs of the disease (paralyzed tail; see table below) and was given daily until the end of the follow up. For the treatment of EAE mice, 250 pl of the new maresin formulation (Example 1 .2) and 250 pl of the maresin saline solution (Example 1.3), both with 2 pg/ml of maresin-1 (500 ng maresin-1), were administered. The control group was treated with 250 pl of vehicle (without maresin-1) (Example 1.1) following the same administration protocol.

Mice were daily scored from day 0 to day 21 after induction of EAE. The researcher was blind to experimental groups during the functional evaluation. A 6-point scale (Table 3) was used to evaluate the clinical signs of EAE.

Table 3. EAE scoring scale.

2.2 Results

EAE onset was observed at 8-12 days after immunization. Neurological decline in EAE mice treated with the vehicle reached a maximal neurological decline by day 25 which was maintained at steady levels until the end of the study. Oral administration of maresin saline solution led to amelioration of neurological decline, which was evident by day 26 onwards. Importantly, oral administration of the new maresin formulation improved functional outcome as compared to mice treated with the vehicle as well as to those treated with maresin saline solution (Figure 1). This data indicates that oral administration of maresin-1 conferred protection against EAE, and that the new maresin formulation enhances the therapeutic actions of maresin-1 . EXAMPLE 3. Effect of new maresin formulation on SOD1-G93A mouse model for ALS

The animal model used in this example to reproduce amyotrophic lateral sclerosis (ALS) disease is G93A human SOD1 mutation (B6SJL-Tg[SOD1-G93A]1 Gur) female mice. SOD1-G93A transgenic mice express a G93A mutant form of human SOD1 and are useful in studying neuromuscular disorders such as ALS. Hemizygotes exhibit a phenotype similar to ALS in humans, becoming paralyzed in one or more limbs with paralysis due to loss of motor neurons in the spinal cord (lower motor neuron) and the brain (upper motor neuron).

3.1 Material and methods

Experiments were performed in female transgenic mice carrying the G93A human SOD1 mutation (B6SJL-Tg[SOD1-G93A]1 Gur) obtained from the Jackson Laboratory (Bar Harbor, ME, USA). Hem- izygous transgenic mice were identified by PCR amplification of DNA extracted from tail samples and then were maintained in local facilities. Mice were housed with food and water ad libitum at room temperature of 22 ± 2°C under a 12:12-h light-dark cycle. It was considered that animals reached the endpoint of the disease when the righting reflex was lost for longer than 30s.

At 8 weeks of age, animals were orally administered with 250 pl of the new maresin formulation (Example 1 .2) five times a week (from Monday to Friday). Therefore, each mouse received a total of 0.5 pg of maresin 1 per administration. The control group was treated with 250 pl of vehicle (without maresin-1) (Example 1.1). Treatment was performed until the end of the study.

Motor coordination, balance and strength of the animals were assessed using the rotarod test. All mice were trained three times a week on the rod rotating at constant speed of 14 rpm (rotating cylinder 3.4 cm diameter) for a maximum of 180 seconds to reach the baseline level of performance. Animals were then tested weekly from 8 until 20 weeks of age at the same speed, and the time for which each animal could remain on the rotating rod was measured. An arbitrary maximum time of remaining on the rotating rod of 180 s was considered. Survival of the mice was determined when mice were not able to right itself within 30 seconds of being placed on its side. At the endpoint, mice were euthanized by overdose of pentobarbital sodium (Dolethal, Vetoquinol) following the requirements of the Animal Experimentation Ethical Committee of the Universitat Autonoma de Barcelona.

3.2 Results

The therapeutic potential of the new maresin formulation in ALS was determined by treating SOD1- G93A mice. Mice treated with the new maresin formulation showed delayed onset and progression of the disease as revealed the rotarod test (Figure 2 (A)). In this line, it was also found that the new maresin formulation prolonged lifespan of ALS mice (Figure 2(B)). Therefore, this data suggest that oral administration of maresin-1 exerts therapeutic actions in ALS mouse model. REFERENCES

W02013170006A2

WO2018134230A1 W02019016580A1

Claims

1 . An oral solution comprising:

- maresin-1 ,

- a first cosolvent which is ethanol,

- a second cosolvent selected from the group consisting of a glycol, glycerin or its derivatives, sorbitol, and dimethyl sulfoxide, and

- water, for use in the treatment of a neurological disease.

2. The oral solution for use according to claim 1 , wherein the second cosolvent is a glycol, particularly propylene glycol.

3. The oral solution for use according to any of claims 1-2, wherein maresin-1 is present in an amount of 2 pg/ml.

4. The oral solution for use according to any of claims 1 -3, wherein the first cosolvent and the second cosolvent are present in a volume ratio of about 1 :4.

5. The oral solution for use according to any of claims 1-4, wherein the neurological disease is selected from the group consisting of multiple sclerosis (MS), Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), optic neuritis (ON), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), spinal and bulbar muscular atrophy (SMA), monomelic amyotrophy, spinal cord injury, traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, schizophrenia, depression, manic depression, neurodevelopmental disorder, autism, migraine, and stroke.

6. The oral solution for use according to claim 5, wherein the neurological disease is amyotrophic lateral sclerosis.

7. The oral solution for use according to claim 5, wherein the neurological disease is multiple sclerosis.

8. An oral solution comprising:

- maresin-1 in an amount from 1 pg/ml to 50 pg/ml,

- a first cosolvent which is ethanol,

- a second cosolvent consisting of a glycol in an amount from 0.1 % v/v to 6% v/v, and

- water.

9. The oral solution according to claim 8, wherein the second cosolvent consists of a glycol selected from the group consisting of ethylene glycol, propylene glycol, polyethylene glycol, butylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol and polypropylene glycol.

10. The oral solution according to claim 9, wherein the glycol is propylene glycol.

11. The oral solution according to any of claims 8-10, wherein the first cosolvent and the second cosolvent are present in a volume ratio of about 1 :4.

12. The oral solution according to any of claims 8-11 , further comprising at least one antioxidant.

13. The oral solution according to claim 12, wherein the antioxidant is selected from the group consisting of a sulfite, hydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, nordihydroguaiaretic acid, a gallate or a gallato compound, benzoic acid or a benzoate, ascorbic acid, vitamin E, and citric acid or a citrate.

14. The oral solution according to claim 13, wherein the antioxidant is a sulfite selected from the group consisting of a sulfite, a bisulfite, a metabisulfite, and a salt thereof, wherein the salt is selected from the group consisting of a sodium salt, a potassium salt, and a calcium salt, particularly, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, calcium sulfite, and calcium metabisulphite.

15. The oral solution according to claim 14, wherein the antioxidant is sodium metabisulfite and sodium bisulfite.

16. The oral solution according to any of claims 8-15, further comprising at least one preservative which is an antifungal preservative, an antimicrobial preservative, or a combination thereof.

17. The oral solution according to claim 16, wherein the preservative is a parahydroxybenzoate selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, and a salt thereof.

18. The oral solution according to claim 17, wherein the preservative is methylparaben and propylparaben.

19. The oral solution according to any of claims 8-18, comprising:

- from 1 pg/ml to 50 pg/ml maresin, particularly 2 pg/ml maresin; - from 0.1% v/vto 20% v/v ethanol;

- from 0.1% v/vto 60% v/v propylene glycol;

- from 0.1% w/vto 1% w/v sodium metabisulfite and sodium bisulfite;

- from 0.1% w/vto 1% w/v methylparaben and propylparaben; and - water.

20. The oral solution according to claim 19, comprising:

- 2 pg/ml maresin-1 ;

- 0.45% v/v ethanol; - 1 .82% v/v propylene glycol;

- 0.09% w/v sodium metabisulfite and 0.09% w/v sodium bisulfite;

- 0.18% w/v methylparaben and 0.018% w/v propylparaben; and

- water.

21 . An oral solution according to any of claims 8-20, for use as a medicament.